☒QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes☒ No ☐

Indicate by check mark whether the registrant has submitted electronically ~~and posted on its corporate Web site, if any,~~ every Interactive Data File required to be submitted ~~and posted~~ pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit ~~and post~~ such files). Yes☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

As of ~~October 30, 2017~~April 28, 2023, there were ~~47,180,775~~114,010,448 shares of Common Stock, $0.0001 par value per share, outstanding.

On April 28, 2017, the Company entered into a license agreement with Anivive Lifesciences, Inc. (“Anivive”), a biopharmaceutical company engaged in the research, development and commercialization of animal health medicines, pursuant to which the Company has granted Anivive an exclusive, worldwide license to develop and commercialize verdinexor (KPT-335) for the treatment of cancer in companion animals (the “Anivive Agreement”). Pursuant to the terms of the Anivive Agreement, the Company received an upfront payment of $1.0 million. In addition, the Company will be eligible to receive potential future technology transfer and clinical, regulatory and commercial development milestone payments totaling up to $43.5 million, as well as a low double digit royalty based on Anivive’s future net sales of verdinexor following commercialization. The potential future milestone payments are comprised of $0.25 million for completion of the technology transfer, $5.75 million based on achievement of clinical and regulatory milestone events and $37.5 million based on achievement of sales milestone events.

In accordance with ASC 605, the Company identified the deliverables at the inception of the Anivive Agreement. The significant deliverables were determined to include the license and the Company’s responsibility to transfer the technology package relating to verdinexor. The Company determined that the license does not have stand-alone value separate and apart from the transfer of the verdinexor technology package to Anivive because (1) there are no other vendors selling similar licenses on a stand-alone basis and (2) Anivive is unable to use the license for its intended purpose without the technology transfer. As such, the Company determined that there is one unit of accounting. The total consideration of $1.25 million, including the $1.0 million upfront payment and a $0.25 million payment for completion of the technology transfer, was allocated to the single unit of accounting and will be recognized as revenue once the technology transfer is completed, which is the final item to be delivered in the unit of accounting. The technology transfer was subsequently completed in October 2017. As of September 30, 2017, $1.0 million was included in deferred revenue and is classified as a current liability in the consolidated balance sheet.

Basic and diluted net loss per common share is calculated by dividing net loss by the weighted-average number of common shares outstanding ~~during~~for the ~~period, without consideration for~~period. Diluted net loss per share is computed by dividing the diluted net loss by the weighted average number of common ~~stock equivalents. The Company’s potentially~~shares outstanding, including potential dilutive common shares ~~which include~~assuming the dilutive effect of outstanding stock options and unvested restricted stock ~~and restricted stock units, are considered to be common stock equivalents and are only included~~units. For periods in ~~the calculation of~~which we have reported net losses, diluted net loss per common share ~~when~~is the same as basic net loss per share, since dilutive common shares are not included if their effect is ~~dilutive.~~anti-dilutive.

The following potentially dilutive securities were excluded from the calculation of diluted net loss per share due to their anti-dilutive ~~effect:~~effect (in thousands):

As discussed further in Note 10, “Long-Term Obligations”, we have the option to settle the conversion obligation for our 3.00% convertible senior notes due 2025 (the “Notes”) in cash, shares or any combination of the two. Based on our net loss position, there was no impact on the calculation of dilutive loss per share during the three months ended March 31, 2023 and 2022.

As discussed further in Note 9, “Stockholders’ Equity”, on December 5, 2022, we issued warrants to purchase up to 9,537,563 shares of common stock to certain institutional investors. The warrants were excluded from the calculation of basic and diluted net loss per share during the three months ended March 31, 2023 as the warrant holders do not have an obligation to share in our losses.

~~A summary of the Company’s stock option activity and related information follows:~~

~~Total~~The following table summarizes stock-based compensation expense ~~related~~included in operating expenses (in thousands):

In 2023, we began granting performance-based restricted stock units (“PSUs”) to ~~stock options for the nine months ended September 30, 2017~~certain employees, which will vest only if challenging performance goals relating to revenue and ~~2016 was $13,140~~relative total stockholder return are achieved over a three-year performance period and ~~$13,758, respectively.~~challenging performance goals relating to clinical milestones are achieved over a four year performance period.

~~As of September 30, 2017, there was $25,164 of total unrecognized stock-based~~Stock-based compensation expense ~~related to stock options. The expense~~for all PSUs is ~~expected to be recognized over a weighted-average period of 2.8 years.~~

~~A restricted stock unit (“RSU”) represents~~determined using the ~~right to receive one~~grant date fair value, which is the quoted closing market price per share of ~~the Company’s common stock upon vesting of the RSU. The fair value of each RSU is based on the closing price of the Company’s~~our common stock on the Nasdaq Global Select Market on the grant date, ~~of grant. In November 2015, the Company granted RSUs with service conditions that vest in two equal annual installments provided~~except that the employee remains employed with the Company (“Time-Based RSUs”). During the nine months ended September 30, 2017, the Company granted performance-based RSUs, which vest upon the achievement of certain performance goals subject to the employee’s continued employment (“Performance-Based RSUs”). In the event the performance goals are not achieved, none of the Performance-Based RSUs will vest. The grant date fair value of the outstanding Performance-Based RSUs is $2.4 million and will be recognized on an accelerated attribution basis when the Performance-Based RSUs are deemed probable of achievement to the date the awards vest. No stock-based compensation expensePSUs related to the ~~Performance-Based RSUs~~performance of our common stock includes a discount which was ~~recognized during the nine months ended September 30, 2017, as~~calculated using a Monte Carlo simulation and represents the likelihood ofthat the ~~Performance-Based RSUs being earned was~~related performance goals will not ~~deemed probable of achievement as of September 30, 2017. The following is a summary of RSU activity under the 2013 Stock Incentive Plan for the nine months ended September 30, 2017:~~be achieved.

~~The total stock-based~~Stock-based compensation expense ~~related to RSUs~~ for the nine months ended September 30, 2017 and 2016 was $2,243 and $3,246, respectively. As of September 30, 2017, $357 of unrecognized compensation costs related to unvested Time-Based RSUs are expected to be recognized over a weighted-average period of 0.2 years.

The Company has an Employee Stock Purchase Plan (“ESPP”) that permits eligible employees to enroll in six-month offering periods. Participants may purchase shares of the Company’s common stock, through payroll deductions, at a price equal to 85% of the fair market value of the common stock on the first or last day of the applicable six-month offering period, whichever is lower. Purchase dates under the ESPP occur on or about May 1 and November 1 of each year. In 2013, the Company’s stockholders approved the reservation of 242,424 shares of the Company’s common stock for issuance under the ESPP, plus an annual increase to be added on the first day of each fiscal year, commencing on January 1, 2015 and ending on December 31, 2023, equal to the lesser of 484,848 shares of the Company’s common stock, 1% of the number of outstanding shares on such date, or an amount determined by the board of directors.

~~For the nine months ended September 30, 2017 and 2016, the Company recorded stock-based compensation expense~~PSUs related to the ~~ESPP~~performance of ~~$152 and $153, respectively. As of September 30, 2017, 454,977 shares of the Company’s~~our common stock ~~remained available for issuance under the ESPP. As of September 30, 2017, there was $17 of total unrecognized stock-based compensation expense related to the ESPP. The expense~~ is ~~expected to be~~ recognized ~~over a period of one month.~~

In March 2014, the Company entered into an operating lease for approximately 29,933 square feet of office and research space in Newton, Massachusetts. The Company uses the leased premises as its corporate headquarters and for research and development purposes. The lease was amended on December 31, 2014 by extending the lease term of the lease from November 30, 2021 to September 30, 2022. The amendment provides for the expansion of the premises leased by the Company by approximately 16,234 square feet, and provides the Company with the rights of first offer to lease approximately 27,701 square feet of additional space. The Company may extend the lease term for one additional five-year period. The Company is recording rent expense on a straight-line basis ~~through~~over the ~~end~~service period. Stock-based compensation expense for all other PSUs is not recognized until the achievement of the ~~lease term, inclusive~~performance goal is deemed probable (the “Probable Date”), a determination that requires significant judgment by management, as the achievement of these goals have inherent risk and uncertainties. At the Probable Date, we record a cumulative catch-up expense for the portion of the grant date fair value attributable to the period ~~in which there are no scheduled rent payments.~~from the grant date to the Probable Date. The Company has recorded deferred rent on the condensed consolidated balance sheets at September 30, 2017 and December 31, 2016, accordingly. The lease provides the Company with an allowance for improvements of $1,616, all of which was incurred in the first quarter of 2015. All improvements were deemed normal tenant improvements, were recorded as leasehold improvements and deferred rent and will be recorded as a reduction to rentremaining expense ~~ratably~~is recognized over the lease term. The Company has provided a security deposit in the form of a cash-collateralized letter of credit in the amount of $400, which amount may be reduced to $200 in January 2018. The amount is classified as restricted cash on the condensed consolidated balance sheet. As of September 30, 2017, $200 has been reclassified to current assets.

~~In November 2014, the Company signed a five-year operating lease agreement in Munich, Germany for approximately 3,681 square feet of office space. The lease is for the~~remaining service period February 2015 through January 2020. Pursuant to the lease agreement, the Company is obligated to make aggregate rent payments of €374 (approximately $427), through January 31, 2020. The Company is recording rent expense on a straight-line ~~basis through the end of the lease term, inclusive of the period in which there are no scheduled rent payments.~~basis.

Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations.

The following discussion and analysis of our financial condition and results of operations is meant to provide material information relevant to an assessment of the financial condition and results of operations of our company, including an evaluation of the amounts and uncertainties of cash ~~payment~~flows from ~~Ono,~~operations and from outside resources, so as ~~well as a percentage of any milestone payments~~to allow investors to better view our company from ~~Ono and a mid-single-digit percentage of any royalty payments from Ono. The maximum aggregate amount the Company may be obligated to pay to MMRF under the research agreement is $6.0 million.~~

management’s perspective. You should read the following discussion and analysis of our financial condition and results of operations together with our financial statements and related notes appearing elsewhere in this quarterly ~~report.~~report and the audited financial information and the notes thereto included in our Annual Report on Form 10-K for the year ended December 31, 2022, as filed with the Securities and Exchange Commission (“SEC”) on February 17, 2023 (“Annual Report”).

This Quarterly Report on Form 10-Q, ~~including the following discussion,~~ contains forward-looking statements ~~that involve substantial risks and uncertainties. All statements, other than statements~~regarding the expectations of ~~historical facts, contained in this Quarterly Report on Form 10-Q, including statements regarding~~Karyopharm Therapeutics Inc., herein referred to as “Karyopharm,” the “Company,” “we,” or “our,” with respect to the possible achievement of discovery and development milestones, our future discovery and development efforts, including regulatory submissions and approvals, our ~~collaborations~~commercialization efforts, our partnerships and ~~partnering agreements~~collaborations with third parties, our ~~strategy, our~~ future ~~operations,~~operating results and financial position, our business strategy, and ~~revenues, projected costs, prospects, plans and~~other objectives ~~of management, are forward looking statements. The~~for future operations. We often use words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” ~~“continue”~~“continue,” and other words and terms of similar ~~expressions are intended~~meaning to help identify forward-looking statements, although not all forward-looking statements contain these identifying words.

~~Forward-looking~~ You also can identify these forward-looking statements by the fact that they do not relate strictly to historical or current facts. There are ~~not guarantees~~a number of ~~future performance~~important risks and ~~our actual results could differ materially from the plans, intentions, expectations or results discussed in the forward-looking statements. Factors~~uncertainties that could cause actual results or events to differ materially from those ~~in the~~indicated by forward-looking ~~statements~~statements. These risks and uncertainties include, but are not limited to, ~~adverse results~~those described in ~~our drug discovery and clinical development activities, decisions made by the U.S. Food and Drug Administration and other regulatory authorities with respect to the development and commercialization~~Part II, Item 1A - Risk Factors of our drug candidates, our ability to raise additional capital to support our clinical development program and other operations, our ability to develop products of commercial value and to identify, discover and obtain rights to additional potential product candidates, our ability to obtain, maintain and enforce our intellectual property, the outcome of research and development activities and the fact that the preclinical and clinical testing of our compounds may not be predictive of the success of later clinical trials, our reliance on third-parties, competitive developments, the effect of current and future legislation and regulation and regulatory actions, as well as other risks described in this Quarterly Report on Form 10-Q, our Annual Report on Form 10-K for the year ended December 31, 2016, or 2016 Form 10-K, as filed with the Securities and Exchange Commission, or SEC, on March 16, 2017, and other filings with the SEC.

10-Q. As a result of these and other factors, we may not actually achieve the plans, intentions, expectations or results disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

~~OVERVIEW~~References to XPOVIO® (selinexor) also refer to NEXPOVIO® (selinexor) when discussing its approval and commercialization in certain countries or territories outside of the U.S.

We are a ~~clinical-stage~~commercial-stage pharmaceutical company ~~focused on~~pioneering novel cancer therapies and dedicated to the discovery, development and ~~subsequent~~ commercialization of ~~novel,~~ first-in-class drugs directed against nuclear ~~transport and related targets~~export for the treatment of cancer and other ~~major~~ diseases. Our scientific expertise is ~~focused on~~based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing ~~wholly-owned,~~and commercializing novel, small molecule Selective Inhibitor of Nuclear Export or ~~SINE™~~, (“SINE”) compounds that inhibit the nuclear export protein ~~XPO1.~~exportin 1 (“XPO1”). These SINE compounds represent a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of diseases ~~in areas of~~with high unmet medical need. Our ~~SINE compounds were~~lead asset, XPOVIO® (selinexor), was the first oral XPO1 inhibitor to receive marketing approval, receiving its initial U.S. approval from the U.S. Food and Drug Administration (“FDA”) in July 2019, and is currently approved and marketed in the U.S. for the following indications:

•

For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (“DLBCL”), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This indication was approved under accelerated approval based on response rate and was based on the results from the SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study. Continued approval for this indication may be contingent upon verification and description of clinical ~~development.~~

benefit in a confirmatory trial.

The commercialization of XPOVIO in the U.S., for both the multiple myeloma and DLBCL indications, is currently supported by sales representatives, nurse liaisons, and a market access team, as well as KaryForward™, an extensive patient and healthcare

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provider support program. Our ~~initial~~commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers. We plan to continue to educate physicians, other healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we continue to expand XPOVIO use.

The commercialization of XPOVIO and NEXPOVIO® (selinexor) (the brand name for selinexor in Europe and the United Kingdom) outside of the U.S. is managed by our partners in their respective territories. XPOVIO/ NEXPOVIO has received regulatory approval in various indications in approximately 40 countries outside the U.S., including the European Union, United Kingdom, Singapore, Mainland China, South Korea, Australia, Canada, Taiwan and Israel and is commercially available in a growing number of countries.

Our primary focus is on marketing XPOVIO in its currently approved indications as well as developing and seeking the regulatory approval ~~and commercialization~~ of ~~our lead drug candidate,~~ selinexor ~~(KPT-330),~~ as an oral agent in multiple myeloma, endometrial cancer, and myelofibrosis; eltanexor as an oral agent in myelodysplastic neoplasms; and in additional cancer indications with significant unmet medical need. We plan to continue to conduct clinical ~~need, initially for hematologic malignancies. We then plan~~trials and to seek additional approvals for the use of selinexor and eltanexor as single agents or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor as well as to move selinexor towards front-line cancer therapy. We are also advancing the clinical development of selinexor in multiple solid tumor indications. To date, over 2,100 patients have been treated with oral selinexor in company- and investigator-sponsored clinical trials in advanced hematologic malignancies and solid tumors. Selinexor is currently being evaluated in several mid- and later-stage clinical trials, including, among others, the pivotal, randomized Phase 3 BOSTON (Bo~~rtezomib,~~ S~~elinexor and Dexame~~t~~has~~on~~e) study in multiple myeloma, the Phase 2b STORM (~~S~~elinexor~~ T~~reatment~~ of R~~efractory~~ M~~yeloma) study in multiple myeloma, the Phase 1b/2 STOMP (~~S~~elinexor and Backbone~~ T~~reatments~~ of M~~ultiple Myeloma~~ P~~atients) study in combination with backbone therapies in multiple myeloma, the Phase 2b SADAL (~~S~~elinexor~~ A~~gainst~~ D~~iffuse~~ A~~ggressive~~ L~~ymphoma) study in diffuse large B-cell lymphoma (DLBCL), and the Phase 2/3 SEAL (~~Se~~linexor in~~ A~~dvanced~~ Liposarcoma) study in liposarcoma. We expect to provide topline data from the expanded cohort for the STORM study by April 2018, topline data from the SADAL study in the second half of 2018, topline data from the BOSTON study in 2019 and topline data from the Phase 3 portion of the SEAL study by the end of 2019. We are also preparing to establish the commercial infrastructure to support a potential launch of selinexor in North America and Western Europe. We have devoted substantially all of our efforts to research and development. It may be several years, if ever, before we have a drug candidate ready for commercialization for the treatment of human disease. To date, we have financed our operations principally through private placements of our preferred stock and proceeds from public offerings of our common stock.or eltanexor.

As of ~~September 30, 2017,~~March 31, 2023, we had an accumulated deficit of ~~$456.3 million.~~$1.4 billion. We had net losses of ~~$30.6~~$34.1 million and ~~$25.4~~$41.4 million for the three months ended ~~September 30, 2017~~March 31, 2023 and ~~2016, respectively, and net losses of $89.9 million and $82.6 million for the nine months ended September 30, 2017 and 2016,~~2022, respectively. ~~We have not generated any revenue to date from the sales of any drugs.~~

We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future. The net losses we incur may fluctuate significantly from quarter to quarter. We anticipate that our expenses will increase substantially if and as we:

~~continue our research and preclinical and clinical development of our drug candidates;~~

~~initiate additional clinical trials for our drug candidates;~~

~~seek marketing approvals for any of our drug candidates that successfully complete clinical trials;~~

~~establish a sales, marketing and distribution infrastructure to commercialize any drugs for which we may obtain marketing approval;~~

~~maintain, expand and protect our intellectual property portfolio;~~

~~manufacture our drug candidates;~~

~~hire additional clinical, quality control and scientific personnel;~~

~~identify additional drug candidates;~~

~~acquire or in-license other drugs and technologies; and~~

add operational, financial and management information systems and personnel, including personnel to support our drug development, any future commercialization efforts and our other operations as a public company.

CRITICAL ACCOUNTING ~~POLICIES AND SIGNIFICANT JUDGMENTS AND~~ ESTIMATES

We believe that several accounting policies are important to understanding our historical and future performance. We refer to these policies as “critical” because these specific areas generally require us to make judgments and estimates about matters that are uncertain at the time we make the estimate, and different ~~estimates—~~estimates - which also would have been ~~reasonable—~~reasonable - could have been used, which would have resulted in different financial results.

There ~~were~~have been no changes to the critical accounting ~~policies~~estimates we identified in Item 7. Management's Discussion and Analysis of Financial Condition and Results of Operations in our Annual Report.

RESULTS OF OPERATIONS

The following table summarizes our results of operations (in thousands, except for percentages):


	For the Three Months Ended March 31,
	2023			2022			$ Change			% Change
Product revenue, net	$	28,288		$	28,300		$	(12	)		0	%
License and other revenue		10,410			19,370			(8,960	)		(46	)%
Total revenue		38,698			47,670			(8,972	)		(19	)%
Operating expenses:
Cost of sales		1,351			1,426			(75	)		(5	)%
Research and development		32,339			42,062			(9,723	)		(23	)%
Selling, general and administrative		35,907			38,768			(2,861	)		(7	)%
Loss from operations		(30,899	)		(34,586	)		3,687			(11	)%
Other expense, net		(3,173	)		(6,683	)		3,510			(53	)%
Loss before income taxes		(34,072	)		(41,269	)		7,197			(17	)%
Income tax provision		(54	)		(130	)		76			(58	)%
Net loss	$	(34,126	)	$	(41,399	)	$	7,273			(18	)%

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Product Revenue, net (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023		2022		$ Change			% Change
Product revenue, net	$	28,288	$	28,300	$	(12	)		0	%

To date, our only source of product revenue has been from the ~~2016 Form 10-K, other than~~U.S. sales of XPOVIO. Net product revenue for the ~~adoption of ASU No. 2016-09,~~three months ended March 31, 2023 was consistent as ~~described further in Note 2~~compared to the ~~Condensed Consolidated Financial Statements. It is important~~three months ended March 31, 2022. A number of myeloma foundations that help support Medicare Part D patients with their out-of-pocket costs for multiple myeloma oral oncolytics, including XPOVIO, closed during the ~~discussion~~first quarter of 2023. As a result, we have provided XPOVIO to these patients at no charge through our ~~operating results that follows be read in conjunction with the critical accounting policies disclosed~~Patient Assistance Program, which adversely impacted our revenues by approximately $1.2 million in the ~~2016 Form 10-K.~~

~~RESULTS OF OPERATIONS~~first quarter of 2023. As patients who utilize our Patient Assistance Program remain in the program through the calendar year and their course of treatment, we expect this trend to increase throughout 2023 if these foundations remain closed or partially closed due to the cumulative impact of both new starts and the associated refills.

~~Comparison~~

License and Other Revenue (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023		2022		$ Change			% Change
Menarini Group ("Menarini")	$	8,737	$	7,086	$	1,651			23	%
Antengene Therapeutics Limited ("Antengene")		1,112		9,014		(7,902	)		(88	)%
Other		561		3,270		(2,709	)		(83	)%
Total license and other revenue	$	10,410	$	19,370	$	(8,960	)		(46	)%

License and other revenue for the three months ended March 31, 2023 decreased by $9.0 million as compared to the three months ended March 31, 2022, primarily due to the recognition of $7.8 million of milestone-related revenue from Antengene in the ~~Three Months Ended September 30, 2017 and September 30, 2016~~

Three Months Ended September 30,

2017

2016

$ Change

% Change

(in thousands)

Contract and grant revenue

$
—

$
48

$
(48
)

(100
)%
Operating expenses:

Research and development

25,237

19,893

5,344

27
%
General and administrative

5,818

5,897

(79
)

(1
)%
Loss from operations

(31,055
)

(25,742
)

(5,313
)

21
%
Other income, net

428

317

111

35
%
Loss before income taxes

(30,627
)

(25,425
)

(5,202
)

21
%
Provision for income taxes

(13
)

—

(13
)

—

Net loss

$
(30,640
)

$
(25,425
)

$
(5,215
)

21
%

~~Contract and Grant Revenue.~~ ~~We recognized~~first quarter of 2022, partially offset by the recognition of $3.5 million of license-related revenue ~~pursuant~~from Menarini in the first quarter of 2023. There was also a $2.3 million decrease in revenue for the reimbursement of development-related expenses from Menarini due to a ~~government grant agreement~~corresponding decrease in the underlying expenses.

We expect license and other revenue will decrease slightly in the second quarter of 2023 as compared to the first quarter of 2023 due to the recognition of non-recurring license revenue in the first quarter of 2023.

Operating Expenses (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023		2022		$ Change			% Change
Cost of sales	$	1,351	$	1,426	$	(75	)		(5	)%
Research and development		32,339		42,062		(9,723	)		(23	)%
Selling, general and administrative		35,907		38,768		(2,861	)		(7	)%
Total operating expenses	$	69,597	$	82,256	$	(12,659	)		(15	)%

Cost of Sales

The cost of sales during the three months ended ~~September 30, 2016.~~ March 31, 2023 and 2022 reflects a portion of the costs related to the manufacturing of XPOVIO and related materials, since, prior to the approval of XPOVIO by the FDA in July 2019, these costs were expensed. The manufacturing costs of XPOVIO on-hand upon FDA approval amounted to approximately $2.8 million, substantially all of which was utilized as of March 31, 2023.

We expect cost of sales to remain relatively consistent in the second quarter of 2023 as compared to the first quarter of 2023.

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Research and Development ~~Expense.~~Expenses (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023		2022		$ Change			% Change
Personnel costs	$	14,173	$	17,240	$	(3,067	)		(18	)%
Clinical trial and related costs		12,041		16,766		(4,725	)		(28	)%
Stock-based compensation		1,938		2,968		(1,030	)		(35	)%
Consulting, professional and other costs		4,187		5,088		(901	)		(18	)%
Total research and development expenses	$	32,339	$	42,062	$	(9,723	)		(23	)%

Research and development ~~expense increased approximately $5.3 million to $25.2 million~~expenses for the three months ended ~~September 30, 2017 from approximately $19.9~~March 31, 2023 decreased by $9.7 million ~~for~~as compared to the three months ended ~~September 30, 2016.~~March 31, 2022. The ~~increase is primarily related to:~~

~~an increase~~decrease in personnel costs of ~~approximately $2.9~~$3.1 million was due, in part, to a $1.0 million decrease in severance-related expense. The decrease in clinical trial and related costs ~~primarily related to the selinexor program;~~

~~an increase~~ of ~~$1.1~~$4.7 million ~~in consulting and professional expense;~~

~~an increase of $0.9 million in personnel costs,~~was primarily due to our prioritization of the core programs in our clinical pipeline and higher ~~headcount,~~trial start-up costs in 2022, partially offset by $2.2 million incurred in 2023 related to our Phase 3 study evaluating selinexor as a ~~decrease~~maintenance therapy following systemic therapy in ~~stock-based compensation of $0.3 million; and~~patients with TP53 wild-type advanced or recurrent endometrial cancer.

~~an increase of approximately $0.3 million in travel and other costs.~~

We expect our research and development expenses to ~~increase for~~remain relatively consistent in the ~~full year 2017~~second quarter of 2023 as compared ~~with~~to the ~~prior year as we continue spending on our development programs and clinical trials.~~first quarter of 2023.

Selling, General and Administrative ~~Expense.~~ ~~General~~Expenses (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023		2022		$ Change			% Change
Personnel costs	$	18,821	$	19,448	$	(627	)		(3	)%
Consulting, professional and other costs		13,716		15,007		(1,291	)		(9	)%
Stock-based compensation		3,370		4,313		(943	)		(22	)%
Total selling, general and administrative expenses	$	35,907	$	38,768	$	(2,861	)		(7	)%

Selling, general and administrative ~~expense decreased approximately $0.1 million to $5.8 million~~expenses for the three months ended ~~September 30, 2017 from approximately $5.9~~March 31, 2023 decreased by $2.9 million as compared to the three months ended March 31, 2022 primarily due to a decrease in consulting, professional, and other costs largely attributable to a decrease in professional services expenses.

We expect our selling, general and administrative expenses to remain relatively consistent in the second quarter of 2023 as compared to the first quarter of 2023.

Other Expense, net (in thousands, except for percentages)


	For the Three Months Ended March 31,
	2023			2022			$ Change			% Change
Interest expense	$	(5,758	)	$	(6,684	)	$	926			(14	)%
Interest income		2,849			74			2,775			3750	%
Other expense:
Foreign currency remeasurement		(264	)		(73	)		(191	)		262	%
Total other expense, net	$	(3,173	)	$	(6,683	)	$	3,510			(53	)%

Other expense, net for the three months ended ~~September 30, 2016. The decrease is primarily related to:~~

~~a decrease of approximately $0.1~~March 31, 2023 decreased by $3.5 million ~~in personnel costs,~~as compared to the three months ended March 31, 2022 primarily due to a ~~decrease of approximately $0.4~~$2.8 million ~~in stock-based compensation offset by an increase in headcount.~~

~~We expect general and administrative expenses to increase in the future in support of our expanding operating activities.~~

~~Other Income, net.~~ Other income, net, increased approximately $0.1 million to $0.4 million for the three months ended September 30, 2017 from approximately $0.3 million for the three months ended September 30, 2016, primarily due to increased returns resulting from a general increase in interest ~~rates and~~income resulting from higher average ~~investment balances from funds raised through~~interest rates on our investments.

We expect other expense, net to remain relatively consistent in the ~~“at-the-market” offering and a follow-on offering in April 2017.~~

~~Comparison~~second quarter of ~~the Nine Months Ended September 30, 2017 and September 30, 2016~~

Nine Months Ended September 30,

2017

2016

$ Change

% Change

(in thousands)

Contract and grant revenue

$
71

$
107

$
(36
)

(34
)%
Operating expenses:

Research and development

72,440

66,267

6,173

9
%
General and administrative

18,717

17,407

1,310

8
%
Loss from operations

(91,086
)

(83,567
)

(7,519
)

9
%
Other income, net

1,196

925

271

29
%
Loss before income taxes

(89,890
)

(82,642
)

(7,248
)

9
%
Provision for income taxes

(54
)

—

��

(54
)

—

Net loss

$
(89,944
)

$
(82,642
)

$
(7,302
)

9
%

~~Contract and Grant Revenue.~~ ~~We recognized revenue pursuant to a government grant agreement during the nine months ended September 30, 2017 and September 30, 2016.~~

~~Research and Development Expense.~~ Research and development expense increased approximately $6.2 million to $72.4 million for the nine months ended September 30, 2017 from approximately $66.3 million for the nine months ended September 30, 2016. The increase is primarily related to:

~~an increase of approximately $4.1 million in clinical trial costs, primarily related~~2023 as compared to the ~~selinexor program;~~

~~an increase~~first quarter of ~~$2.3 million in consulting and professional expense;~~

~~an increase of $0.4 million in toxicology study costs; and~~

~~an increase of $0.3 million in personnel costs, primarily due to higher headcount and compensation increases offset by decreased stock-based compensation expense of $1.1 million,~~

~~partially offset by a decrease of $1.0 million in discovery costs.~~

~~We expect our research and development expenses to continue to increase for the full year 2017 compared with the prior year as we continue spending on our development programs and clinical trials.~~ 2023.

~~General and Administrative Expense.~~ General and administrative expense increased approximately $1.3 million to $18.7 million for the nine months ended September 30, 2017 from approximately $17.4 million for the nine months ended September 30, 2016. The increase is primarily related to:

an increase of approximately $0.7 million in personnel costs due to increased headcount, severance costs and compensation increases offset by decreased stock-based compensation expense of $0.6 million; and

~~an increase of approximately $0.6 million in travel, occupancy and other costs.~~

~~We expect general and administrative expenses to increase in the future in support of our expanding operating activities.~~

~~Other Income, net.~~ Other income, net, increased approximately $0.3 million to $1.2 million for the nine months ended September 30, 2017 from approximately $0.9 million for the nine months ended September 30, 2016, primarily due to increased returns resulting from a general increase in interest rates.

LIQUIDITY AND CAPITAL RESOURCES

~~Sources of Liquidity~~Cash Flows

To date, we have ~~not generated any material revenues. We have~~ financed our operations ~~to date principally~~ through a combination of product revenue sales, private placements of our common and preferred stock, ~~and~~ proceeds from public offerings of our common ~~stock.~~stock, proceeds from the issuance of convertible debt, proceeds

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pursuant to the deferred royalty obligation, and cash generated from our business development activities. As of ~~September 30, 2017, we had $159.4~~March 31, 2023, our principal source of liquidity was $260.4 million inof cash, cash equivalents ~~restricted cash~~ and ~~short-~~investments. We have had recurring losses since inception and ~~long-term investments compared to $175.5~~incurred a loss of $34.1 million infor the three months ended March 31, 2023. We expect that our cash, cash equivalents ~~restricted~~and investments at March 31, 2023 will be sufficient to fund our current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in this Quarterly Report on Form 10-Q.

The following table provides information regarding our cash flows (in thousands):


	For the Three Months Ended March 31,
	2023			2022
Net cash used in operating activities	$	(18,910	)	$	(59,197	)
Net cash used in investing activities		(32,388	)		(14,035	)
Net cash provided by financing activities		—			30,783
Effect of foreign exchange rates		(45	)		(90	)
Net decrease in cash, cash equivalents and restricted cash	$	(51,343	)	$	(42,539	)

Operating activities. The $40.3 million decrease in net cash used in operating activities for the three months ended March 31, 2023 compared to the three months ended March 31, 2022 was primarily driven by a decrease in expenses and ~~short-~~the collection of $22.4 million of milestone payments from Antengene in the first quarter of 2023.

Investing activities. The $18.4 million increase in net cash used in investing activities for the three months ended March 31, 2023 compared to the three months ended March 31, 2022 was primarily driven by a $24.8 million increase in purchases of investments, partially offset by a $6.4 million increase in proceeds from the sales and ~~long-term investments as~~maturities of ~~December~~investments.

Financing activities. The $30.8 million decrease in net cash provided by financing activities for the three months ended March 31, ~~2016.~~

~~In December 2015, we entered into a sales agreement (the “Sales Agreement”) relating~~2023 compared to ~~an “at-the-market” offering, pursuant~~the three months ended March 31, 2022 was primarily due to ~~which we may sell~~the net cash proceeds of $29.3 million from the sale of shares of our common stock ~~with an aggregate offering price~~under our 2018 Open Market Sale Agreement (as defined below) in the first quarter of ~~up to $50.0 million.~~ 2022. There were no sales of our common stock under the 2018 Open Market Sale Agreement or the 2023 Open Market Sale Agreement in the first quarter of 2023.

Sources of Liquidity

On ~~November 7, 2016,~~June 23, 2021, we and certain of our subsidiaries entered into an amendment to the ~~Sales~~Revenue Interest Financing Agreement with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”) dated September 14, 2019 (the “Revenue Interest Agreement” and, as amended, the “Amended Revenue Interest Agreement”). Pursuant to the Revenue Interest Agreement, HCR paid us $75.0 million, less certain transaction expenses, on September 27, 2019, and pursuant to the Amended Revenue Interest Agreement, HCR paid us $60.0 million, less certain transaction expenses, on June 23, 2021. For additional information on the Amended Revenue Interest Agreement, see Note 10, “Long-Term Obligations”, to the condensed consolidated financial statements included under Part I, Item I of this Quarterly Report on Form 10-Q.

On May 5, 2020, we entered into Amendment No. 1 to the Open Market Sale Agreement,dated August 17, 2018 (the “2018 Open Market Sale Agreement”) with Jefferies LLC, as agent (“Jefferies”) pursuant to which we increased the maximum aggregate offering price of shares of our common stock that we may issue and sell from time to time through Jefferies, by $100.0 million from $75.0 million to up to $175.0 million (the “Open Market Shares”). We sold an aggregate of 2,941,517 Open Market Shares under the 2018 Open Market Sale Agreement, for net proceeds of approximately $29.3 million during the three months ended March 31, 2022.

On February 17, 2023, we entered into a new Open Market Sale Agreement (the “2023 Open Market Sale Agreement”) with Jefferies, as agent. Under the 2023 Open Market Sale Agreement, we may issue and sell shares of our common stock having an ~~additional~~ aggregate offering price of up to ~~$50.0~~$100.0 million ~~on or after November 7, 2016. As of October 31, 2017, we had sold an aggregate of 7,064,513 shares pursuant~~(the “Shares”) from time to ~~this “at-the-market” offering, for net proceeds of approximately $66.7 million.~~ time through Jefferies. Upon entry into the 2023 Open Market Sale Agreement, the 2018 Open Market Sale Agreement was terminated.

We ~~sold no shares~~did not sell any Open Market Shares under the 2018 Open Market Sale Agreement nor any Shares under the 2023 Open Market Sales Agreement during the three months ended ~~September 30, 2017~~March 31, 2023. As of March 31, 2023, $100.0 million of Shares was available for issuance and ~~22,100 shares~~sale under the 2023 Open Market Sale Agreement.

During the three months ended March 31, 2023, we received $22.4 million in ~~October 2017 for net proceeds of $0.3 million.~~

~~On April 28, 2017, we completed a follow-on offering~~milestone payments under our ~~shelf registration statement on Form S-3 (File No. 333-214489)~~license and distribution arrangements pursuant to which we issued an aggregate of 3,902,439 shares of our common stock at a public offering price of $10.25 per share. We received net proceeds of approximately $37.9 million from the offering, after deducting the underwriting discounts and commissions and offering expenses payable by us. After the completion of this follow-on offering, upare entitled to a maximum aggregate offering price of $160 million of our common stock, preferred stock, debt securities and/or warrants remain available under our shelf registration statement on Form S-3 (File No. 333-214489).

On October 11, 2017 (the “Effective Date”), we entered into a license agreement (the “Agreement”) with Ono Pharmaceutical Co., Ltd., a corporation organized and existing under the laws of Japan (“Ono”), pursuant to which we granted Ono exclusive rights to develop and commercialize, at its own cost, selinexor and KPT-8602 for the diagnosis, treatment and/or prevention of all human oncology indications (the “Field”) in Japan, Republic of Korea, Republic of China (Taiwan) and Hong Kong as well as in the ten Southeast Asian countries currently comprising the Association of Southeast Asian Nations (the “Ono Territory”). ~~Pursuant to the terms of the Agreement, we will~~ receive ~~an upfront payment of~~ ~~¥2.5 billion (US$22.3 million at the exchange rate as of the Effective Date)~~, ~~up to ¥10.15 billion (US$90.5 million at the exchange rate as of the Effective Date) in~~additional milestone payments, if certain development goals ~~are achieved~~ and ~~up to ¥9.0 billion (US$80.2 million at the exchange rate as of the Effective Date) in milestone payments if certain~~ sales milestones are achieved, as well as ~~a low double-digit royalty based~~royalties on future net sales of ~~selinexor~~the licensed and ~~KPT-8602~~sold products in the ~~Ono Territory.~~territories under such arrangements. In addition, under the license agreement we entered into with Menarini in December 2021, Menarini will reimburse us

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for 25% of all documented expenses we incur for the global development of selinexor from 2022 through 2025, provided that such reimbursements shall not exceed $15.0 million per calendar year.

Commitments, Contingencies and Contractual Obligations

Operating Leases

We are a party to an operating lease of 98,502 square feet of office and research space in Newton, Massachusetts with a ~~research agreement with~~term through September 30, 2025 (the “Newton, MA Lease”). Pursuant to the ~~Multiple Myeloma Research Foundation, or MMRF. Under~~Newton, MA Lease, we have provided a security deposit in the form of a cash-collateralized letter of credit in the amount of $0.6 million which is classified in long-term restricted cash on our condensed consolidated balance sheets. We expect lease costs under this ~~research agreement,~~commitment to total $3.7 million in 2023 and increase annually. We expect total lease costs of $9.5 million from March 31, 2023 to September 30, 2025.

In addition, we are ~~obligated~~party to ~~make~~ certain ~~payments~~short-term leases having a term of twelve months or less at the commencement date. We recognize short-term lease expense on a straight-line basis and do not record a related right-of use asset or lease liability for such leases. These costs were insignificant for the three months ended March 31, 2023 and 2022.

Contractual Obligations

We have contractual obligations under our Notes and under our Amended Revenue Interest Agreement as disclosed in Note 10, “Long-Term Obligations”, to ~~MMRF, including if we out-license selinexor. The terms~~the condensed consolidated financial statements included under Part I, Item 1 of this research agreement do not apply to KPT-8602. In connection with the transactions contemplated under the Agreement, we expect that we will be obligated to pay to MMRF approximately ¥225 million (approximately US$2.0 million at the exchange rate as of the Effective Date) of the upfront cash payment from Ono, as well as a percentage of any milestone payments from Ono and a mid-single-digit percentage of any royalty payments from Ono. The maximum aggregate amount we may be obligated to pay to MMRF under the research agreement is $6.0 million.Quarterly Report on Form 10-Q.

We expect that our cash, cash equivalents, restricted cash and short- and long-term investments as of September 30, 2017, totaling $159.4 million, will be sufficient to fund our current operating plan and capital expenditure requirements into 2019 while we are preparing to establish a commercial infrastructure for a potential launch of selinexor in North America and Western Europe.

~~Cash Flows~~

~~The following table provides information regarding our cash flows:~~

Nine Months Ended September 30,

2017

2016

(in thousands)

Net cash used in operating activities

$
(68,179
)

$
(64,393
)
Net cash provided by investing activities

20,009

17,993

Net cash provided by financing activities

52,786

31,915

Effect of exchange rate changes

171

35

Net increase (decrease) in cash and cash equivalents

$
4,787

$
(14,450
)

~~Operating activities.~~ The net cash used in operating activities in both periods resulted primarily from our net losses adjusted for non-cash charges and changes in the components of working capital. The increase in cash used in operating activities during the nine months ended September 30, 2017 compared to the nine months ended September 30, 2016 was driven primarily by an increase in our net loss due to an increase in our operating expenses, as adjusted for stock-based compensation and offset by an increase in our accrued expenses and other liabilities.

~~Investing activities.~~ The net cash provided by investing activities during the nine months ended September 30, 2017 reflects a decrease of $48.7 million in purchases of investments offset by a decrease of $46.7 million in proceeds from maturities of investments compared to the nine months ended September 30, 2016.

~~Financing activities.~~ The net cash provided by financing activities for the nine months ended September 30, 2017 reflects an increase of $20.9 million compared to the nine months ended September 30, 2016. The increase was primarily related to the net proceeds of $37.9 million from our follow-on offering in April 2017, offset by lower net proceeds of $17.0 million from the sale of shares of common stock as part of the “at-the-market” offering in April 2017 compared to the sale of shares in September 2016.

Funding Requirements

We expect our expenses, excluding stock-based compensation expense, to ~~increase~~decrease in ~~connection with our ongoing activities, particularly~~2023 as wecompared to 2022. We expect to continue ~~the clinical trials of, and assuming positive results of~~to incur costs related to our clinical trials and based on regulatory feedback, if and when we seek marketing approval for, selinexor and our other drug candidates. In addition, if we obtain marketing approval for any of our drug candidates, we expect to incur significantdevelopment programs as well as commercialization expenses related to ~~drug~~ sales, marketing, manufacturing and distribution of any of our approved products, to the extent that ~~such sales, marketing, manufacturing and distribution~~these functions are not the responsibility of ~~any collaborator that we may have at such time for any such drug. Furthermore, we~~our collaborators. We expect to continue to incur additional costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and developmentdecrease expenses through spend discipline, which includes the accelerated closure of non-core programs ~~or future commercialization efforts.~~while simultaneously, rapidly advancing three pivotal Phase 3 programs.

~~the progress and results of our current and planned clinical trials of selinexor;~~

~~the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our other drug candidates;~~

~~the costs, timing and outcome of regulatory review of our drug candidates;~~

~~our ability to establish and maintain collaborations on favorable terms, if at all;~~

~~the success of any collaborations that we may enter into with third parties;~~

~~the extent to which we acquire or in-license other drugs and technologies;~~

the costs of future commercialization activities, including drug sales, marketing, manufacturing and distribution, for any of our drug candidates for which we receive marketing approval, to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of any collaborator that we may have at such time;

~~the amount of revenue, if any, received from commercial sales of our drug candidates, should any of our drug candidates receive marketing approval; and~~

~~the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.~~

Identifying potential ~~drug~~product candidates and conducting preclinical studies and clinical trials is a time-consuming, expensive and uncertain process that takes years to ~~complete, and we may never generate the necessary data or results required to obtain marketing approval and achieve drug sales.~~complete. In addition, our ~~drug~~product candidates ~~if approved,~~for which we receive marketing approval may not achieve commercial success. Our ~~commercial revenues, if~~ability to become and remain profitable depends on our ability to generate revenue. There can be no assurance as to the amount or timing of any ~~will be derived from sales of drugs that~~such revenue, and we domay not ~~expect to be commercially available~~achieve profitability for ~~many~~several years, if at ~~all.~~all, as described more fully in the risk factor entitled “We have incurred significant losses since inception, expect to continue to incur significant losses, and may never achieve or maintain profitability,” under the heading “Risk Factors” in this Quarterly Report on Form 10-Q. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. Adequate additional financing may not be available to us on acceptable terms, or at all. ~~In addition, we~~We may seek additional capital due to favorable market conditions or strategic considerations, even if we believe we have sufficient funds for our current or future operating plans. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and development programs or commercialization efforts.

~~Contractual Obligations~~

~~There have been no material changes~~We currently expect that cash, cash equivalents and investments at March 31, 2023 will be sufficient to fund our ~~contractual obligations described~~current operating plans and capital expenditure requirements for at least twelve months from the date of issuance of the financial statements contained in ~~Management’s Discussion and Analysis of Financial Condition and Results of Operations~~this Quarterly Report on Form 10-Q while we continue to commercialize XPOVIO in the ~~2016~~U.S. and continue the clinical trials of our product candidates. Our future long-term capital requirements will depend on many factors, as described more fully in the risk factor entitled “We will need additional funding to achieve our business objectives. If we are unable to raise capital when needed or on acceptable terms, we would be forced to delay, reduce or eliminate our research and development programs and/or commercialization efforts,” under the heading “Risk Factors” in this Quarterly Report on Form ~~10-K.~~10-Q.

In addition to the expenses required to fund our operations described above, our funding requirements also include the following:

•

Lease costs for our headquarters in Newton, Massachusetts with a term through September 30, 2025. We expect lease costs under this commitment to total $3.7 million in 2023 and increase annually; we expect total future lease costs to be approximately $9.5 million;

•

Future long-term debt obligations related to the Notes of $188.0 million over the next three years; and

•

Future royalty obligations to HCR under the Amended Revenue Interest Agreement of approximately $200.0 million.

Table of Contents~~OFF-BALANCE SHEET ARRANGEMENTS~~

~~We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under SEC rules.~~

~~Item 3.~~

~~Quantitative and Qualitative Disclosures About Market Risk.~~

Item 3. Quantitative and Qualitative Disclosures About Market Risk.

We are exposed to market risk related to changes in interest rates. We had cash, cash equivalents ~~restricted cash~~ and investments of ~~$159.4~~$260.4 million as of ~~September 30, 2017.~~March 31, 2023. Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest ~~rates, particularly because all of our investments are in short-term securities.~~rates. Due to the short-term duration of our investment portfolio and the low risk profile of our investments, an immediate ~~10% change~~100 basis point shift in interest rates would not have a material effect on the fair market value of our investment portfolio.

We do not believe our cash, cash equivalents ~~restricted cash~~ and investments have significant risk of default or illiquidity. While we believe our cash, cash equivalents and investments do not contain excessive risk, we cannot provide absolute assurance that in the future our investments will not be subject to adverse changes in securities at one or more financial institutions that are in excess of federally insured limits. ~~Give~~Given the potential instability of financial institutions, we cannot provide assurance that we will not experience losses on these ~~deposits.~~deposits and investments.

We are also exposed to market risk related to ~~change~~changes in foreign currency exchange rates. We contract with contract research organizations and contract manufacturing organizations that are located in Canada and Europe, which are denominated in foreign currencies. We also contract with a number of clinical trial sites outside of the ~~United States,~~U.S., and our budgets for those studies are frequently denominated in foreign currencies. We are subject to fluctuations in foreign currency rates in connection with these agreements. We do not currently hedge our foreign currency exchange rate risk.

~~Item 4.~~

~~Controls and Procedures.~~

Item 4. Controls and Procedures.

Evaluation of Disclosure Controls and Procedures

Our management, with the participation of our President and Chief Executive Officer (principal executive officer) and Executive Vice President, Chief Financial Officer and Treasurer (principal financial officer), evaluated the effectiveness of our disclosure controls and procedures as of ~~September 30, 2017.~~March 31, 2023. The term “disclosure controls and procedures,” as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as amended (the “Exchange Act”), means controls and other procedures of a company that are designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is recorded, processed, summarized and reported, within the time periods specified in the SEC’s rules and forms. Disclosure controls and procedures include, without limitation, controls and procedures designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is accumulated and communicated to ~~the Company’s~~our management, including ~~its~~our principal executive and principal financial officers, as appropriate to allow timely decisions regarding required disclosure. Management recognizes that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving their objectives and management necessarily applies ~~its~~our judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on the evaluation of our disclosure controls and procedures as of ~~September 30, 2017,~~March 31, 2023, our President and Chief Executive Officer and our Executive Vice President, Chief Financial Officer and Treasurer concluded that, as of such date, our disclosure controls and procedures were effective at the reasonable assurance level.

Changes in Internal Control Over Financial Reporting

~~No change~~There were no changes in our internal control over financial reporting identified in connection with the evaluation required by Rule 13a-15(d) and 15d-15(d) of the Exchange Act that occurred during the fiscal quarter ended ~~September 30, 2017~~March 31, 2023 that ~~has~~have materially affected, or isare reasonably likely to materially affect, ~~the Company’s~~our internal control over financial reporting.

Table of Contents ~~PART II—~~

PART II - OTHER INFORMATION

~~Item 1A.~~

~~Risk Factors.~~

Item 1A. Risk Factors.

Careful consideration should be given to the following material risk factors, in addition to the other information set forth in this Quarterly Report on Form 10-Q and in other documents that we file with the ~~SEC,~~U.S. Securities and Exchange Commission (“SEC”) in evaluating ~~the Company~~us and our business. Investing in our common stock involves a high degree of risk. If any of the following risks and uncertainties actually occurs, our business, prospects, financial condition and results of operations could be materially and adversely affected. The risks described below are not intended to be exhaustive and are not the only risks ~~facing the Company.~~we face. New risk factors can emerge from time to time, and it is not possible to predict the impact that any factor or combination of factors may have on our business, prospects, financial condition and results of operations.

References to XPOVIO® (selinexor) also refer to NEXPOVIO® (selinexor) when discussing its approval and commercialization in certain countries or territories outside of the U.S.

Risks Related to ~~the Discovery,~~Commercialization and Product Development ~~and Commercialization of~~

Our ~~Drug Candidates~~

~~We depend heavily~~business is substantially dependent on the commercial success of ~~our lead drug candidate selinexor (KPT-330), which is currently in clinical trials. Our clinical trials of selinexor may not be successful.~~XPOVIO. If we, either alone or with our collaborators, are unable to successfully commercialize ~~selinexor~~current and future indications of XPOVIO or ~~experience significant delays~~other products or product candidates on a timely basis, including achieving widespread market acceptance by physicians, patients, third-party payors and others in ~~doing so,~~the medical community, our business, financial condition and future profitability will be materially harmed.

~~We have invested a significant portion of~~Our business and our ~~efforts and financial resources in the research and development of our lead drug candidate, selinexor. Our~~ ability to generate ~~revenues~~product revenue from the ~~sale~~sales of drugs that treat cancer and other diseases in humans ~~which may not occur for several years, if ever, will~~ depend heavily on our and our collaborators’ ability to successfully commercialize our lead drug, XPOVIO® (selinexor), on a global basis in currently approved and future indications, and the ~~successful development, regulatory approval~~level of market adoption for, and ~~eventual commercialization~~the continued use of, ~~selinexor.~~

~~We cannot commercialize drug~~our products and product candidates, if approved. XPOVIO is currently approved and marketed in the ~~United States without first obtaining regulatory approval~~U.S. in multiple hematologic malignancy indications, including in combination with Velcade® (bortezomib) and dexamethasone for the ~~drug from~~treatment of patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (“DLBCL”). Efforts to drive adoption within the medical community and third-party payors based on the benefits of our products and product candidates require significant resources and may not be successful. The success of XPOVIO and any current or future product candidates, whether alone or in collaboration with third parties, including achieving and maintaining an adequate level of market adoption, depends on several factors, including:

•

our ability to successfully launch and achieve broad adoption of our approved products in earlier lines of therapy, any future indications for which XPOVIO may be approved, or any product candidates for which we obtain marketing approval;

•

the competitive landscape for our products, including the timing of new competing products entering the market and the level and speed at which these products achieve market acceptance;

•

actual or perceived advantages or disadvantages of our products or product candidates as compared to alternative treatments, including their respective safety, tolerability and efficacy profiles, the potential convenience and ease of administration, access or cost effectiveness;

•

the effectiveness of our sales, marketing, manufacturing and distribution strategies and operations;

•

the consistency of any new data we collect and analyses we conduct with prior results, whether they support a favorable safety, efficacy and effectiveness profile of XPOVIO and any potential impact on our U.S. Food and Drug Administration (“FDA”) approvals and/or ~~FDA; similarly, we cannot commercialize drug candidates outside~~FDA package insert for XPOVIO and comparable foreign regulatory approvals and package inserts;

•

our ability to comply with the FDA’s and comparable foreign regulatory authorities’ post-marketing requirements and commitments, including through successfully conducting, on a timely basis, additional studies that confirm clinical efficacy, effectiveness and safety of XPOVIO and acceptance of the ~~United States without~~same by the FDA or similar foreign regulatory bodies, such as requirements in connection with the FDA’s June 2020 approval of XPOVIO based on the results of the SADAL study to treat patients with DLBCL, which was approved under the FDA’s Accelerated Approval Program;

•

acceptance of current indications of XPOVIO and future indications of XPOVIO and other product candidates, if approved, by patients, the medical community and third-party payors;

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•

obtaining and maintaining coverage, adequate pricing and reimbursement by third-party payors, including government payors, for XPOVIO and our product candidates, if approved;

•

the willingness of patients to pay out-of-pocket in the absence of third-party coverage or as co-pay amounts under third-party coverage;

•

our ability to enforce intellectual property rights in and to our products to prohibit a third-party from marketing a competing product and our ability to avoid third-party patent interference or intellectual property infringement claims;

•

current and future restrictions or limitations on our approved or future indications and patient populations or other adverse regulatory actions;

•

the performance of our manufacturers, license partners, distributors, providers and other business partners, over which we have limited control;

•

any significant misestimations of the size of the market and market potential for any of our products or product candidates;

•

establishing and maintaining commercial manufacturing capabilities or making arrangements with third-party manufacturers;

•

the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies, based, in part, on their perception of our clinical trial data and/or the actual or perceived safety, tolerability and effectiveness profile;

•

maintaining an acceptable safety and tolerability profile of our approved products, including the prevalence and severity of any side effects;

•

the ability to offer our products for sale at competitive prices;

•

adverse publicity about our products or favorable publicity about competitive products;

•

our ability to maintain compliance with existing and new health care laws and regulations, including government pricing, price reporting and other disclosure requirements related to such laws and regulations, and the potential impact of such laws and regulations on physician prescribing practices and payor coverage; and

•

the impact of the novel coronavirus disease (“COVID-19”) pandemic on the above factors.

If we do not achieve one or more of these factors in a timely manner, or at all, either on our own or with our collaborators, we could experience significant delays or an inability to successfully commercialize XPOVIO or our product candidates, if approved, which would materially harm our business.

We face substantial competition, which may result in others discovering, developing or commercializing drugs before or more successfully than we do.

The discovery, development and commercialization of new drugs is highly competitive, particularly in the cancer field. We and our collaborators face competition with respect to XPOVIO and will face competition with respect to any product candidates that we may seek to discover and develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies, biotechnology companies, academic institutions and governmental agencies as well as public and private research institutions worldwide, many of which have significantly greater financial resources and expertise in research and development, manufacturing, preclinical studies, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. There are a number of major pharmaceutical, specialty pharmaceutical and biotechnology companies that currently market and sell drugs and/or are pursuing the development of drugs for the treatment of cancer and the other disease indications for which we, and our collaborators, are developing our product candidates. Several new novel therapeutics have recently entered, and are expected to continue to enter, the multiple myeloma treatment landscape. For example, TECVAYLI™ (teclistamab-cqyv), the first bispecific T-Cell engager was approved by the FDA in October 2022. Other T-cell engaging therapies, bispecifics with different targets, immunomodulators, and a BCL-2 inhibitor are in clinical development and may be introduced into the multiple myeloma market in 2023. In addition, future label expansions into earlier lines of existing therapies are anticipated in 2023 and beyond. The approval ~~from similar~~of these anti-cancer agents, or any others which may receive regulatory ~~authorities outside~~approval, may have a significant impact on the therapeutic landscape and our product revenues. See Item 1 under the heading Business - Competition in our Annual Report on Form 10-K for the year ended December 31, 2022 as filed with the SEC on February 17, 2023 (“Annual Report”) for more information on competition.

We are currently focused on developing and commercializing our current products and product candidates for the treatment of cancer and there are a variety of available therapies marketed for cancer. In many cases, cancer drugs are administered in combination

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to enhance efficacy. Some of these drugs are branded and subject to patent protection, and others are available on a generic basis. Many of these approved drugs are well-established therapies and are widely accepted by physicians, patients and third-party payors. Insurers and other third-party payors may also encourage the ~~United States. Even~~use of generic drugs. Our products are priced at a significant premium over competitive generic drugs, which may make it difficult for us to achieve our business strategy of using our products in combination with existing therapies or replacing existing therapies with our products.

Further, our commercial opportunity could be reduced or eliminated if ~~selinexor~~our competitors develop and commercialize drugs that are or ~~another drug candidate were~~are perceived to ~~successfully~~be more effective, safer, more tolerable, more convenient and/or less costly than any of our currently approved products or product candidates or that would render our products obsolete or non-competitive. Our competitors may also obtain marketing approval from the FDA ~~and non-U.S.~~or other regulatory authorities ~~any~~for their products more rapidly than we, or our collaborators, may obtain approval ~~might contain~~for ours, which could result in our competitors establishing a stronger market position before we, or our collaborators, are able to enter the market or preventing us, or our collaborators, from entering into a particular indication at all.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller and other early-stage companies may also prove to be significant ~~limitations related~~competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, ~~use restrictions for specified age groups, warnings, precautions~~ or ~~contraindications, or~~that may be ~~subject to burdensome post-approval study or risk management requirements.~~ necessary for, our programs.

If we are not able to compete effectively against current or potential competitors, our business will not grow and our financial condition and operations will suffer.

Clinical development is a lengthy and expensive process, with uncertain timelines and outcomes. If clinical trials of our product candidates fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we, or our collaborators, may incur additional costs or experience delays in completing, or ultimately be unable to ~~obtain regulatory approval for~~complete, the development and commercialization of such product candidates.

Our long-term success depends in a large part on our ability to continue to successfully develop new indications of selinexor, ~~in one or more jurisdictions,~~our product candidates, including eltanexor, or any new product candidates we may develop or acquire. Clinical testing is expensive, time consuming, difficult to design and implement, inherently uncertain as to outcome and can fail at any stage of testing. Furthermore, the failure of any product candidates to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of selinexor, eltanexor or our other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before any of our product candidates are approved.

We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our or our collaborators’ ability to receive marketing approval ~~contains significant limitations,~~of our product candidates, including, but not limited to, the following:

•

delays or failure to reach agreement with regulatory authorities on a trial design or the receipt of feedback requiring us to modify the design of our clinical trials, perform additional or unanticipated clinical trials to obtain approval or alter our regulatory strategy, as is the case in connection with the feedback we received from the FDA in February 2022 on our SIENDO Study;

•

clinical trials of our product candidates may produce negative or inconclusive results or other patient safety concerns, including undesirable side effects or other unexpected characteristics, and we may decide, or regulatory authorities may require us, to conduct additional clinical trials, suspend ongoing clinical trials or abandon drug development programs, including as a result of a finding that the participants are being exposed to unacceptable health risks;

•

enrollment in our clinical trials may be slower than we anticipate, including as a result of competition with other ongoing clinical trials for the same indications as our product candidates;

•

regulators may revise the requirements for approving our product candidates, even after providing a positive opinion on or otherwise reviewing and providing comments to a clinical trial protocol, and/or such requirements may not be ~~able~~as we anticipate;

•

delays or failure in obtaining the necessary authorization from regulatory authorities or institutional review boards to ~~obtain sufficient funding~~permit us or ~~generate sufficient revenue~~our investigators to commence a clinical trial, conduct a clinical trial at a prospective trial site, or the suspension or termination of a clinical trial once commenced;

•

delays or failure to reach agreement on acceptable terms with prospective clinical trial sites or contract research organizations (“CROs”);

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•

the number of patients required for clinical trials of our product candidates may be larger than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate;

•

our third-party contractors, including manufacturers or CROs, may fail to comply with regulatory requirements, perform effectively, or meet their contractual obligations to us in a timely manner, or at all;

•

we or our investigators might be found to be non-compliant with regulatory requirements;

•

the cost of clinical trials of our product candidates may be greater than we anticipate;

•

the supply or quality of our product candidates or other materials necessary to conduct clinical trials may be insufficient or inadequate; for example, the global supply shortages of non-human primate subjects has impacted timing and execution of certain pre-clinical research activities;

•

for any biomarker driven clinical trial, the potential regulatory requirement to utilize a companion diagnostic, for example the required use of a companion diagnostic for our ongoing study evaluating selinexor in patients with TP53 wild-type advanced or recurrent endometrial cancer;

•

any partners or collaborators that help us conduct clinical trials may face any of the above issues, and may conduct clinical trials in ways they view as advantageous to them but that are suboptimal for us; and

•

negative impacts resulting from the ongoing COVID-19 pandemic, including impacts to healthcare systems and our trial sites’ ability to conduct trials.

The COVID-19 pandemic has had and may continue to have an impact on our clinical trials. For more information, please see the ~~development, marketing and/or commercialization of selinexor or any other drug candidate that we~~risk factor entitled, “The COVID-19 pandemic has adversely disrupted, and may ~~discover, in-license, develop or acquire~~ in the ~~future. Furthermore, even if~~future adversely disrupt, our or our collaborators' operations, including our or their clinical trial activities and commercial operations, which could have an adverse effect on our business and financial results.” At this time, however, we ~~obtain~~cannot fully forecast the scope of the impact that the COVID-19 pandemic may continue to have on our ability to, among other things, initiate and oversee trial sites, enroll and assess patients, supply study drug and report trial results. In addition, we have and may continue to experience delays in the regulatory process as a result of the COVID-19 pandemic, which may impact our approval for selinexor, we will still need to develop a commercial organization, or collaborate with a third party for the commercialization of selinexor, establish commercially viable pricing and obtain approval for adequate reimbursement from third-party and government payors. timelines.

If we, or our ~~commercialization~~ collaborators, are required to conduct additional clinical trials or other testing of our product candidates or a companion diagnostic beyond those that we currently contemplate or are unable to successfully complete clinical trials of our product candidates or other testing, on a timely basis or at all, and/or if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we, or our collaborators, may:

•

be delayed in obtaining, or not obtain at all, marketing approval for the indication or product candidate;

•

obtain marketing approval in some countries and not in others;

•

obtain approval for indications or patient populations that are not as broad as intended or desired;

•

obtain approval with labeling that includes significant use or distribution restrictions or safety warnings, including boxed warnings;

•

be subject to additional post-marketing testing requirements;

•

not receive royalty or milestone revenue under our collaboration agreements for several years, or at all; or

•

have the product removed from the market after obtaining marketing approval.

Further, we do not know whether clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our products, allow our competitors to bring products to market before we do or impair our ability to successfully commercialize our products, which would harm our business and results of operations. In addition, many of the factors that cause, or lead to, clinical trial delays may ultimately lead to the denial of regulatory approval of our product candidates.

Serious adverse or unacceptable side effects related to XPOVIO, our product candidates or future products may delay or prevent their regulatory approval, cause us or our collaborators to suspend or discontinue clinical trials, limit the commercial value of approved indications or result in significant negative financial consequences following any marketing approval.

We currently have two product candidates in clinical development as company sponsored trials for the treatment of human disease: selinexor and eltanexor. Their risk of failure is high. If our current or future indications of XPOVIO, any of our product

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candidates or future products are associated with undesirable side effects or have characteristics that are unexpected in clinical trials or following approval and/or commercialization, we may need to abandon or limit their development or limit marketing to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

Adverse events (“AEs”) in our clinical trials to date have been generally predictable and typically manageable, including through prophylactic care or dose reductions, although some patients have experienced more serious AEs. The most common drug-related AEs in our clinical trials for XPOVIO include fatigue, nausea, anorexia, diarrhea, peripheral neuropathy, upper respiratory tract infection, vomiting, cytopenias, hyponatremia, weight loss, decreased appetite, cataract, dizziness, syncope, depressed level of consciousness, and mental status changes. These side effects were generally mild or moderate in severity. The most common AEs that are grade 3 or grade 4, meaning they are more than mild or moderate in severity, include thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. To date, the most common AEs in the multiple myeloma patient population have been managed with supportive care and dose modifications. However, a number of patients have withdrawn from our clinical trials as a result of AEs and some patients across our clinical trials have experienced serious AEs deemed by us and the clinical investigator to be related to selinexor. Serious AEs generally refer to AEs that result in death, are life threatening, require hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.

The occurrence of AEs in either our clinical trials or following regulatory approval could result in a more restrictive label for any product candidates approved for marketing or could result in the delay or denial of approval to market any product candidates by the FDA or comparable foreign regulatory authorities, which could prevent us from generating sufficient revenue from product sales or ultimately achieving profitability. Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete the trial, result in potential product liability claims or cause patients and/or healthcare providers to elect alternative courses of treatment. In addition, these side effects may not be appropriately recognized or managed by the treating medical staff. Inadequate training or education of healthcare professionals to recognize or manage the potential side effects of XPOVIO or our product candidates, if approved, could result in increased treatment-related side effects and cause patients to discontinue treatment. Any of these occurrences may harm our business, financial condition and prospects significantly.

Results of our trials could reveal an unacceptably high severity and prevalence of side effects. In such an event, our trials could be suspended or terminated by us or the FDA or comparable foreign regulatory authorities could order us or our collaborators to cease further development of or deny approval of our product candidates for any or all targeted indications. Many compounds that initially showed promise in early-stage trials for treating cancer or other diseases have later been found to cause side effects that prevented further development of the compound. If such an event occurs after any of our or our collaborators’ product candidates are approved and/or commercialized, a number of potentially significant negative consequences may result, including:

•

regulatory authorities may withdraw the approval of such drug;

•

regulatory authorities may require additional warnings on the label or impose distribution or use restrictions;

•

patients and/or healthcare providers may elect to utilize other treatment options that have or are perceived to have more tolerable side effects;

•

regulatory authorities may require one or more post-marketing studies;

•

we may be required to create a medication guide outlining the risks of such side effects for distribution to patients;

•

we could be sued and held liable for harm caused to patients; and

•

our reputation may suffer.

Further, we, our collaborators and our clinical trial investigators, currently determine if serious adverse or unacceptable side effects are drug-related. The FDA or foreign regulatory authorities may disagree with our, our collaborators’ or our clinical trial investigators’ interpretation of data from clinical trials and the conclusion by us, our collaborators or our clinical trial investigators that a serious adverse effect or unacceptable side effect was not drug-related. The FDA or foreign regulatory authorities may require more information related to the safety of our products or product candidates, including additional preclinical or clinical data to support approval, which may cause us to incur additional expenses, delay or prevent the approval of one of our product candidates, and/or delay or cause us to change our commercialization plans, or we may decide to abandon the development of the product candidate altogether.

In addition, if we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies governing clinical trials, our development plans may be impacted. For example, in December 2022, with the passage of Food

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and Drug Omnibus Reform Act (“FDORA”), Congress required sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product. These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products. Similarly, the regulatory landscape related to clinical trials in the EU recently evolved. The EU Clinical Trials Regulation (“CTR”), which was adopted in April 2014 and repeals the EU Clinical Trials Directive, became applicable on January 31, 2022. While the Clinical Trials Directive required a separate clinical trial application to be submitted in each member state, to both the competent national health authority and an independent ethics committee, the CTR introduces a centralized process and only requires the submission of a single application to all member states concerned. If we are not able to ~~generate~~fulfill these new requirements, our ability to conduct clinical trials may be delayed or halted.

Any of these events could prevent us or our collaborators from achieving or maintaining market acceptance of the affected product candidate, if approved, or could substantially increase costs and expenses of development or commercialization, which could delay or prevent us from generating sufficient ~~revenues~~revenue from the sale of our products and harm our business and results of operations.

The COVID-19 pandemic has adversely disrupted, and may in the future adversely disrupt, our or our collaborators’ operations, including our or their clinical trial activities and commercial operations, which could have an adverse effect on our business and financial results.

As a result of the COVID-19 pandemic that has affected many segments of the global economy, we and our collaborators have experienced, and may in the future experience, disruptions that could adversely impact our business, clinical trial activities and commercial operations, including:

•

negative impact to revenue for XPOVIO, which may continue as the COVID-19 pandemic evolves, including as a result of decreased new patient starts due to the reduced ability of our sales force and our patients to meet with healthcare professionals in person;

•

delays or difficulties in enrolling patients in our clinical trials;

•

delays or difficulties in initiating new clinical studies, including clinical site initiation and oversight as well as limitations related to clinical site investigators and clinical site staff;

•

interruption of key clinical trial activities, such as clinical trial site data monitoring, due to limitations on travel imposed or recommended by government officials or entities, employers and others or interruption of clinical trial patient visits and study procedures (particularly any procedures that may be deemed non-essential), which may impact the integrity of clinical trial data and clinical study endpoints;

•

interruptions or delays in the operations of the FDA and comparable foreign regulatory agencies, including the EMA, which have and may impact regulatory review and approval timelines; and

•

negative impacts on any or all aspects of our operations due to business disruptions related to COVID-19 at our third-party vendors who we rely upon in the conduct of our business, including supply chain disruptions.

Further, on January 30, 2023, the Biden Administration announced that it will end the public health emergency declarations related to COVID-19 on May 11, 2023. Thereafter, on March 13, 2023, the FDA announced that it will end 22 COVID-19-related policies when the public health emergency ends May 11 and allow 22 to continue for 180 days. The FDA plans to retain 24 COVID-19-related policies with appropriate changes and four whose duration is not tied to the end of the public health emergency. As a result of these and other measures, we may in the future face disruptions in our ~~business.~~ability to prepare and submit applications to regulatory authorities for drug approvals and to build and maintain a commercial infrastructure for our product and product candidates.

Any future impact of the disruptions to our business, including commercial sales and clinical trials, as a result of the pandemic will depend on the availability, administration rates and effectiveness of vaccines and their effectiveness against variants as new strains of the virus evolve, and therapeutics and future developments, all of which are highly uncertain and cannot be predicted with confidence, such as the duration and severity of the pandemic, and the effectiveness of actions taken in the U.S. and other countries to contain and treat the disease. Due to the ongoing uncertainty regarding the severity and duration of the COVID-19 pandemic, including the emergence of new variants of COVID-19, we cannot predict whether our response to date or the actions we may take in the future will be effective in mitigating the effects of the COVID-19 pandemic on our business, results of operations or financial condition. Accordingly, we are unable at this time to predict the future impact of the COVID-19 pandemic on our operations, liquidity, and financial results.

The results of previous clinical trials may not be predictive of future trial results, and interim or top-line data may be subject to change or qualification based on the complete analyses of data and, therefore, may not be predictive of the final results of ~~our current and planned clinical trials may not satisfy the requirements~~a trial.

Table of ~~the FDA or non-U.S. regulatory authorities.~~Contents

~~We currently have no drugs approved for sale and we cannot guarantee that we will ever have marketable drugs.~~ Clinical failure can occur at any stage of the clinical ~~development. Clinical trials may produce negative or inconclusive results,~~development process and, we or any collaborators may decide, or regulators may require us, to conduct additional clinical trials or preclinical studies. We will be required to demonstrate with substantial evidence through well-controlled clinical trials that our drug candidates are safe and effective for use in a diverse population before we can seek regulatory approvals for their commercial sale. Success in early-stage clinical trials does not mean that future larger registration clinical trials will be successful because drug candidates in later-stage clinical trials may fail to demonstrate sufficient safety and efficacy to the satisfaction of the FDA and non-U.S. regulatory authorities despite having progressed through early-stage clinical trials. Drug candidates that have shown promising results in early-stage clinical trials may still suffer significant setbacks in subsequent registration clinical trials. Additionally,therefore, the outcome of preclinical studies and early-stage clinical trials may not be predictive of the success of ~~later-stage~~later stage clinical trials. For example, certain data from our Phase 1 and Phase 2 clinical trials ~~and interim results~~ of aselinexor are based on unaudited data provided by our clinical trial ~~are not necessarily indicative~~investigators. Finalization and cleaning of ~~final results. For example, in 2016 we released top-line interim results~~this data may change the conclusions drawn from our Selinexor Treatment of Refractory Myeloma (STORM) study. While we believe the results we have observed to date are positive, there can be no assurance that further analysis will confirm our initial observations regarding this ~~interim~~unaudited data ~~or that data from the expansion of~~provided by our ~~STORM study will reflect similar results.~~

~~In addition, the design of a~~ clinical trial can determine whether its results will support approval of a drug, and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. We have limited experience in designing clinical trials and may be unable to design and conduct a clinical trial to support regulatory approval. Further, if our drug candidates are found to be unsafe or lack efficacy, we will not be able to obtain regulatory approval for them and our business would be harmed. A number of companies in the pharmaceutical industry, including those with greater resources and experience than us, have suffered significant setbacks in advanced clinical trials, even after obtaininginvestigators indicating less promising results ~~in earlier clinical trials.~~

~~In some instances,~~than we currently anticipate. Further, there can be significant variability in safety and/or efficacy results between different trials of the same ~~drug~~product candidate due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, adherence to the dosing regimen and other trial protocols and the dropout rate ~~of dropout~~ among clinical trial participants. We do not know whether any Phase 2, Phase 3 or other clinical trials we may conduct will demonstrate consistent or adequate efficacy and safety data sufficient to obtain regulatory approval to market our product candidates, if approved. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we could face similar setbacks.

We may publicly disclose preliminary, interim or top-line data from our clinical trials. These interim updates are based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change as further patient data become available and following a more comprehensive review of the data related to the particular study or trial. For example, on February 8, 2022, we announced positive top-line data results for the SIENDO Study. On February 25, 2022, we discussed these data with the FDA in a pre-sNDA meeting. We and the FDA meeting participants had differing views on the statistical significance of the study and the overall clinical benefit for the whole study population. For this study or any other study for which we report preliminary, interim or top-line data, we make assumptions, estimations, calculations and conclusions as part of our analyses of data. We may not have received or had the opportunity to fully and carefully evaluate all data or our conclusions may differ from those of the FDA or other regulatory authorities. Consequently, the preliminary, interim or top-line data results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated or based on differing views from regulatory agencies, such as in the SIENDO Study. Preliminary, interim or top-line data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, these early data points should be viewed with caution until the final data are available. Adverse differences between previous preliminary or interim data and future interim or final data could significantly harm our business.

In addition, the information we choose to publicly disclose regarding a particular study or clinical trial is typically selected from a more extensive amount of available information. Furthermore, we may report interim analyses of only certain endpoints rather than all endpoints. Investors may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular product, product candidate or our business.

If the interim or top-line data that we report differ from future or more comprehensive data, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for and commercialize our product candidates, our business, operating results, prospects, or financial condition may be harmed.

We may not be successful in our efforts to identify or discover additional potential product candidates, or our decisions to prioritize the development of certain product candidates over others may later prove wrong.

Part of our strategy involves identifying and developing product candidates to build a pipeline of product candidates. Our drug ~~candidates.~~discovery efforts may not be successful in identifying compounds that are useful in treating cancer or other diseases. Our research programs may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development for a number of reasons, including:

~~Further, our drug~~

•

the research methodology used may not be successful in identifying potential product candidates;

•

potential product candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to be drugs that will receive marketing approval and/or achieve market acceptance; or

•

potential product candidates may not be effective in treating their targeted diseases.

We are currently advancing multiple clinical development studies of selinexor and eltanexor, which may create a strain on our limited human and financial resources. As a result, we may not be able to provide sufficient resources to any single product candidate to permit the successful development and commercialization of such product candidate, which could result in material harm to our business. Further, because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to

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capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any additional commercially-viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

If we are unable to maintain or expand our sales, marketing and distribution capabilities, we may not be successful in commercializing XPOVIO or any of our products or product candidates, if approved, that we may acquire or develop.

We have built a commercial infrastructure in the U.S. for XPOVIO, our first commercial product, in hematological malignancies and our company did not previously have any prior experience in the sales, marketing or distribution of pharmaceutical drugs. If XPOVIO or any of our product candidates is approved for additional indications beyond hematological malignancies, such as solid tumors, we may need to evolve our sales, marketing and distribution capabilities and we may not be able to do so successfully or on a timely basis. In the future, we may choose to expand our sales, marketing and distribution infrastructure to market or co-promote one or more of our product candidates, if and when they are approved, or enter into additional collaborations with respect to the sale, marketing and distribution of our product candidates. We are working with existing and potential partners to establish the commercial infrastructure to support the sale of selinexor outside of the U.S. For example, in December 2021, we entered into a license agreement with the Menarini Group (“Menarini”) to, among other things, develop and commercialize NEXPOVIO® (selinexor) for all human oncology indications in Europe (including the United Kingdom (“UK”)), Latin America and other key countries. For additional risks associated with commercializing our products outside of the U.S., please see the risk factor entitled “We depend on collaborations with third parties for certain aspects of the development, marketing and/or commercialization of XPOVIO and/or our product candidates. If those collaborations are not successful, or if we are not able to maintain our existing collaborations or establish additional collaborations, we may have to alter our development and commercialization plans and may not be able to capitalize on the market potential of XPOVIO or our product candidates” below.

There are risks involved with establishing and maintaining our own sales, marketing and distribution capabilities. For example, recruiting and training a sales force is expensive and time-consuming and could delay any commercial launch of a product candidate or negatively impact ongoing commercialization efforts for our approved products. Further, we may underestimate the size of the sales force required for a successful product launch and we may need to expand our sales force earlier and at a higher cost than we anticipated. If the commercial launch of any of our product candidates is delayed or does not occur for any reason, including if we do not receive marketing approval in the timeframe we expect, we may have prematurely or unnecessarily incurred commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

Factors that may inhibit our efforts to successfully commercialize XPOVIO or any product candidates, if approved, on our own include:

•

our inability to recruit, train and retain adequate numbers of effective sales, market access, market analytics, operations and marketing personnel;

•

the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe current or future products;

•

the lack of complementary drugs, which may put us at a competitive disadvantage relative to companies with more extensive drug lines;

•

unforeseen costs and expenses associated with creating an independent sales, marketing and distribution organization;

•

our inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies;

•

our ability to supply sufficient inventory of our products for commercial sale; and

•

existing or new competitors taking share from XPOVIO or any other future product or preventing XPOVIO or any other future product from gaining share in its approved indications.

Even if we, or our collaborators, are able to effectively commercialize XPOVIO or any approved products that we may develop or acquire, the products may not receive coverage or may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, all of which would harm our business.

The legislation and regulations that govern marketing approvals, pricing and reimbursement for new drug products vary widely from country to country. As a result, we or our collaborators might obtain marketing approval for a drug in a particular country, but then be subject to price regulations that delay the commercial launch of the product, possibly for lengthy time periods, and negatively

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impact the revenues we, or our collaborators, are able to generate from product sales in that country. In the U.S., approval and reimbursement decisions are not linked directly, but there is increasing scrutiny from the Congress, regulatory authorities, payers, patients and pathway organizations of the pricing of pharmaceutical products. Adverse pricing limitations may also hinder our ability to recoup our investment in one or more product candidates, even if our product candidates obtain marketing approval.

Our, and our collaborators’, ability to successfully commercialize XPOVIO and any other products that we may develop or acquire will depend, in part, on the extent to which reimbursement for these products is available from government health administration authorities, private health insurers and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they ~~achieve~~will pay for and establish reimbursement levels. Obtaining and maintaining adequate reimbursement for XPOVIO and any of our product candidates, if approved, may be difficult. Moreover, the process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price of a product or for establishing the reimbursement rate that such a payor will pay for the product. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for our products. Even with payer coverage, patients may be unwilling or unable to pay the copay required and may choose not to take XPOVIO.

A primary trend in the healthcare industry in the U.S. and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. Third-party payors may also seek, with respect to an approved product, additional clinical evidence that goes beyond the data required to obtain marketing approval. They may require such evidence to demonstrate clinical benefits and value in specific patient populations or they may call for costly pharmaceutical studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies before covering our products. Accordingly, we cannot be sure that reimbursement will be or will continue to be available for XPOVIO and any product that we, or our collaborators, commercialize and, if reimbursement is available, we cannot be sure as to the level of reimbursement and whether it will be adequate. Coverage and reimbursement may impact the demand for or the price of XPOVIO or any product candidate for which we, or our collaborators, obtain marketing approval. If reimbursement is not available or is available only at limited levels, we, or our collaborators, may not be able to successfully commercialize XPOVIO or any other approved products.

There may be significant delays in obtaining reimbursement for newly-approved drugs, and coverage may be more limited than the indications for which the drug is approved by the FDA or comparable foreign regulatory authorities. Moreover, eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their ~~primary endpoints~~own reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved drugs that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize our products and our overall financial condition.

Product liability lawsuits against us could divert our resources, cause us to incur substantial liabilities and limit commercialization of XPOVIO or any other products that we may develop or acquire.

We face an inherent risk of product liability exposure related to our commercialization of XPOVIO and the testing of our product candidates in ~~Phase 3~~human clinical trials as the administration of our products to humans may expose us to liability claims, whether or not our products are actually at fault for causing any harm or injury. As XPOVIO is used over longer periods of time by a wider group of patients taking numerous other medicines or by patients with additional underlying conditions, the likelihood of adverse drug reactions or unintended side effects, including death, may increase. For example, we may be sued if any drug we develop allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourselves against claims that our products or product candidates caused injuries, we will incur substantial liabilities or be required to limit commercialization of our products. Regardless of merit or eventual outcome, liability claims may result in:

•

decreased demand for XPOVIO and any other products that we may develop or acquire;

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•

injury to our reputation and significant negative media attention;

•

withdrawal of clinical trial participants;

•

initiation of investigations by regulators;

•

product recalls, withdrawals or labeling, marketing or promotional restrictions;

•

significant costs to defend the related litigation;

•

substantial monetary awards to trial participants or patients;

•

loss of revenue;

•

reduced resources of our management to pursue our business strategy; and

•

the inability to successfully commercialize XPOVIO and any other products that we may develop or acquire.

We currently hold clinical trial and general product liability insurance coverage, but that coverage may not be adequate to cover any and all liabilities that we may incur. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

The business that we or our collaborators conduct outside of the U.S. may be adversely affected by international risks and uncertainties.

Although our operations are primarily based in the U.S., we and our collaborators conduct business outside of the U.S. and expect to continue to do so in the future. For instance, many of the sites at which our clinical trials are being conducted are located outside of the U.S. In addition, we and our collaborators are seeking and continue to plan to seek approvals to sell our and their products in foreign countries. Any business that we, or our collaborators, conduct outside of the U.S. is subject to additional risks that may materially adversely affect our or their ability to conduct business in international markets, including:

•

potentially reduced protection of our intellectual property rights;

•

the potential for so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally;

•

unexpected changes in tariffs, trade barriers or regulatory requirements;

•

economic weakness, including the uncertainty associated with current worldwide economic conditions as a result of the COVID-19 pandemic, rising inflation, increasing interest rates, natural disasters and military conflicts, including the conflict between Russia and Ukraine; volatility in currency exchange rates; or political instability in particular foreign economies and markets;

•

workforce uncertainty in countries where labor unrest is more common than in the U.S.;

•

production shortages resulting from any events affecting a product candidate and/or finished drug product supply or manufacturing capabilities abroad;

•

business interruptions resulting from pandemics (including the COVID-19 pandemic), geo-political actions, including war and terrorism, such as the ongoing conflict between Russia and Ukraine, climate change or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires; and

•

failure to comply with Office of Foreign Asset Control rules and regulations and the Foreign Corrupt Practices Act (“FCPA”).

Risks Related to Regulatory Matters

Even if we, or our collaborators, complete the necessary preclinical studies and clinical trials for our product candidates, the regulatory approval process is expensive, time-consuming and uncertain and we or they may not receive approvals for the commercialization of some or all of our or their product candidates in a timely manner, or at all.

Our long-term success and ability to sustain and grow revenue depends on our and our collaborators’ ability to continue to successfully develop our product candidates and obtain regulatory approval to market our or their products both in and outside of the U.S. In order to market and sell our products in the EU and many other jurisdictions, we and our collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The FDA and comparable foreign regulatory

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authorities, whose laws and regulations may differ from country to country, impose substantial requirements on the development of product candidates to become eligible for marketing approval and have substantial discretion in the process and may refuse to accept any application or may decide that the data are insufficient for approval and require additional preclinical studies, clinical trials or other ~~registration trials. The FDA or non-U.S. regulatory authorities may disagree with our trial design and our interpretation of data from preclinical~~ studies and ~~clinical trials. In addition, any~~testing. The time required to obtain approval outside of ~~these regulatory authorities~~the U.S. may ~~change requirements~~differ substantially from that required to obtain FDA approval. For example, in many countries outside of the U.S., it is required that the drug be approved for reimbursement before the ~~approval of a~~ drug ~~candidate even after reviewing and providing comments or advice on a protocol~~can be approved for ~~a clinical trial~~sale in that ~~has the potential to result in approval~~country. Approval by the FDA ~~or another regulatory authority. In addition, any of these~~does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside of the U.S. does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. However, a failure or delay in obtaining regulatory approval in one country may ~~also approve~~have a ~~drug candidate for fewer or more limited indications than we request or may grant approval contingent~~negative effect on the ~~performance~~regulatory process in other countries. For additional risks related to conducting business outside of ~~costly post-marketing clinical trials. Furthermore,~~ the ~~FDA or other non-U.S. regulatory authorities may not approve~~U.S., please see the ~~labeling claims~~risk factor above entitled “The business that we ~~believe would~~or our collaborators conduct outside of the U.S. may be ~~necessary or desirable for the successful commercialization of our drug candidates.~~adversely affected by international risks and uncertainties.”

~~To date, we have had fairly limited discussions with~~In addition, the FDA and non-U.S. regulatory authorities regarding the design of our later phase clinical trials for selinexor, including the BOSTON, STORM, SADAL and SEAL studies currently underway. We plan to seek regulatory approvals of selinexor in North America and Europe in each indication with respect to which such later phase clinical trial is being conducted and with respect to which we receive positive results that may support full or accelerated approval, as the case may be. We may also seek such approvals in other geographies. We cannot be certain that we will commence additional later phase trials or complete ongoing later phase trials as anticipated. Before obtaining regulatory approvals for the commercial sale of any drug candidate for a target indication, we must demonstrate with substantial evidence gathered in preclinical studies and well-controlled clinical studies, and, with respect to approval in the United States, to the satisfaction of the FDA, that the drug candidate is safe and effective for use for that target indication. There is no assurance that the FDA or non-U.S. regulatory authorities would consider our current and planned later phase clinical trials to be sufficient to serve as the basis for filing for approval or to gain approval of selinexor for any indication. The FDA and non-U.S.foreign regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor, eltanexor or any other product candidate is safe and effective. If we are required to conduct additional clinical trials of selinexor, eltanexor or other product candidates prior to approval of additional indications, in earlier lines of therapy or in combination with other drugs, including additional earlier phase clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we ~~will~~may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.

The ~~results to date~~process of obtaining marketing approvals, both in the U.S. and abroad, is lengthy, expensive and uncertain. It may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved. Securing marketing approval requires the submission of extensive preclinical and early clinical studies conducted by us or our academic collaborators and in Phase 1 and Phase 2 clinical trials that we are currently conducting include the response of tumors to selinexor. We expect that in any later phase clinical trial where patients are randomized to receive either selinexor on the one hand, or standard of care, supportive care or placebo on the other hand, the primary endpoint will be either progression free survival, meaning the length of time on treatment until objective tumor progression, or overall survival, while the primary endpoint in any later phase clinical trial that is not similarly randomized may be different. For example, the primary endpoint of our Phase 2/3 SEAL study, the clinical trial of selinexor in patients with dedifferentiated liposarcoma, and a primary endpoint of our Phase 3 BOSTON study, the clinical trial of selinexor in combination with Velcade (bortezomib) and dexamethasone in patients with multiple myeloma, is progression free survival. We are in the early stages of collecting clinical data ~~in humans relating~~and supporting information, including manufacturing information, to regulatory authorities for each therapeutic indication to establish the ~~impact of selinexor on overall survival~~product candidate’s safety and ~~comparative clinical data between selinexor and supportive care. If selinexor does not demonstrate an overall survival benefit, it will likely not be approved. In some instances, the~~efficacy.

The FDA ~~and~~or other regulatory ~~bodies~~authorities may determine that (i) our product candidates are not safe and effective, only moderately effective or have ~~accepted overall response rate as a surrogate for a clinical benefit, and have granted regulatory approvals based on this~~undesirable or unintended side effects, toxicities or other ~~surrogate endpoints. Overall response rate is defined as~~characteristics that preclude our obtaining marketing approval or prevent or limit commercial use; (ii) the ~~portion of patients with tumor size reduction of a predefined amount for a minimum time period. For some types of cancer, we may use overall response rate as a primary endpoint, as we are doing~~dose used in our SADAL study and our STORM study. These clinical trials will not be randomized against control arms and the primary endpoints of these trials are overall response rate. If selinexor does not demonstrate sufficient overall response rates in these indications, or any other indication for which a clinical trial has ~~overall response rate as~~not been optimized and require us to conduct additional dose optimization studies; or (iii) the comparator arm in a ~~primary endpoint,~~trial is no longer the appropriate comparator due to the evolution of the competitive landscape or subsequent data of the comparator product, even if the FDA or ~~non-U.S.~~other regulatory ~~authorities do~~authority had previously approved the trial design, and we may be required to amend the trial or we may not ~~deem overall response rate~~receive approval of the indication.

Further, under the Pediatric Research Equity Act (“PREA”), an NDA or supplement to an NDA for certain drugs must contain data to assess the safety and effectiveness of the drug in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective, unless the sponsor receives a ~~sufficient endpoint, it will likely not~~deferral or waiver from the FDA. A deferral may be ~~approved~~granted for several reasons, including a finding that ~~indication.~~

Wethe product or therapeutic candidate is ready for approval for use in adults before pediatric trials are ~~early~~complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin. The law requires the FDA to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation. It further requires the FDA to publicly post the PREA Non-Compliance letter and sponsor’s response. The applicable legislation in ~~our development efforts~~the EU also requires sponsors to either conduct clinical trials in a pediatric population in accordance with a ~~limited number~~Pediatric Investigation Plan approved by the Pediatric Committee of ~~drug candidates in human clinical development. If we are unable~~the EMA or to ~~successfully develop and commercialize our drug candidates~~obtain a waiver or ~~experience significant delays in doing so, our business will be materially harmed.~~

~~We are early in our development efforts and have four drug candidates, selinexor, verdinexor, KPT-8602 and KPT-9274, in clinical development for treatment of human diseases. The success~~deferral from the conduct of these ~~and~~studies by this Committee. For any of our ~~other drug~~product candidates ~~will depend on several factors, including the following:~~

~~successful completion of preclinical studies;~~

~~acceptance by the FDA of investigational new drug applications, or INDs, for our drug candidates prior to commencing clinical studies;~~

~~successful enrollment in, and completion of, clinical trials, including demonstration of a favorable risk-benefit ratio;~~

~~receipt of marketing approvals from applicable regulatory authorities;~~

~~establishing commercial manufacturing capabilities or making arrangements with third-party manufacturers;~~

~~obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our drug candidates;~~

~~establishing sales, marketing, manufacturing and distribution capabilities to commercialize any drugs~~ for which we ~~may~~are seeking regulatory approval in the U.S. or the EU, we cannot guarantee that we will be able to obtain ~~marketing approval;~~

~~launching commercial sales of the drugs, if~~a waiver or alternatively complete any required studies and ~~when approved, whether alone or in collaboration with others;~~

~~acceptance of the drugs, if and when approved, by patients, the medical community and third-party payors;~~

~~effectively competing with~~ other ~~therapies;~~

~~obtaining and maintaining coverage and adequate reimbursement by third-party payors, including government payors, for any approved drugs;~~

~~maintaining an acceptable safety profile of the drugs following approval;~~

~~enforcing and defending intellectual property rights and claims; and~~

~~maintaining and growing an organization of scientists and business people, including collaborators, who can develop and commercialize our drug candidates.~~

~~If we do not achieve one or more of these factors~~requirements in a timely manner, or at all, which could result in an issuance and publication of a PREA Non-Compliance letter and associated reputational harm, our product candidate being considered misbranded and subject to relevant enforcement action, invalidation of the marketing application, and/or financial penalties.

Finally, our ability to develop and market new drug products may be threatened by ongoing litigation challenging the FDA’s approval of mifepristone. Specifically, on April 7, 2023, the U.S. District Court for the Northern District of Texas invalidated the approval by the FDA of mifepristone, a drug product which was originally approved in 2000 and whose distribution is governed by various measures adopted under a Risk Evaluation and Mitigation Strategy (“REMS”). In reaching that decision, the district court made a number of findings that numerous representatives of the pharmaceutical and biotechnology industry believe will chill the development, approval and distribution of new drug products in the U.S. Among other determinations, the district court substituted its scientific judgement for that of the FDA and it held that FDA must provide a special justification for any differences between an approved drug’s labeling and the conditions that existed in the drug’s clinical trials. Further, the district court read the jurisdictional requirements governing litigation in federal court so as to potentially allow virtually any party to bring a lawsuit against the FDA in connection with its decision to approve an NDA or establish requirements under a REMS. On April 13, 2023, the district court

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decision was stayed, in part, by the U.S. Court of Appeals for the Fifth Circuit. Thereafter, on April 21, 2023, the U.S. Supreme Court entered a stay pending disposition of the appeal of the district court decision in the Court of Appeals for the Fifth Circuit or the Supreme Court. Depending on the outcome of this litigation and the regulatory uncertainty it has engendered, our ability to develop new drug product candidates and to maintain approval of existing drug products and measures adopted under a REMS is at risk and our efforts to develop and market new drug products could be delayed, undermined or subject to protracted litigation.

The approval of our and our collaborators’ current or future product candidates for commercial sale could be delayed, limited or denied or we or they may be required to conduct additional studies for a number of reasons, including, but not limited to, the following:

•

regulatory authorities may determine that our or our collaborators’ product candidates do not demonstrate safety and effectiveness in accordance with regulatory agency standards based on a number of considerations, including AEs that are reported during clinical trials;

•

regulatory authorities could analyze and/or interpret data from clinical trials and preclinical testing in different ways than we, or our collaborators, interpret them and determine that our data is insufficient for approval;

•

regulatory authorities may require more information, including additional preclinical or clinical data or trials, to support approval, as in the case of our new trial for selinexor in endometrial cancer following discussions with the FDA in early 2022 on our SIENDO Study;

•

regulatory authorities could determine that our manufacturing processes are not properly designed, are not conducted in accordance with federal or other laws or otherwise not properly managed, and we may be unable to obtain regulatory approval for a commercially viable manufacturing process for our product candidates in a timely manner, or at all;

•

the supply or quality of our or our collaborators’ product candidates for our clinical trials may be insufficient, inadequate or delayed;

•

the size of the patient population required to establish the efficacy of our or our collaborators’ product candidates to the satisfaction of regulatory agencies may be larger than we or they anticipated;

•

our failure or the failure of clinical investigational sites and the records kept at the respective locations, including clinical trial data, to be in compliance with the FDA’s current good clinical practices regulations (“GCP”) or comparable regulations outside of the U.S., including the failure to pass inspections of our corporate site or our clinical trial sites;

•

regulatory authorities may change their approval policies or adopt new regulations;

•

regulatory authorities may not be able to undertake reviews, applicable inspections or approval processes in a timely manner;

•

the results of our earlier clinical trials may not be representative of our future, larger trials;

•

regulatory authorities may not agree with our or our collaborators’ regulatory approval strategies or components of our or their regulatory filings, such as the design or implementation of the relevant clinical trials; or

•

a product may not be approved for the indications that we, or our collaborators, request or may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable.

Further, we could ~~experience significant delays~~face heightened risks with respect to seeking marketing approval in the UK as a result of the withdrawal of the UK from the EU, commonly referred to as Brexit. The UK is no longer part of the European Single Market and EU Customs Union. As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”) became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law, whereas Northern Ireland will continue to be subject to EU rules under the Northern Ireland Protocol. The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended) (“HMR”) as the basis for regulating medicines. The HMR has incorporated into the domestic law of the body of EU law instruments governing medicinal products that pre-existed prior to the UK’s withdrawal from the EU. Any delay in obtaining, or an inability to ~~successfully commercialize~~obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to restrict or delay efforts to seek regulatory approval in the UK for our ~~drug~~product candidates, which ~~would~~could significantly and materially harm our business.

We, or our collaborators, may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our or their products in any market. Any failure, delay or setback in obtaining regulatory approval for our or our collaborators’ product candidates could materially adversely affect our or our collaborators’ ability to generate revenue from a particular product candidate, which could result in significant harm to our financial position and adversely impact our stock price.

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We, or our collaborators, may seek approval from the FDA or comparable ~~non-U.S.~~foreign regulatory authorities to use accelerated development pathways for our product ~~candidates, including for selinexor in multiple myeloma.~~candidates. If we, or our collaborators, are not able to use such pathways, we, or they, may be required to conduct additional clinical trials beyond those that ~~we contemplate and that~~are contemplated, which would increase the expense of obtaining, and delay the receipt of, necessary marketing approvals, if we, or they, receive them at all. In addition, even if ~~we are able to use~~ an accelerated approval pathway is available to us, or our collaborators, it may not lead to expedited approval of our product candidates, or approval at all.

Under the Federal Food, Drug and Cosmetic Act ~~or FDCA,~~(“FDCA”) and implementing regulations, the FDA may grant accelerated approval to a product candidate to treat a serious or life-threatening condition that provides meaningful therapeutic benefit over available therapies, upon a determination that the product has an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. The FDA considers a clinical benefit to be a positive therapeutic effect that is clinically meaningful in the context of a given disease, such as irreversible morbidity or mortality. For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. An intermediate clinical endpoint is a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug. The accelerated approval pathway may be used in cases in which the advantage of a new drug over available therapy may not be a direct therapeutic advantage, but is a clinically important improvement from a patient and public health perspective.

Prior to seeking such accelerated approval, we, or our collaborators, will continue to seek feedback from the FDA or comparable foreign regulatory agencies and otherwise evaluate our, or their, ability to seek and receive such accelerated approval. Assuming positive results from our expanded STORM study and remaining unmet medical need, we intend to use the data from the expanded study to support a request that the FDA consider granting accelerated approval for selinexor in penta-refractory multiple myeloma. The FDA has reiterated to us in its feedback that accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments at the time of consideration of the application for accelerated approval. Although we are not aware of any experimental therapies currently being evaluated in patients with penta-refractory multiple myeloma or any experimental or approved therapies showing activity in these patients, such therapies may exist at the time the FDA acts on any request we may make for accelerated approval, which could cause the FDA to deny our request. In addition, the FDA has indicated that additional therapies may receive full approval in multiple myeloma prior to the submission of a New Drug Application, or NDA, by us, which could mean that, at the time the FDA takes action on our accelerated approval submission, treatment of the penta-refractory group is no longer considered an unmet medical need or a patient population that has exhausted available therapies. The FDA has recommended that we plan for regular approval based on a randomized trial for the evaluation of safety and efficacy of selinexor for the treatment of multiple myeloma, and has previously indicated to us its preference for studies that isolate the effects of individual drugs. Although we believe that the STORM study design and the expansion in the penta-refractory patient group present an opportunity for us to request that the FDA grant accelerated approval if data from our Phase 2b STORM study support such an application, there

There can be no assurance that the FDA ~~will grant such approval, whether on an accelerated basis,~~ or ~~at all.~~

~~There can also be no assurance that the FDA~~foreign regulatory agencies will agree with our, or our collaborators’, surrogate endpoints or intermediate clinical endpoints in any of our, or their, clinical trials, or that we, or our collaborators, will decide to pursue or submit ~~an NDA~~any additional New Drug Applications (“NDA”) for accelerated approval or any other form of expedited development, review or approval. Similarly, there can be no assurance that, after feedback from the FDA or comparable foreign regulatory agencies, we, or our collaborators, will continue to pursue or apply for accelerated approval or any other form of expedited development, review or ~~approval, even if we initially decide to do so.~~approval. Furthermore, ~~if we decide to submit~~for any submission of an application for accelerated approval or application under another expedited regulatory designation, there can be no assurance that such submission or application will be accepted for filing or that any expedited development, review or approval will be granted on a timely basis, or at all.

~~Moreover, for drugs~~Finally, there can be no assurance that we will satisfy all FDA requirements, including new provisions, that govern accelerated approval. For example, with passage of the FDORA in December 2022, Congress modified certain provisions governing accelerated approval of drug and biologic products. Specifically, the new legislation authorized the FDA to (i) require a sponsor to have its confirmatory clinical trial underway before accelerated approval is awarded; (ii) require a sponsor of a product granted accelerated approval to submit progress reports on its post-approval studies to FDA every six months until the study is completed; and (iii) use expedited procedures to withdraw accelerated approval of an NDA or a Biologic License Application after the confirmatory trial fails to verify the product’s clinical benefit. Further, FDORA requires the agency to publish on its website “the rationale for why a post-approval study is not appropriate or necessary” whenever it decides not to require such a study upon granting accelerated approval. We will need to fully comply with these and other requirements in connection with the development and approval of any product candidate that qualifies for accelerated approval.

Accordingly, a failure to obtain and maintain accelerated approval or any other form of expedited development, review or approval for our product candidates, or withdrawal of a product candidate, would result in a longer time period until commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.

Under accelerated or conditional approval regulations of the FDA or comparable foreign regulatory authorities, we, and our collaborators, must comply with post-approval development and regulatory requirements to maintain the approval of XPOVIO or any future approved products, and if we, or our collaborators, fail to do so, the FDA or comparable foreign regulatory authorities could withdraw its approval of XPOVIO or any future approved products for the indication that received accelerated or conditional approval, which would lead to substantially lower revenues.

For drugs approved under the FDA’s Accelerated Approval Program, the FDA typically requires post-marketing confirmatory trials to evaluate the anticipated effect on irreversible morbidity or mortality or other clinical benefit. These confirmatory trials must be completed with due diligence. ~~The~~For example, in June 2020, the FDA ~~may withdraw~~approved XPOVIO to treat DLBCL under the FDA’s accelerated approval ofregulations and as a ~~product candidate approved under~~condition of the accelerated approval ~~pathway if,~~ for ~~example,~~this indication we are required to (i) complete and submit a final report with full datasets from a randomized, double-blind, placebo-controlled Phase 3 trial that verifies and describes the clinical benefit of selinexor in patients with relapsed or refractory DLBCL and (ii) provide the interim and final analyses of a randomized Phase 2 clinical trial of selinexor to characterize the safety and efficacy of at least two different dosing regimens of

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selinexor monotherapy in patients with relapsed or refractory DLBCL after at least two prior lines of systemic therapy. We intend to satisfy the Phase 3 trial requirement though our XPORT-DLBCL-030 study, and we may not be able to successfully and timely complete this study or any other post-marketing confirmatory study as required to maintain approval or achieve full approval. If the required post-approval studies fail to verify the ~~predicted~~ clinical ~~benefit~~benefits of ~~our product candidate fails~~XPOVIO or confirm that the surrogate marker used for accelerated approval of XPOVIO to ~~verify such benefit~~treat DLBCL showed an adequate correlation with clinical outcomes, if a sufficient number of participants cannot be enrolled, or ~~does not demonstrate sufficient clinical benefit to justify the risks associated with the drug. The FDA may also withdraw approval~~ if ~~other evidence demonstrates that our product candidate is not shown to be safe or effective under the conditions of use,~~ we fail to ~~conduct any~~perform the required ~~post approval trial of our product candidate~~post-approval studies with due diligence or on a timely basis, the FDA has the authority to withdraw approval of the drug following a hearing conducted under the FDA’s regulations, which could have a material adverse impact on our business. We cannot be certain of the results of the confirmatory clinical studies for the DLBCL indication or any other future conditional approval we ~~disseminate false~~receive or ~~misleading promotional materials relating to our product candidate.~~ what action the FDA may take if the results of those studies are not as expected based on clinical data that FDA has already reviewed.

Similar risks to those described above are also applicable to any application that we, or our collaborators, have submitted or may submit to the ~~European Medicines Agency, or~~ EMA to support ~~conditional~~ approval of selinexor to treat ~~penta-refractory~~heavily pretreated multiple ~~myeloma. A failure to obtain accelerated approval~~myeloma, relapsed or refractory DLBCL, or any other ~~form~~cancer indication. For medicinal products where the benefit of ~~expedited development, review or approval for our product candidates, or withdrawal~~immediate availability outweighs the risk of less comprehensive data than normally required, based on the scope and criteria defined in legislation and guidelines, it is possible to obtain a product candidate, would result in a longer time period for commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive positionconditional marketing authorization in the ~~marketplace.~~

~~Our approach~~EU with a 12-month validity period and annual renewal pursuant to Regulation No 507/2006. These are granted only if the ~~discovery and development~~EMA’s Committee for Medicinal Products for Human Use (“CHMP”) finds that all four of ~~drug candidates~~the following requirements are met: (i) the benefit-risk balance of the product is positive; (ii) it is likely that ~~target Exportin 1, or XPO1, is unproven, and we do not know whether we~~the sponsor will be able to ~~develop any drugs~~provide comprehensive data; (iii) unmet medical needs will be fulfilled; and (iv) the benefit to public health of ~~commercial value. If selinexor~~the medicinal product’s immediate availability on the market outweighs the risks due to the need for further data. Once a conditional marketing authorization has been granted, the marketing authorization holder must fulfil specific obligations within defined timelines. These obligations could include completing ongoing or new studies or collecting additional data to confirm the medicine’s benefit-risk balance remains positive. For example, the July 2022 marketing authorization from the European Commission (“EC”) for NEXPOVIO to treat adult patients with multiple myeloma after at least one prior therapy satisfied the conditional approval obligation for NEXPOVIO for patients with multiple myeloma who have received at least four prior therapies and whose disease is ~~unsuccessful in proving that drug candidates targeting XPO1~~refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, and who have ~~commercial value or experiences significant delays in doing so, our business may~~demonstrated disease progression on the last therapy. Conditional marketing authorization is valid for a period of one year and can be ~~materially harmed.~~

~~Our SINE™ compounds inhibit~~renewed/prolonged if the ~~nuclear export protein XPO1. We believe that no currently approved cancer treatments are selectively targeting the restoration and increase~~conditions set out in the ~~levels of multiple tumor suppressor proteins in the nucleus. Despite promising results to date in preclinical and early clinical studies of selinexor that~~conditional marketing authorization are met. If we, ~~have conducted and in Phase 1 and Phase 2 clinical trials of selinexor conducted by us~~ or our ~~academic~~ collaborators, ~~we may~~are not ~~succeed~~able to fulfill the specific obligations set out in ~~demonstrating safety and efficacy of SINE™ compounds in our current and future human clinical trials. Any drug candidates that we develop may not effectively prevent~~any conditional marketing authorization requirements, the exportation of tumor suppressor and/or growth regulatory proteins from the nucleus in humans with a particular form of cancer. If selinexor is unsuccessful in proving that drug candidates targeting the regulation of intracellular transport of XPO1 have commercial value or experiences significant delays in doing so, our business may be materially harmed and weconditional marketing authorization may not be ~~able to generate sufficient revenues to continue~~prolonged and we, or our ~~business.~~

~~We may not be successful in our efforts to identify or discover additional potential drug candidates.~~

Part of our strategy involves identifying and developing drug candidates to build a pipeline of novel drug candidates. Our drug discovery efforts may not be successful in identifying compounds that are useful in treating cancer or other diseases. Our research programs may initially show promise in identifying potential drug candidates, yet fail to yield drug candidates for clinical development for a number of reasons, including:

~~the research methodology used may not be successful in identifying potential drug candidates;~~

~~potential drug candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to be drugs that~~collaborators, will ~~receive marketing approval and/or achieve market acceptance; or~~

~~potential drug candidates may not be effective in treating their targeted diseases.~~

Research programs to identify new drug candidates require substantial technical, financial and human resources. We may choose to focus our efforts and resources on a potential drug candidate that ultimately proves to be unsuccessful.

~~If we are unable to identify suitable compounds for preclinical and clinical development, we will not~~no longer be able to ~~obtain revenues from sale of drugs in future periods, which likely would result in significant harm to our financial position~~market the product for the indication receiving conditional approval.

XPOVIO and ~~adversely impact our stock price.~~

~~Clinical drug development is a lengthy and expensive process, with an uncertain outcome. If clinical trials~~any of our ~~drug~~product candidates ~~fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities~~for which we, or ~~do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of~~ our ~~drug candidates.~~

Before obtaining marketing approval from regulatory authorities for the sale of our drug candidates, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of our drug candidates in humans. Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. A failure of one or more clinical trials can occur at any stage of testing. The outcome of preclinical studies and early-stage clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results. For example, the results of our Phase 1 and Phase 2 clinical trials of selinexor to date are based on unaudited data provided by our clinical trial investigators. An audit of this data may change the conclusions drawn from this unaudited data provided by our clinical trial investigators indicating less promising results than we currently anticipate. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that believed their drug candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed tocollaborators, obtain marketing approval ~~of their drugs.~~

~~We may experience numerous unforeseen events during,~~in the future are subject to post-marketing regulatory requirements and could be subject to post-marketing restrictions or ~~as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize our drug candidates, including:~~

~~regulatory authorities or institutional review boards may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;~~

~~feedback~~withdrawal from ~~regulatory authorities that requires us to modify~~ the ~~design of our clinical trials;~~

~~we may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical trial protocols with prospective trial sites or contract research organizations;~~

~~clinical trials of our drug candidates may produce negative or inconclusive results,~~market, and we, ~~may decide, or regulatory authorities may require us, to conduct additional clinical trials, suspend ongoing clinical trials or abandon drug development programs;~~

~~the number of patients required for clinical trials of~~and our ~~drug candidates~~collaborators, may be ~~larger than~~subject to substantial penalties if we, ~~anticipate, enrollment in these clinical trials may be slower than we anticipate~~ or ~~participants may drop out of these clinical trials at a higher rate than we anticipate;~~

~~our third-party contractors may~~they, fail to comply with regulatory requirements or ~~meet their contractual obligations~~if we, or they, experience unanticipated problems with our products following approval.

Once marketing approval has been granted, an approved product and its manufacturer and marketer are subject to ~~us in a timely manner, or at all;~~

ongoing review and extensive regulation. XPOVIO and any of our product candidates for which we, or our ~~investigators might have~~collaborators, obtain marketing approval in the future, as well as the manufacturing processes, post-approval studies and measures, labeling, advertising and promotional activities for such drug, among other things, will be subject to ~~suspend or terminate clinical trials~~continual requirements of ~~our drug candidates for various reasons, including non-compliance with~~and review by the FDA and other U.S. and foreign regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and recordkeeping. For example, as a ~~finding that our drug candidates have undesirable side effects or other unexpected characteristics, or a finding that the participants are being exposed to unacceptable health risks;~~

~~the cost of clinical trials of our drug candidates may be greater than we anticipate;~~

•

~~the supply or quality of our drug candidates or other materials necessary to conduct clinical trials of our drug candidates may be insufficient or inadequate;~~

~~regulators may revise the requirements for approving our drug candidates, or such requirements may not be as we anticipate; and~~

~~any partners and collaborators that conduct clinical trials may face any~~condition of the ~~above issues,~~XPOVIO approval by the FDA for the multiple myeloma and ~~may conduct clinical trials in ways they view as advantageous to them but that are suboptimal for us.~~

IfDLBCL indications, we are required to ~~conduct additional~~complete certain post-marketing commitments. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the drug may be marketed or to the conditions of approval, including the requirement to implement a Risk Evaluation and Mitigation Strategy, which could include requirements for a restricted distribution system.

The FDA and comparable foreign regulatory authorities may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of a drug. The FDA and other ~~testing~~U.S. or foreign agencies, including the Department of Justice (the “DOJ”), closely regulate and monitor the post-approval marketing and promotion of drugs to ensure that they are manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label use, and if we, or our collaborators communicate about any of our ~~drug~~product candidates ~~beyond those that~~for which we, ~~currently contemplate, if we are unable to successfully complete clinical trials of our drug candidates~~ or ~~other testing, if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we may:~~

~~be delayed in obtaining marketing approval for our drug candidates;~~

~~not obtain marketing approval at all;~~

~~obtain~~they, receive marketing approval in ~~some countries and not in others;~~

~~obtain approval for~~a way that regulators assert goes beyond their approved indications, we, or ~~patient populations that are not as broad as intended or desired;~~

~~obtain approval with labeling that includes significant use or distribution restrictions or safety warnings, including boxed warnings;~~

they, may be subject to ~~additional post-marketing testing requirements;~~warnings or

~~have~~ enforcement action for off-label marketing. Alleged violations of the FDCA or other statutes, including the False Claims Act (the “FCA”), relating to the promotion and advertising of prescription drugs may lead to investigations or allegations of violations of federal and state health care fraud and

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abuse laws and state consumer protection laws. In September 2021, the FDA published final regulations which describe the types of evidence that the agency will consider in determining the intended use of a drug ~~removed from~~or biologic.

In addition, manufacturers of approved products and those manufacturers’ facilities are required to comply with extensive requirements by the ~~market after obtaining marketing approval.~~

~~Our drug development costs will also increase if we experience delays in testing or marketing approvals.~~FDA and comparable foreign regulatory authorities, including ensuring that quality control and manufacturing procedures conform to current Good Manufacturing Practice (“cGMP”), which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation and reporting requirements. We, do not know whether clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our ~~drug candidates, allow~~contract manufacturers, our ~~competitors to bring drugs to market before we do or impair our ability to successfully commercialize our drug candidates, which would harm our business~~collaborators and ~~results of operations.~~

If we experience delays or difficulties in the enrollment of patients in clinical trials, or we are otherwise delayed in our ability to conduct clinical trials, our receipt of necessary regulatory approvalstheir contract manufacturers could be ~~delayed or prevented.~~

~~We may not be able~~subject to ~~initiate or continue clinical trials for our drug candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required~~periodic unannounced inspections by the FDA or ~~similar~~foreign regulatory authorities to monitor and ensure compliance with cGMPs or other regulations.

Post-approval discovery of previously unknown problems with our products, including AEs of unanticipated severity or frequency, or relating to our manufacturing processes, data integrity issues with regulatory filings, or failure to comply with regulatory requirements, may yield various results, including:

•

litigation involving patients taking our drug;

•

restrictions on our manufacturers or manufacturing processes;

•

restrictions on the labeling or marketing of our products;

•

restrictions on the distribution or use of our products;

•

requirements to conduct post-marketing studies or clinical trials;

•

warning letters or untitled letters;

•

withdrawal, recall or seizure of our products from the market;

•

refusal to approve pending applications or supplements to approved applications that we submit;

•

fines, restitution or disgorgement of profits or revenues;

•

suspension or withdrawal of marketing approvals;

•

damage to relationships with our current or potential collaborators;

•

unfavorable press coverage and damage to our reputation;

•

refusal to permit the import or export of our products; or

•

injunctions or the imposition of civil or criminal penalties.

Similar restrictions apply to the approval of our products in the EU. The holder of the marketing authorization is required to comply with a range of requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products. These include:

•

compliance with the EU’s stringent pharmacovigilance or safety reporting rules, which can impose post-authorization studies and additional monitoring obligations;

•

the manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the EC Guidelines for Good Manufacturing Practice. These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the ~~United States. In addition, some~~EU with the intention to import the active pharmaceutical ingredients into the EU; and

•

the marketing and promotion of ~~our competitors may have ongoing clinical trials for drug candidates that treat~~authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the ~~same indications as our drug candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials~~prescribers of ~~our competitors’ drug candidates.~~

~~Patient enrollment is affected by other factors, including:~~

~~severity of the disease under investigation;~~

~~availability and efficacy of approved~~ drugs ~~for the disease under investigation;~~

~~patient eligibility criteria for the study in question;~~

~~competing drugs in clinical development;~~

~~perceived risks and benefits of the drug candidate under study;~~

~~restrictions on our ability to conduct clinical trials, including full or partial clinical holds on ongoing or planned trials;~~

~~efforts to facilitate timely enrollment in clinical trials;~~

~~patient referral practices of physicians;~~

~~the ability to monitor patients adequately during and after treatment; and~~

~~proximity and availability of clinical trial sites for prospective patients.~~

~~In addition, patient enrollment may be affected by future regulatory actions, such as Form 483 observations~~ and/or the ~~partial clinical hold we were~~general public, are strictly regulated in the EU notably under Directive 2001/83/EC, as amended, and are also subject to ~~previously. In February 2017, following~~EU Member State laws. Direct-to-consumer advertising of prescription medicines is prohibited across the ~~conclusion of a joint inspection conducted by the FDA and Danish Medicines Agency at our corporate headquarters, the FDA issued a Form 483 noting certain deficiencies~~EU.

Accordingly, in procedures and documentation that were identified in our selinexor development program. We implemented corrective actions, preventative actions and other initiatives directed at resolving the deficiencies identified in the Form 483 observations and provided the FDAconnection with our ~~responses to the Form 483 observations in February 2017.~~

~~In addition, in March 2017, the FDA notified us that it had placed the clinical trials under~~currently approved products and assuming we, or our ~~IND~~collaborators, receive marketing approval for selinexor on partial clinical hold, which is an order by the FDA to delay or suspend part of a sponsor’s clinical work requested under its IND as well as investigator-sponsored trials. The partial clinical hold was due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor, and not as a result of any new information regarding the safety profile of selinexor. The partial clinical holds on the clinical trials of selinexor were lifted by the FDA Division of Hematology Products (effective March 30, 2017), Division of Oncology Products 1 (effective April 5, 2017) and Division of Oncology Products 2 (effective March 31, 2017). However, if in the future we are delayed in addressing, or unable to address, any concerns of the FDA or other regulators, we could be delayed or prevented from enrolling patients in our clinical trials.

Our inability to enroll a sufficient number of patients for our clinical trials would result in significant delays or may require us to abandon one or more clinical trials altogether. Enrollment delays in our clinical trials may result in increased development costs for our drug candidates, which would cause the value of our company to decline and limit our ability to obtain additional financing.

If serious adverse or unacceptable side effects are identified during the development of our drug candidates or we observe limited efficacy of our drug candidates, we may need to abandon or limit the development of one or more of our ~~drug candidates.~~

~~Four of our drug~~product candidates, ~~are in clinical development for treatment of human diseases~~we, and our ~~other drug candidates for human diseases~~collaborators, and our and their contract manufacturers will continue to expend time, money and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance and quality control. If we, and our collaborators, are ~~in preclinical development. Their risk~~not able to comply with post-approval regulatory requirements, our or our

Table of failure is high. It is impossible to predict when or if any of our drug candidates will prove effective or safe in humans or will receive marketing approval. If our drug candidates are associated with undesirable side effects or have characteristics that are unexpected, we may need to abandon their development or limit development to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective. For example, we have modified our informed consent form and advised patients already enrolled in our clinical trials of the potential for worsening of pre-existing cataracts as a result of treatment with selinexor. Also, even though selinexor has generally been well-tolerated by patients in our Phase 1 and Phase 2 clinical trials to date, in some cases there were adverse events, some of which were serious. The most common drug-related adverse events, or AEs, were gastrointestinal, such as nausea, anorexia, diarrhea and vomiting, and fatigue. These side effects were generally mild or moderate in severity. The most common AEs that were Grade 3 or Grade 4, meaning they were more than mild or moderate in severity, were thrombocytopenia, or low count of platelets in the blood, and neutropenia, or low neutrophil counts. A small percentage of patients have withdrawn from our clinical trials as a result of AEs. A small percentage of patients across our clinical trials have experienced serious adverse events, or SAEs, deemed by us and the clinical investigator to be related to selinexor. SAEs generally refer to AEs that result in death, are life threatening, require hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.Contents

~~As a result of these AEs or further safety or toxicity issues that we may experience in our clinical trials in the future, we may not receive approval~~collaborators’ ability to market any ~~drug candidates,~~future products could be limited, which could ~~prevent us from ever generating revenue from~~adversely affect our ability to achieve or sustain profitability. Further, the ~~sale~~cost of ~~drugs~~compliance with post-approval regulations may have a negative effect on our operating results and financial condition.

If we, or ~~achieving profitability. Results of~~ our ~~trials could reveal an unacceptably high severity and prevalence of side effects. In such an event, our trials could be suspended or terminated and~~collaborators, are required by the FDA or comparable foreign regulatory authorities ~~could order us~~ to ~~cease further development of~~obtain clearance or ~~deny~~ approval of ~~our drug candidates for any or all targeted indications. Many compounds that initially showed promise~~a companion diagnostic in ~~early-stage trials for treating cancer or other diseases have later been found to cause side effects that prevented further development of the compound.~~

~~The FDA or non-U.S. regulatory authorities may disagree~~connection with ~~our and/or our clinical trial investigators’ interpretation of data from clinical trials in determining if serious adverse or unacceptable side effects are drug-related.~~

We, and our clinical trial investigators, currently determine if serious adverse or unacceptable side effects are drug-related. The FDA or non-U.S. regulatory authorities may disagree with our or our clinical trial investigators’ interpretation of data from clinical trials and the conclusion by us or our clinical trial investigators that a serious adverse effect or unacceptable side effect was not drug-related. The FDA or non-U.S. regulatory authorities may require more information, including additional preclinical or clinical data to support approval, which may cause us to incur additional expenses, delay or prevent the approval of ~~one of our drug candidates, and/~~a product candidate, and we or ~~delay or cause us to change our commercialization plans, or we may decide to abandon the development or commercialization of the drug candidate altogether.~~

We may expend our limited resources to pursue a particular drug candidate or indication and fail to capitalize on drug candidates or indications that may be more profitable or for which there is a greater likelihood of success.

Because we have limited financial and managerial resources, we focus on research programs and drug candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other drug candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial drugs or profitable market opportunities. Our spending on current and future research and development programs and drug candidates for specific indications may not yield any commercially-viable drugs. If wethey do not ~~accurately evaluate the commercial potential~~obtain or ~~target market for a particular drug candidate, we may relinquish valuable rights to that drug candidate through collaboration, licensing~~there are delays in obtaining clearance or ~~other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such drug candidate.~~

~~Even if any of our drug candidates receives marketing~~ approval ~~such drug may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.~~

If any of our drug candidates receives marketing approval, it may nonetheless fail to gain sufficient market acceptance by physicians, patients, third-party payors and others in the medical community. For example, current cancer treatments like chemotherapy and radiation therapy are well-established in the medical community, and doctors may continue to rely on these treatments. If our drug candidates do not achieve an adequate level of acceptance, we may not generate significant revenues from sales of drugs and we may not become profitable. The degree of market acceptance of our drug candidates, if approved for commercial sale, will depend on a number of factors, including:

~~efficacy and potential advantages compared to alternative treatments;~~

~~the ability to offer our drugs for sale at competitive prices;~~

~~convenience and ease of administration compared to alternative treatments;~~

~~the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;~~

~~the strength of marketing and distribution support;~~

~~sufficient third-party coverage or reimbursement;~~

~~the prevalence and severity of any side effects;~~

~~any restrictions on the use of our drugs together with other medications; and~~

~~inability of certain types of patients to take our drugs.~~

If, in the future, we are unable to establish sales and marketing capabilities or maintain current agreements or enter into additional agreements with third parties to sell and market our drug candidates, we may not be successful in commercializing our drug candidates if and when they are approved.

We do not have a sales or marketing infrastructure and have no experience in the sale or marketing of pharmaceutical drugs. To achieve commercial success for any approved drug for which sales and marketing is not the responsibility of any strategic collaborator that we may have in the future, we must either develop a sales and marketing organization or outsource these functions to other third parties. In the future, we may choose to build a sales and marketing infrastructure to market or co-promote some of our drug candidates, if and when they are approved, or enter into additional collaborations with respect to the sale and marketing of our drug candidate. We currently intend to establish a commercial infrastructure to enable us to market selinexor in North America and Western Europe.

There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services. For example, recruiting and training a sales force is expensive and time-consuming and could delay any commercial launch of a drug candidate. If the commercial launch of a drug candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

~~Factors that may inhibit our efforts to commercialize our drugs on our own include:~~

~~our inability to recruit and retain adequate numbers of effective sales and marketing personnel;~~

~~the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future drugs;~~

•

~~the lack of complementary drugs to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive drug lines;~~

~~unforeseen costs and expenses associated with creating an independent sales and marketing organization; and~~

~~inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies.~~

Entering into arrangements with third parties to perform sales and marketing services may result in lower revenues from the sale of drug or the profitability of these revenues to us than if we were to market and sell any drugs that we develop ourselves. In addition, we may not be successful in maintaining current arrangements or entering into additional arrangements with third parties to sell and market our drug candidates or may be unable to do so on terms that are favorable to us. We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our drugs effectively. If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties,diagnostic device, we will not be ~~successful~~able to commercialize the product candidate and our ability to generate revenue will be materially impaired.

Under the FDCA, companion diagnostics are regulated as medical devices and the FDA has generally required companion diagnostics intended to select the patients who will respond to cancer treatment to obtain premarket approval (“PMA”). In connection with our ongoing development of a registration-enabling study of selinexor in ~~commercializing our drug candidates.~~

~~We may not receive royalty~~patients whose endometrial cancer is TP53 wild-type, we are utilizing a companion diagnostic. Consequently, we expect that this companion diagnostic, or ~~milestone revenue under our license agreements for several years, or at all.~~

Our license agreements provide for payments on achievement of development or commercialization milestones and for royalties on product sales. However, because none of our drug candidates have been approved for commercial sale, our drug candidates are at early stages of development and drug development entails a high risk of failure,any others we may ~~never realize much of the milestone revenue provided in our license agreements and we do not expect to receive any royalty revenue for several years, if at all.~~

~~We face substantial competition, which may result in others discovering, developing or commercializing drugs before or more successfully than we do.~~

The discovery, development and commercialization of new drugs is highly competitive. We face competition with respect to our current drug candidates, and will face competition with respect to any drug candidates that we may seek to discover and develop or commercializeutilize in the future, ~~from major pharmaceutical companies, specialty pharmaceutical companies~~may require us or our collaborators to obtain a PMA.

The PMA process, including the gathering of clinical and ~~biotechnology companies worldwide. There~~preclinical data and the submission to and review by the FDA, involves a rigorous premarket review during which the sponsor must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling. PMA approval is not guaranteed and may take considerable time, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

Similar risks to those described above are also applicable to any companion diagnostic that we, or our collaborators, utilize in our clinical trials in connection with approval of a product candidate outside of the U.S. As a result, if we or our collaborators are required by the FDA or comparable foreign regulatory authoritiesto obtain approval of a companion diagnostic for a candidate therapeutic product, and we or our collaborators do not obtain or there are delays in obtaining approval of a diagnostic device, we will not be able to commercialize the product candidate and our ability to generate revenue will be materially impaired.

We may seek certain designations for our product candidates in or outside of the U.S., including Breakthrough Therapy, Fast Track and Priority Review designations, and PRIME Designation in the EU, but we might not receive such designations, and even if we do, such designations may not lead to a faster development or regulatory review or approval process.

We may seek certain designations for one or more of our product candidates that could expedite review and approval by the FDA. A Breakthrough Therapy product is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For products that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of ~~major pharmaceutical, specialty pharmaceutical and biotechnology companies that currently market and sell drugs~~patients placed in ineffective control regimens.

The FDA may also designate a product for Fast Track review if it is intended, whether alone or ~~are pursuing the development of drugs~~in combination with one or more other products, for the treatment of ~~cancer~~a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For Fast Track products, sponsors may have greater interactions with the FDA and the ~~other disease indications~~FDA may initiate review of sections of a Fast Track product’s application before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective.

We may also seek a Priority Review designation for ~~which we~~one or more of our product candidates. If the FDA determines that a product candidate offers major advances in treatment or provides a treatment where no adequate therapy exists, the FDA may designate the product candidate for priority review. A Priority Review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months.

These designations are ~~developing our drug candidates, although~~within the discretion of the FDA. Accordingly, even if we believe that to date, none of these competitive drugs and therapies currently in development are based on scientific approaches that are the same as our approach. Potential competitors also include academic institutions and governmental agencies and public and private research institutions.

We are initially focused on developing our current drug candidates for the treatment of cancer. There are a variety of available therapies marketed for cancer. In many cases, cancer drugs are administered in combination to enhance efficacy. Some of these drugs are branded and subject to patent protection, and others are available on a generic basis. Many of these approved drugs are well-established therapies and are widely accepted by physicians, patients and third-party payors. Insurers and other third-party payors may also encourage the use of generic drugs. We expect that if our drug candidates are approved, they will be priced at a significant premium over competitive generic drugs. This may make it difficult for us to achieve our business strategy of using our drug candidates in combination with existing therapies or replacing existing therapies with our drug candidates.

Our competitors may develop drugs that are more effective, safer, more convenient or less costly than any that we are developing or that would render our drug candidates obsolete or non-competitive. Our competitors may also obtain marketing approval from the FDA or other regulatory authorities for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

Many of our competitors have significantly greater financial resources and expertise in research and development, manufacturing, preclinical studies, conducting clinical trials, obtaining regulatory approvals and marketing approved drugs than we do. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or that may be necessary for, our programs.

Even if we are able to commercialize any drug candidates, the drugs may not receive coverage or may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, all of which would harm our business.

The legislation and regulations that govern marketing approvals, pricing and reimbursement for new drug products vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or drug licensing approval is granted. In some foreign markets, prescription

pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. In the United States, approval and reimbursement decisions are not linked directly, but there is increasing scrutiny from the Congress and regulatory authorities of the pricing of pharmaceutical products. As a result, we might obtain marketing approval for a drug in a particular country, but then be subject to price regulations that delay our commercial launch of the drug, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the drug in that country. Adverse pricing limitations may hinder our ability to recoup our investment in one ~~or more drug candidates, even if our drug candidates obtain marketing approval.~~

~~Significant uncertainty exists as to the coverage and reimbursement status~~ of our product candidates ~~for which we seek regulatory approval. Our ability to commercialize any drugs successfully will depend, in part, on~~meets the ~~extent to which reimbursement~~criteria for these ~~drugs~~designations, the FDA may disagree and ~~related treatments will be available from government health administration authorities, private health insurers and other organizations. Government authorities and third-party payors,~~instead determine not to make such designation. Further, even if we receive a designation, such as ~~private health insurers~~the recent receipt of Fast Track designation for eltanexor to treat myelodysplastic neoplasms, the receipt of such designation for a product candidate may not result in a faster development or regulatory review or approval process compared to products considered for approval under conventional FDA procedures and ~~health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. Obtaining and maintaining adequate reimbursement for~~does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualifies for these designations, the FDA may later decide that the product

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candidates no longer meet the conditions for qualification and rescind the designation or decide that the time period for FDA review or approval will not be shortened.

In the EU, we or our collaborators may seek PRIME designation for some of our product candidates in the future. PRIME is a voluntary program aimed at enhancing the EMA’s role to reinforce scientific and regulatory support in order to optimize development and enable accelerated assessment of new medicines that are of major public health interest with the potential to address unmet medical needs. The program focuses on medicines that target conditions for which there exists no satisfactory method of treatment in the EU or even if ~~approved,~~such a method exists, it may offer a major therapeutic advantage over existing treatments. PRIME is limited to medicines under development and not authorized in the EU and the sponsor intends to apply for an initial MAA through the centralized procedure. To be ~~difficult. Moreover, the process~~accepted for ~~determining whether a third-party payor will provide coverage for~~PRIME, a product ~~may be separate from~~candidate must meet the ~~process for setting~~eligibility criteria with respect to its major public health interest and therapeutic innovation based on information that is capable of substantiating the ~~price~~claims. The benefits of a ~~product or for establishing~~PRIME designation include the ~~reimbursement rate that such~~appointment of a ~~payor will pay for the product. Further, one payor’s determination~~CHMP rapporteur to provide ~~coverage~~continued support and help to build knowledge ahead of a MAA, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review, meaning reduction in the review time for an opinion on approvability to be issued earlier in the application process. PRIME enables a sponsor to request parallel EMA scientific advice and health technology assessment advice to facilitate timely market access. Even if we or our collaborators receive PRIME designation for any of our product candidates, the designation may not result in a materially faster development process, review or approval compared to conventional EMA procedures. Further, obtaining PRIME designation does not assure ~~that other payors will also provide coverage and reimbursement for our products, if they are approved, by third-party payors.~~or increase the likelihood of the EMA’s grant of a marketing authorization.

A primary trend in the healthcare industry in the United States and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. Third-party payors may also seek, with respect to an approved product, additional clinical evidence that goes beyond the data required to obtain marketing approval. They may require such evidence to demonstrate clinical benefits and value in specific patient populations or they may call for costly pharmaceutical studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies before covering our products. Accordingly, we cannot be sure that reimbursement will be available for any drug that we commercialize and, if reimbursement is available, we cannot be sure as to the level of reimbursement and whether it will be adequate. Coverage and reimbursement may impact the demand for, or the price of, any drug candidate for which we obtain marketing approval. If reimbursement is not available or is available only at limited levels, weWe may not be able to ~~successfully commercialize~~obtain orphan drug exclusivity for any product candidates we may develop, and even if we do, that exclusivity may not prevent the FDA or the EMA from approving other competing products.

Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition. A similar regulatory scheme governs approval of orphan products by the EMA in the EU. Generally, if a product candidate with an Orphan Drug Designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA or the EMA, as applicable, from approving another marketing application for the same product for the same therapeutic indication for that time period. The applicable period is seven years in the U.S. and ten years in the EU. The exclusivity period in the EU can be reduced to six years if a product no longer meets the criteria for Orphan Drug Designation, in particular if the product is sufficiently profitable so that market exclusivity is no longer justified.

In order for the FDA to grant orphan drug exclusivity to one of our products, the agency must find that the product is indicated for the treatment of a condition or disease with a patient population of fewer than 200,000 individuals annually in the U.S. The FDA may conclude that the condition or disease for which we seek orphan drug exclusivity does not meet this standard. Even if we obtain ~~marketing approval.~~orphan drug exclusivity for a product, such as the recent receipt of orphan drug exclusivity for selinexor for the treatment of myelofibrosis, that exclusivity may not effectively protect the product from competition because different products can be approved for the same condition. In addition, even after an orphan drug is approved, the FDA and comparable foreign regulatory authorities, such as the EMA, can subsequently approve the same product for the same condition if the FDA or such other authorities conclude that the later product is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care. Orphan drug exclusivity may also be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition.

~~There~~In 2017, the Congress passed the FDA Reauthorization Act of 2017 (“FDARA”). FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity. Under omnibus legislation signed by former President Trump in December 2020, the requirement for a product to show clinical superiority applies to drugs and biologics that received Orphan Drug Designation before the enactment of FDARA in 2017, but have not yet been approved or licensed by the FDA.

The FDA and Congress may further reevaluate the Orphan Drug Act and its regulations and policies. This may be ~~significant delays~~particularly true in ~~obtaining reimbursement~~light of a decision from the Court of Appeals for ~~newly-approved drugs,~~the 11th Circuit in September 2021 finding that, for the purpose of determining the scope of exclusivity, the term “same disease or condition” means the designated “rare disease or condition” and ~~coverage may~~could not be ~~more limited~~interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” Although there have been legislative proposals to overrule this decision, they have not been enacted into law. On January 23, 2023, the FDA announced that, in matters beyond the scope of that court order, the FDA will continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved. We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the

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future or whether Congress will take legislative action, and it is ~~approved by~~uncertain how any changes might affect our business. Depending on what changes the FDA or ~~comparable regulatory authorities outside~~Congress may make to orphan drug regulations and policies, our business could be adversely impacted.

Inadequate funding for the FDA, the SEC and other government agencies, including from government shut downs, or other disruptions to these agencies’ operations, could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.

The ability of the ~~United States. Moreover, eligibility for reimbursement does not imply that any drug will~~FDA to review and approve new products can be ~~paid for~~affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory and policy changes. Average review times at the agency have fluctuated in ~~all cases or~~recent years as a result. Disruptions at ~~a rate that covers our costs, including research, development, manufacture, sale~~the FDA and ~~distribution. Interim reimbursement levels~~other agencies may also slow the time necessary for new ~~drugs, if applicable,~~product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. In addition, government funding of the SEC and other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. For example, over the last several years the U.S. government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical employees and stop critical activities. On January 30, 2023, the Biden Administration announced that it will end the public health emergency declarations related to COVID-19 on May 11, 2023. Thereafter, on March 13, 2023, the FDA announced that it will end 22 COVID-19-related policies when the public health emergency ends May 11 and allow 22 to continue for 180 days. The FDA plans to retain 24 COVID-19-related policies with appropriate changes and four whose duration is not ~~be sufficient to cover our costs and may not be made permanent. Reimbursement rates may vary according~~tied to the ~~use~~end of the ~~drug and the clinical setting in which~~public health emergency. At this point, it is ~~used, may be based on reimbursement levels already set for lower cost drugs~~unclear how, if at all, these developments will impact our efforts to develop and ~~may be incorporated into existing payments for other services. Net prices for drugs may be reduced by mandatory discounts or rebates required by~~commercialize our products and product candidates. Nonetheless, if a prolonged government ~~healthcare programs or private payors~~shutdown occurs, it could significantly impact the ability of the FDA to timely review and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved drugs that we developprocess our regulatory submissions, which could have a material adverse effect on our ~~operating results,~~business. Further, future government shutdowns could impact our ability to ~~raise~~access the public markets and obtain necessary capital ~~needed~~in order to ~~commercialize drugs~~properly capitalize and continue our ~~overall financial condition.~~operations.

~~Product liability lawsuits against us could cause us to incur substantial liabilities and to limit commercialization of any drugs that we may develop.~~

~~We face an inherent risk of product liability exposure related~~Separately, in response to the ~~testing~~COVID-19 pandemic, a number of ~~our drug candidates~~companies in ~~human clinical trials~~2021 and will face an even greater risk if we commercially sell any drugs that we may develop. If we cannot successfully defend ourselves against claims that our drug candidates or drugs caused injuries, we will incur substantial liabilities. Regardless2022 announced receipt of ~~merit or eventual outcome, liability claims may result in:~~

~~decreased demand for any drug candidates or drugs that we may develop;~~

~~injury~~complete response letters due to ~~our reputation and significant negative media attention;~~

~~withdrawal of clinical trial participants;~~

~~significant costs to defend~~ the ~~related litigation;~~

~~substantial monetary awards to trial participants or patients;~~

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~~loss of revenue;~~

~~reduced resources of our management to pursue our business strategy; and~~

~~the~~FDA’s inability to ~~commercialize any drugs that we may develop.~~

~~We currently hold clinical trial liability insurance coverage, but that coverage may not be adequate to cover any~~complete required inspections for their applications. Although the FDA has now resumed domestic and all liabilities that we may incur. We would need to increase our insurance coverage when we begin the commercialization of our drug candidates, if ever. Insurance coverage is increasingly expensive. Weforeign inspections, it may not be able to ~~maintain insurance coverage at~~continue its current pace and review timelines could be extended, including where a ~~reasonable~~pre-approval inspection or an inspection of clinical sites is required. Regulatory authorities outside the U.S. may adopt similar restrictions or other policy measures in response to the COVID-19 pandemic and may experience delays in their regulatory activities. If a prolonged government shutdown or other disruption occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Future shutdowns or other disruptions could also affect other government agencies such as the SEC, which may also impact our business by delaying review of our public filings, to the extent such review is necessary, and our ability to access the public markets.

Current and future legislation may increase the difficulty and cost for us, or ~~in an amount adequate~~any collaborators, to ~~satisfy~~obtain marketing approval and commercialize our or their product candidates, if approved, and affect the prices we, or they, may obtain.

In the U.S. and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our or our collaborators’ product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any ~~liability~~collaborators, to profitably sell or commercialize XPOVIO or any product candidate for which we, or they, obtain marketing approval. We expect that current laws, as well as other healthcare reform measures that may ~~arise.~~

~~The business~~be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, ~~conduct outside~~or any collaborators, may receive for any approved products. If reimbursement of our products is unavailable or limited in scope, our business could be materially harmed.

In March 2010, President Obama signed into law the ~~United States~~Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act (collectively the “PPACA”). In addition, other legislative changes have been proposed and adopted since the PPACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2031. Pursuant to the Coronavirus Aid, Relief and Economic Security Act (the “CARES Act”) and subsequent legislation, these Medicare

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sequester reductions were reduced and suspended, with the full 2% cut resuming in July 2022. The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. Further, with the passage of the Inflation Reduction Act (the “IRA”) in August 2022, Congress extended the expansion of PPACA premium tax credits through 2025.

These and other laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our products or product candidates for which we may obtain regulatory approval or the frequency with which any such product is prescribed or used. For example, the Consolidated Appropriations Act, which was signed into law by President Biden in December 2022, made several changes to sequestration of the Medicare program. Section 1001 of the Act delays the 4% Statutory Pay-As-You-Go Act of 2010 (PAYGO) sequester for two years, through the end of calendar year 2024. Triggered by enactment of the American Rescue Plan Act of 2021, the 4% cut to the Medicare program would have taken effect in January 2023. The Act’s health care offset title includes Section 4163, which extends the 2% Budget Control Act of 2011 Medicare sequester for six months into FY 2032 and lowers the payment reduction percentages in FYs 2030 and 2031.

Since enactment of the PPACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law. For example, with the enactment of the Tax Cuts and Jobs Act of 2017 (the “TCJA”), Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019. Further, in December 2018, a U.S. District Court judge in the Northern District of Texas ruled that the individual mandate portion of the PPACA is an essential and inseverable feature of the PPACA, and therefore because the mandate was repealed as part of the TCJA, the remaining provisions of the PPACA are invalid as well. The U.S. Supreme Court heard this case in November 2020 and, in June 2021, dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the PPACA. Litigation and legislation over the PPACA are likely to continue, with unpredictable and uncertain results.

The Trump Administration also took executive actions to undermine or delay implementation of the PPACA, including directing federal agencies with authorities and responsibilities under the PPACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the PPACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices. In January 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access. Under this Executive Order, federal agencies are directed to re-examine: policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19; demonstrations and waivers under Medicaid and the PPACA that may reduce coverage or undermine the programs, including work requirements; policies that undermine the health insurance marketplace or other markets for health insurance; policies that make it more difficult to enroll in Medicaid and the PPACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.

We expect that these healthcare reforms, as well as other healthcare reform measures that may be ~~adversely affected by international risk and uncertainties.~~

~~Although our operations are based~~adopted in the ~~United States,~~future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria and new payment methodologies that govern XPOVIO or any other approved product and/or the level of reimbursement physicians receive for administering XPOVIO or any other approved product we, ~~conduct business outside~~or our collaborators, might bring to market. Reductions in reimbursement levels may negatively impact the ~~United States~~prices we receive or the frequency with which our products are prescribed or administered. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. Accordingly, such reforms, if enacted, could have an adverse effect on anticipated revenue from XPOVIO or from product candidates for which we may obtain marketing approval and ~~expect~~may affect our overall financial condition and ability to ~~continue to do so~~develop or commercialize product candidates.

The prices of prescription pharmaceuticals in the ~~future. For instance,~~U.S. and foreign jurisdictions are subject to considerable legislative and executive actions and could impact the prices we obtain for our products, if and when licensed.

The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the U.S. There have been several recent U.S. congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid. In 2020, former President Trump issued several executive orders intended to lower the costs of prescription products and certain provisions in these orders have been incorporated into regulations. These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021. That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, the Centers for Medicare & Medicaid Services (“CMS”) issued a final rule to rescind it. With issuance of this rule, CMS

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stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries’ access to evidence-based care.

In addition, in October 2020, the Department of Health and Human Services (the “HHS”) and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program (“SIP”) to import certain prescription drugs from Canada into the U.S. The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA. Further, in November 2020, the HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers. The final rule would also eliminate the current safe harbor for Medicare drug rebates and create new safe harbors for beneficiary point-of-sale discounts and pharmacy benefit manager service fees. It originally was set to go into effect on January 1, 2022, but with passage of the IRA has been delayed by Congress to January 1, 2032.

In July 2021, President Biden signed Executive Order 14063, which focuses on, among other things, the price of pharmaceuticals. The Order directs the HHS to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such pharmaceuticals, and to address the recurrent problem of price gouging.” In September 2021, the HHS released its plan to reduce pharmaceutical prices. The key features of that plan are to: (a) make pharmaceutical prices more affordable and equitable for all consumers and throughout the health care system by supporting pharmaceutical price negotiations with manufacturers; (b) improve and promote competition throughout the prescription pharmaceutical industry by supporting market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase transparency; and (c) foster scientific innovation to promote better healthcare and improve health by supporting public and private research and making sure that market incentives promote discovery of valuable and accessible new treatments.

More recently, on August 16, 2022, the IRA was signed into law by President Biden. The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025). The IRA permits the Secretary of the HHS to implement many of these provisions through guidance, as opposed to regulation, for the ~~sites~~initial years.

Specifically, with respect to price negotiations, Congress authorized Medicare to negotiate lower prices for certain costly single-source drug and biologic products that do not have competing generics or biosimilars and are reimbursed under Medicare Part B and Part D. CMS may negotiate prices for ten high-cost drugs paid for by Medicare Part D starting in 2026, followed by 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028, and 20 Part B or Part D drugs in 2029 and beyond. This provision applies to drug products that have been approved for at ~~which our clinical trials~~least nine years and biologics that have been licensed for 13 years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition. Further, the legislation subjects drug manufacturers to civil monetary penalties and a potential excise tax for failing to comply with the legislation by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law or for taking price increases that exceed inflation. The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation. The new law also caps Medicare out-of-pocket drug costs at an estimated $4,000 a year in 2024 and, thereafter beginning in 2025, at $2,000 a year.

At the state level, individual states are ~~being conducted are located outside the United States.~~increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. In addition, ~~we plan~~regional healthcare organizations and individual hospitals are increasingly using bidding procedures to ~~seek approvals to sell~~determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing. We expect that additional state and federal healthcare reform measures will be adopted in ~~foreign countries. Any business~~the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

Finally, outside of the U.S., in some nations, including those of the EU, the pricing of prescription pharmaceuticals is subject to governmental control and access. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in some countries, we, or our collaborators, may be required to conduct a clinical trial that compares the cost-effectiveness of our product to other available therapies.

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These measures, as well as others adopted in the future, may result in additional downward pressure on the price that we ~~conduct outside the United States~~receive for XPOVIO or any other approved product we or our collaborators might bring to market. Accordingly, such reforms, if enacted, could have an adverse effect on anticipated revenue from XPOVIO or from product candidates that we, or our collaborators, may successfully develop and for which we, or they, may obtain marketing approval and may affect our overall financial condition and ability to develop or commercialize product candidates.

Our relationships with healthcare providers, physicians and third-party payers will be subject to ~~additional risks~~applicable anti-kickback, fraud and abuse, and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare professionals, including but not limited to physicians, nurses, medical directors, hospitals, pharmacies, pharmacy benefit managers, group purchasing organizations, wholesalers, insurers, and all individuals employed by such entities (collectively, “HCPs”), may influence the recommendation and prescription of our approved products. Our arrangements with HCPs and others who have the ability to influence the recommendation and prescription of our products may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute our medicines for which we obtain marketing approval. Restrictions under applicable federal and state healthcare laws and regulations include the following:

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the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order, or recommendation of, any good or service, for which payment may be made under federal and state healthcare programs such as Medicare and Medicaid;

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the FCA imposes criminal and civil penalties, including civil whistleblower or qui tam actions, against individuals or entities for knowingly presenting or causing to be presented, to the federal government, claims for payment or approval from Medicare, Medicaid or other government payers that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties;

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the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as further amended by the Health Information Technology for Economic and Clinical Health Act, which imposes certain requirements, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information without appropriate authorization by entities subject to the rule, such as health plans, healthcare clearinghouses and healthcare providers;

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the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;

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the federal transparency requirements under the federal Physician Payment Sunshine Act, which requires manufacturers of drugs, devices, biologics and medical supplies to report to the HHS, information related to payments and other transfers of value to physicians, other healthcare providers and teaching hospitals and ownership and investment interests held by physicians and their immediate family members and applicable group purchasing organizations; and

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analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payers, including private insurers, and certain state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug manufacturers to report information related to payments to physicians and other healthcare providers or marketing expenditures.

Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws. If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, imprisonment and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations and prospects.

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our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations. If any of the physicians or other providers or entities with whom we expect to do business are found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs. Liabilities they incur pursuant to these laws could result in significant costs or an interruption in operations, which could have a material adverse effect on our business, financial condition, results of operations and prospects.

Our reporting and payment obligations under the Medicaid Drug Rebate Program and other governmental drug pricing programs are complex and may involve subjective decisions. Any failure to comply with those obligations could subject us to penalties and sanctions.

As a condition of reimbursement by various federal and state health insurance programs, we are required to calculate and report certain pricing information to federal and state agencies. The regulations governing the calculations, price reporting and payment obligations are complex and subject to interpretation by various government and regulatory agencies, as well as the courts. Reasonable assumptions have been made where there is lack of regulations or clear guidance and such assumptions involve subjective decisions and estimates. We are required to report any revisions to our calculation, price reporting and payment obligations previously reported or paid. Such revisions could affect our liability to federal and state payers and also adversely impact our reported financial results of operations in the period of such restatement. Further, a number of states have either implemented or are considering implementation of drug price transparency legislation that may prevent or limit our ability to take price increases at certain rates or frequencies. Requirements under such laws include advance notice of planned price increases, reporting price increase amounts and factors considered in taking such increases, wholesale acquisition cost information disclosure to prescribers, purchasers, and state agencies, and new product notice and reporting. Such legislation could limit the price or payment for certain drugs, and a number of states are authorized to impose civil monetary penalties or pursue other enforcement mechanisms against manufacturers for the untimely, inaccurate, or incomplete reporting of drug pricing information or for otherwise failing to comply with drug price transparency requirements. If we are found to have violated state law requirements, we may become subject to significant penalties or other enforcement mechanisms, which could have a material adverse effect on our business.

Uncertainty exists as new laws, regulations, judicial decisions, or new interpretations of existing laws, or regulations related to our calculations, price reporting or payments obligations increases the chances of a legal challenge, restatement or investigation. If we become subject to investigations, restatements, or other inquiries concerning our compliance with price reporting laws and regulations, we could be required to pay or be subject to additional reimbursements, penalties, sanctions or fines, which could have a material adverse effect on our business, financial condition and results of operations. In addition, it is possible that future healthcare reform measures could be adopted, which could result in increased pressure on pricing and reimbursement of our products and thus have an adverse impact on our financial position or business operations.

Further, state Medicaid programs may be slow to invoice pharmaceutical companies for calculated rebates resulting in a lag between the time a sale is recorded and the time the rebate is paid. This results in us having to carry a liability on our consolidated balance sheets for the estimate of rebate claims expected for Medicaid patients. If actual claims are higher than current estimates, our financial position and results of operations could be adversely affected.

In addition to retroactive rebates and the potential for 340B Program refunds, if we are found to have knowingly submitted any false price information related to the Medicaid Drug Rebate Program to CMS, we may be liable for civil monetary penalties. Such failure could also be grounds for CMS to terminate our Medicaid drug rebate agreement, pursuant to which we participate in the Medicaid program. In the event that CMS terminates our rebate agreement, federal payments may not be available under government programs, including Medicaid or Medicare Part B, for our covered outpatient drugs.

Additionally, if we overcharge the government in connection with the Federal Supply Schedule pricing program or Tricare Retail Pharmacy Program, whether due to a misstated Federal Ceiling Price or otherwise, we are required to refund the difference to the government. Failure to make necessary disclosures and/or to identify contract overcharges can result in allegations against us under the FCA and other laws and regulations. Unexpected refunds to the government, and responding to a government investigation or enforcement action, would be expensive and time-consuming, and could have a material adverse effect on our business, financial condition, results of operations and growth prospects.

Our collaborators are also subject to similar requirements outside of the U.S. and thus the attendant risks and uncertainties. If our collaborators suffer material and adverse effects from such risks and uncertainties, our rights and benefits for our licensed products could be negatively impacted, which could have a material and adverse impact on our revenues.

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We are subject to stringent privacy laws, information security laws, regulations, policies and contractual obligations related to data privacy and security and changes in such laws, regulations, policies, contractual obligations and failure to comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.

We are subject to data privacy and protection laws and regulations that apply to the collection, transmission, storage and use of personally-identifying information, which among other things, impose certain requirements relating to the privacy, security and transmission of personal information, including comprehensive regulatory systems in the U.S., EU, UK and other countries in which we may conduct business. The legislative and regulatory landscape for privacy and data protection continues to evolve in jurisdictions worldwide, and there has been an increasing focus on privacy and data protection issues with the potential to affect our business. Failure to comply with any of these laws and regulations could result in enforcement action against us, including fines, imprisonment of company officials and public censure, claims for damages by affected individuals, damage to our reputation and loss of goodwill, any of which could have a material adverse effect on our business, financial condition, results of operations or prospects.

There are numerous U.S. federal and state laws and regulations related to the privacy and security of personal information. In particular, regulations promulgated pursuant to HIPAA establish privacy and security standards that limit the use and disclosure of individually identifiable health information, or protected health information, and require the implementation of administrative, physical and technological safeguards to protect the privacy of protected health information and ensure the confidentiality, integrity and availability of electronic protected health information. Determining whether protected health information has been handled in compliance with applicable privacy standards and our contractual obligations can be complex and may be subject to changing interpretation. These obligations may be applicable to some or all of our business activities now or in the future.

If we are unable to properly protect the privacy and security of protected health information, we could be found to have breached our contracts. Further, if we fail to comply with applicable privacy laws, including applicable HIPAA privacy and security standards, we could face civil and criminal penalties. HHS enforcement activity can result in financial liability and reputational harm, and responses to such enforcement activity can consume significant internal resources. In addition, state attorneys general are authorized to bring civil actions seeking either injunctions or damages in response to violations that threaten the privacy of state residents. We cannot be sure how these regulations will be interpreted, enforced or applied to our operations in the future. In addition to the risks associated with enforcement activities and potential contractual liabilities, our ongoing efforts to comply with evolving laws and regulations at the federal and state level may be costly and require ongoing modifications to our policies, procedures and systems.

In 2018, California passed into law the California Consumer Privacy Act (the “CCPA”), which took effect on January 1, 2020 and imposed many requirements on businesses that process the personal information of California residents. Many of the CCPA’s requirements are similar to those found in the European General Data Protection Regulation (the “GDPR”), including requiring businesses to provide notice to data subjects regarding the information collected about them and how such information is used and shared, and providing data subjects the right to request access to such personal information and, in certain cases, request the erasure of such personal information. The CCPA also affords California residents the right to opt-out of “sales” of their personal information. The CCPA contains significant penalties for companies that violate its requirements. In November 2020, California voters passed a ballot initiative for the California Privacy Rights Act (the “CPRA”), which went into effect on January 1, 2023 and significantly expanded the CCPA to incorporate additional GDPR-like provisions including requiring that the use, retention, and sharing of personal information of California residents be reasonably necessary and proportionate to the purposes of collection or processing, granting additional protections for sensitive personal information, and requiring greater disclosures related to notice to residents regarding retention of information. The CPRA also created a new enforcement agency – the California Privacy Protection Agency – whose sole responsibility is to enforce the CPRA, which will further increase compliance risk. The provisions in the CPRA may apply to some of our business activities. In addition, other states, including Virginia, Colorado, Utah, and Connecticut already have passed state privacy laws with potentially different requirements. Virginia’s privacy law also went into effect on January 1, 2023, and the laws in the other three states will go into effect later in the year. There are also states that are strongly considering or have already passed comprehensive privacy laws during the 2023 legislative sessions that will go into effect in 2024 and beyond, including Indiana, Montana, and Tennessee. Other states will be considering these laws in the future, and Congress has also been debating passing a federal privacy law. There are also states that are specifically regulating health information that may affect our business. For example, Washington state is on the verge of passing a health privacy law that will regulate the collection and sharing of health information, and the law would also have a private right of action, which would further increase the relevant compliance risk. In addition to compliance costs, these laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products.

Similar to the laws in the U.S., there are significant privacy and data security laws that apply in Europe and other countries. The collection, use, disclosure, transfer, or other processing of personal data, including personal health data, regarding individuals who are located in the European Economic Area (“EEA”), and the processing of personal data that takes place in the EEA, is regulated by the

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GDPR, which went into effect in May 2018 and which imposes obligations on companies that operate in our industry with respect to the processing of personal data and the cross-border transfer of such data. The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing and policies. If our or our partners’ or service providers’ privacy or data security measures fail to comply with the GDPR requirements, we may be subject to litigation, regulatory investigations, enforcement notices requiring us to change the way we use personal data and/or fines of up to 20 million Euros or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, as well as compensation claims by affected individuals, negative publicity, reputational harm and a potential loss of business and goodwill.

The GDPR places restrictions on the cross-border transfer of personal data from the EU to countries that have not been found by the EC to offer adequate data protection legislation, such as the U.S. There are ongoing concerns about the ability of companies to transfer personal data from the EU to other countries. In July 2020, the Court of Justice of the EU (the “CJEU”) invalidated the EU-U.S. Privacy Shield, one of the mechanisms used to legitimize the transfer of personal data from the EEA to the U.S. The CJEU decision also drew into question the long-term viability of an alternative means of data transfer, the standard contractual clauses, for transfers of personal data from the EEA to the U.S. This CJEU decision may lead to increased scrutiny on data transfers from the EEA to the U.S. generally and increase our costs of compliance with data privacy legislation as well as our costs of negotiating appropriate privacy and security agreements with our vendors and business partners.

Additionally, in October 2022, President Biden signed an executive order to implement the EU-U.S. Data Privacy Framework, which would serve as a replacement to the EU-US Privacy Shield. The EC initiated the process to adopt an adequacy decision for the EU-US Data Privacy Framework in December 2022. It is unclear if and when the framework will be finalized and whether it will be challenged in court. The uncertainty around this issue may further impact our business operations in the EU.

Following the withdrawal of the UK from the EU, the UK Data Protection Act 2018 applies to the processing of personal data that takes place in the UK and includes parallel obligations to those set forth by GDPR. In relation to data transfers, both the UK and the EU have determined, through separate “adequacy” decisions, that data transfers between the two jurisdictions are in compliance with the UK Data Protection Act and the GDPR, respectively. Any changes or updates to these adequacy decisions have the potential to impact our business.

Beyond GDPR, there are privacy and data security laws in a growing number of countries around the world. While many loosely follow GDPR as a model, other laws contain different or conflicting provisions. These laws will impact our ability to conduct our business activities, including both our clinical trials and the sale and distribution of commercial products, through increased compliance costs, costs associated with contracting and potential enforcement actions.

While we continue to address the implications of the recent changes to data privacy regulations, data privacy remains an evolving landscape at both the domestic and international level, with new regulations coming into effect and continued legal challenges, and our efforts to comply with the evolving data protection rules may be unsuccessful. It is possible that these laws may be interpreted and applied in ~~international markets, including:~~

~~potentially reduced~~a manner that is inconsistent with our practices. We must devote significant resources to understanding and complying with this changing landscape. Failure to comply with laws regarding data protection ~~for intellectual property rights;~~

would expose us to risk of enforcement actions taken by data protection authorities in the EEA and elsewhere and carries with it the potential for ~~so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts~~significant penalties if we are found to ~~import goods from a foreign market (with low or lower prices) rather than buying them locally;~~

~~unexpected changes in tariffs, trade barriers and regulatory requirements;~~

~~economic weakness, including inflation, volatility in currency exchange rates or political instability in particular foreign economies and markets;~~

~~workforce uncertainty in countries where labor unrest is more common than in the United States;~~

~~production shortages resulting from any events affecting a product candidate and/or finished drug product supply or manufacturing capabilities abroad;~~

~~business interruptions resulting from geo-political actions, including war and terrorism, or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires; and~~

be non-compliant. Similarly, failure to comply with federal and state laws in the U.S. regarding privacy and security of personal information could expose us to penalties under such laws. Any such failure to comply with data protection and privacy laws could result in government-imposed fines or orders requiring that we change our practices, claims for damages or other liabilities, regulatory investigations and enforcement action, litigation and significant costs for remediation, any of which could adversely affect our business. Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our business, financial condition, results of operations or prospects.

Our employees, independent contractors, consultants, collaborators and vendors may engage in misconduct or other improper activities, including non-compliance with regulatory standards and/or requirements and insider trading, which could cause significant liability for us and harm our reputation.

We are exposed to the risk of fraud or other misconduct by our employees, independent contractors, consultants, collaborators and vendors. Misconduct by these partners could include intentional, reckless and/or negligent conduct or unauthorized activities that violate FDA regulations or similar regulations of comparable foreign regulatory authorities; provide inaccurate information to the FDA or comparable foreign regulatory authorities; fail to comply with manufacturing standards, federal and state healthcare fraud and abuse laws and regulations and similar laws and regulations established and enforced by comparable foreign regulatory authorities; fail to comply with state drug pricing transparency filing requirements; fail to report financial information or data accurately; or fail to disclose unauthorized activities to us. Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. This could include violations of

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HIPAA, other U.S. federal and state laws, and requirements of foreign jurisdictions, including the GDPR. We are also exposed to risks in connection with any insider trading violations by employees or others affiliated with us. It is not always possible to identify and deter employee or third-party misconduct, and the precautions we take to detect and prevent these activities may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from significant penalties, governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards, regulations, guidance or codes of conduct. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and results of operations, including the imposition of significant fines or other sanctions.

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals and biological and radioactive materials. Our operations also produce hazardous waste products. We generally contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties.

Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological, hazardous or radioactive materials.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or commercialization efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.

Laws and regulations governing international operations we may have in the future may preclude us from developing, manufacturing and selling certain products outside of the U.S. and require us to develop and implement costly compliance programs.

We are subject to numerous laws and regulations in each jurisdiction outside of the U.S. in which we operate. The creation, implementation and maintenance of international business practices compliance programs is costly and such programs are difficult to enforce, particularly where reliance on third parties is required.

The FCPA prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the U.S. to comply with certain accounting provisions requiring us to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls. The FCPA is enforced by the DOJ and the SEC.

Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem. In addition, the FCPA presents particular challenges in the pharmaceutical industry, because, in many countries, hospitals, clinics, universities and similar institutions are operated by the government, and doctors and other healthcare professionals are considered foreign officials. Certain payments to healthcare professionals in connection with clinical trials, regulatory approvals, sales and marketing, and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions. Because the FCPA applies to indirect payments, the use of third parties and other collaborators can increase potential FCPA risk, as we could be held liable for the acts of third parties that do not comply with the FCPA’s requirements.

The failure to comply with laws governing international business practices may result in substantial penalties, including suspension or debarment from government contracting. Violation of the FCPA can result in significant civil and criminal penalties. Indictment alone under the FCPA can lead to suspension of the right to do business with the U.S. government until the pending claims are resolved. Conviction of a violation of the FCPA can result in long-term disqualification as a government contractor. The termination of a government contract or relationship as a result of our failure to satisfy any of our obligations under laws governing international business practices would have a negative impact on our operations and harm our reputation and ability to procure

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government contracts. The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions.

Like the FCPA, the UK Bribery Act and other anti-corruption laws throughout the world similarly prohibit offers and payments made to obtain improper business advantages, including offers or payments to healthcare professionals and other government and non-government officials. These other anti-corruption laws also can result in substantial financial penalties and other collateral consequences.

Various laws, regulations and executive orders also restrict the use and dissemination outside of the U.S., or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. Our expansion outside of the U.S., has required, and will continue to require, us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain drugs and product candidates outside of the U.S., which could limit our growth potential and increase our development costs.

With the passage of the CREATES Act, we are exposed to possible litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of their ANDAs and 505(b)(2) applications.

In December 2019, former President Trump signed legislation intended to facilitate the development of generic and biosimilar products. The bill, previously known as the CREATES Act, authorizes sponsors of abbreviated new drug applications (“ANDAs”) and 505(b)(2) applications to file lawsuits against companies holding NDAs that decline to provide sufficient quantities of an approved reference drug on commercially reasonable, market-based terms. Drug products on FDA’s drug shortage list are exempt from these new provisions unless the product has been on the list for more than six continuous months or the FDA determines that the supply of the product will help alleviate or prevent a shortage.

To bring an action under the statute, an ANDA or 505(b)(2) sponsor must take certain steps to request the reference product, which, in the case of products covered by a Risk Evaluation and Mitigation Strategy with elements to assure safe use, include obtaining authorization from the FDA for the acquisition of the reference product. If the sponsor does bring an action for failure to provide a reference product, there are certain affirmative defenses available to the NDA holder, which must be shown by a preponderance of evidence. If the sponsor prevails in litigation, it is entitled to a court order directing the NDA holder to provide, without delay, sufficient quantities of the applicable product on commercially reasonable, market-based terms, plus reasonable attorney fees and costs.

Additionally, the new statutory provisions authorize a federal court to award the product developer an amount “sufficient to deter” the NDA holder from refusing to provide sufficient product quantities on commercially reasonable, market-based terms if the court finds, by a preponderance of the evidence, that the NDA holder did not have a legitimate business justification to delay providing the product or failed to comply with the court’s order. For the purposes of the statute, the term “commercially reasonable, market-based terms” is defined as (1) the nondiscriminatory price at or below the most recent wholesale acquisition cost for the product, (2) a delivery schedule that meets the statutorily defined timetable, and (3) no additional conditions on the sale.

Although we intend to comply fully with the terms of these statutory provisions, we are still exposed to potential litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of ANDAs and 505(b)(2) applications. Such litigation would subject us to additional litigation costs, damages and reputational harm, which could lead to lower revenues. The CREATES Act may enable generic competition with XPOVIO and any of our product candidates, if approved, which could impact our ability to maximize product revenue.

We are subject to governmental export and import controls that could impair our or our collaborators’ ability to compete in international markets due to licensing requirements and subject us or them to liability if we or they are not in compliance with applicable laws.

Our products are subject to export control and import laws and regulations, including the U.S. Export Administration Regulations, U.S. Customs regulations, and various economic and trade sanctions regulations administered by the U.S. Treasury Department’s Office of Foreign ~~Asset Control rules~~Assets Controls. Exports of our products outside of the U.S. must be made in compliance with these laws and regulations. If we or our collaborators fail to comply with these laws and regulations, we or they and certain of our or their employees could be subject to substantial civil or criminal penalties, including the possible loss of export or import privileges; fines, which may be imposed on us or our collaborators and the ~~Foreign Corrupt Practices Act,~~respective responsible employees or ~~FCPA.~~managers; and, in extreme cases, the incarceration of responsible employees or managers.

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In addition, changes in our products or changes in applicable export or import laws and regulations may create delays in the introduction, provision, or sale of our products in international markets, prevent customers from using our products or, in some cases, prevent the export or import of our products to certain countries, governments or persons altogether. Any limitation on our ability to export, provide, or sell our products could adversely affect our business, financial condition and results of operations.

Risks Related to Our Financial Position and ~~Need for Additional~~ Capital Requirements

We have incurred significant losses since ~~inception. We~~inception, expect to continue to incur significant losses, ~~for the foreseeable future~~ and may never achieve or maintain profitability.

Since inception, we have incurred significant operating losses. Our net loss was ~~$30.6~~$34.1 million for the ~~three months~~quarter ended ~~September 30, 2017.~~March 31, 2023. As of ~~September 30, 2017,~~March 31, 2023, we had an accumulated deficit of ~~$456.3 million.~~$1.4 billion. Although we received our first FDA-approval for XPOVIO in July 2019, we may never attain profitability or positive cash flows from operations. We have ~~not generated any revenue to date from sales of any drugs and have~~historically financed our operations principally through product sales, private placements of our preferred and common stock, proceeds from our initial public offering and ~~public~~follow-on offerings of common stock, proceeds from the issuance of convertible debt, proceeds from a revenue interest financing agreement, proceeds from sales of common stock under our ~~common stock. We have devoted substantially~~“at the market offering” program and cash generated from our business development activities. Substantially all of our ~~efforts to~~operating losses have resulted from costs incurred in connection with our research and ~~development. Our lead drug candidate, oral selinexor (KPT-330)~~development programs, the pursuit of regulatory approvals within and outside of the U.S., ~~as well as verdinexor (KPT-335), KPT-8602~~ and ~~KPT-9274, are in clinical development and our other drug candidates for~~ the ~~treatment~~commercialization of human disease are in preclinical development. As a result, we expect that it will be several years, if ever, before we have a drug candidate ready for commercialization for the treatment of human disease.XPOVIO. We expect to continue to incur significant expenses and ~~increasing~~ operating losses as we continue to commercialize XPOVIO in the U.S. and engage in activities to prepare for the ~~foreseeable future.~~potential approval and commercialization of additional indications for selinexor and eltanexor as well as our other product candidates. The net losses we incur may fluctuate significantly from quarter to quarter. ~~We anticipate that~~

While we began to generate revenue from the sales of XPOVIO in July 2019 and have received revenue from our ~~expenses will increase substantially if and~~license arrangements, such as ~~we:~~

~~continue our research and preclinical and clinical development of our drug candidates;~~

~~initiate additional clinical trials~~the partnership we have with Antengene Therapeutics Limited (“Antengene”) for our ~~drug candidates;~~

~~seek marketing approvals~~programs across most of the Asia-Pacific region, and with Menarini for ~~any~~our programs in Europe, Latin America and other key countries, there can be no assurance as to the amount or timing of ~~our drug candidates that successfully complete clinical trials;~~

~~establish a sales, marketing~~future product or license and ~~distribution infrastructure to commercialize any drugs for which~~other revenues, and we may ~~obtain marketing approval;~~

~~maintain, expand and protect our intellectual property portfolio;~~

~~manufacture our drug candidates;~~

•

~~hire additional clinical, quality control and scientific personnel;~~

~~identify additional drug candidates;~~

~~acquire or in-license other drugs and technologies; and~~

~~add operational, financial and management information systems and personnel, including personnel~~not achieve profitability for several years, if at all. Our ability to ~~support our drug development, any future commercialization efforts and our other operations as a public company.~~

To become and remain profitable ~~we must develop and eventually commercialize a drug~~depends significantly on our success in many areas, including:

•

effectively commercializing XPOVIO or ~~drugs with significant market potential,~~any future products either on our own or with a ~~collaborator. This will require us~~collaborator, including by maintaining a full commercial organization required to ~~be successful~~market, sell and distribute our products, and achieving an adequate level of market acceptance;

•

the impact of current or future competing products on product sales of XPOVIO or any of our future products;

•

obtaining sufficient pricing, coverage and reimbursement, including government pricing and reimbursement policies or a change in ~~a range~~the mix of ~~challenging activities, including~~our business effecting rebates related to 340B Programs, Medicare and Medicaid, for XPOVIO and any of our other approved products from private and government payers and the impact of any pricing changes;

•

initiating and successfully completing ~~preclinical studies and~~ clinical trials ~~of our drug candidates, obtaining~~required to file for, obtain and maintain marketing approval for ~~these drug candidates,~~ our product candidates;

•

obtaining and maintaining regulatory approvals, either by us or our collaborators, and the timing of such approvals;

•

manufacturing ~~marketing and selling those drugs for which we may obtain marketing approval and~~ at commercial scale;

•

establishing and managing any collaborations for the development, marketing and/or commercialization of our ~~drug candidates.~~products and product candidates, including the level of success of our collaborators’ efforts and the timing and amount of any milestone or royalty payments we may receive;

•

obtaining, maintaining and protecting our intellectual property rights; and

•

navigating the negative impacts resulting from the ongoing COVID-19 pandemic to the healthcare systems, the ability of our clinical trial sites to conduct current or future trials and the regulatory review process.

Further, a number of myeloma foundations that help support Medicare Part D patients with their out-of-pocket costs for multiple myeloma oral oncolytics, including XPOVIO, closed during the first quarter of 2023. As a result, we have provided XPOVIO to these patients at no charge through our Patient Assistance Program, which adversely impacted our revenues in the first quarter of 2023. As patients who utilize our Patient Assistance Program remain in the program through the calendar year and their course of treatment, we expect this trend to increase throughout 2023 if these foundations remain closed or partially closed due to the cumulative impact on both new starts and the associated refills. We ~~may never succeed~~believe that this trend will be limited to 2023 since, beginning in ~~these activities~~2024, certain changes in the design of Medicare Part D under the IRA will eliminate the patient co-insurance requirement.

We anticipate that our operating expenses will continue to be significant and ~~even~~increase as we continue to:

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commercialize XPOVIO in the U.S., including maintaining our commercial infrastructure;

•

obtain and/or maintain regulatory approval for XPOVIO and our product candidates, including completing any required post-marketing requirements to the satisfaction of the FDA or other regulatory agencies;

•

expand our research and development programs, identify additional product candidates and initiate and conduct clinical trials, including clinical trials required by the FDA or other regulatory agencies in addition to those that have been or are currently expected to be conducted;

•

maintain, expand and protect our intellectual property portfolio;

•

manufacture XPOVIO and our product candidates; and

•

acquire or in-license other products, product candidates or technologies.

Because of the numerous risks and uncertainties associated with pharmaceutical product development and commercialization, we are unable to accurately predict the timing or amount of our revenue and expenses or when, or if, we ~~do,~~will be able to achieve profitability. We cannot be certain that our revenue from sales of XPOVIO alone, in the currently approved indications, will be sufficient for us to become profitable for several years, if at all. We may never generate revenues that are significant or large enough to achieve profitability. IfEven if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of ~~the~~our company and could impair our ability to raise capital, maintain our research and development and commercialization efforts, expand our business and/or continue our operations. A decline in the value of our company could also cause our stockholders to lose all or part of their investment.

~~Our short operating history may make it difficult for stockholders to evaluate the success of our business to date and to assess our future viability.~~

We are an early-stage company. We were incorporated in 2008 and commenced operations in 2009. Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, developing our platform, identifying potential drug candidates and conducting preclinical studies and early-phase and later-phase clinical trials of our drug candidates. Our lead drug candidate is currently in multiple Phase 1 and Phase 2 clinical trials and a Phase 3 clinical trial and all of our other drug candidates for the treatment of human disease are in early clinical development or preclinical development. We have not yet demonstrated our ability to successfully complete any late-phase clinical trials in humans, including large-scale clinical trials, obtain marketing approvals, manufacture a commercial scale drug, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful drug commercialization. Typically, it takes about six to ten years to develop one new drug from the time it is in Phase 1 clinical trials to when it is commercially available for treating patients. Consequently, any predictions stockholders make about our future success or viability may not be as accurate as they could be if we had a longer operating history.

~~In addition, as a business with a short operating history, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors.~~ We will need additional funding to ~~transition from a company with a research focus to a company capable of supporting commercial activities. We may not be successful in such a transition.~~

~~As we continue to build~~achieve our business we expect our financial condition and operating results may fluctuate significantly from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control. Accordingly, stockholders should not rely upon the results of any particular quarterly or annual periods as indications of future operating performance.

~~We will need substantial additional funding.~~objectives. If we are unable to raise capital when needed or on acceptable terms, we would be forced to delay, reduce or eliminate our research and ~~drug~~ development programs and/or commercialization efforts.

Discovering, developing and commercializing products involve time-consuming, expensive and uncertain processes that take years to complete. We have used substantial funds to develop XPOVIO and expect our operating expenses to continue to increase ~~in connection with our ongoing activities, particularly~~ as we continue ~~the clinical trials~~to commercialize XPOVIO or any future approved product, conduct further research and development of ~~and~~our product candidates, seek marketing approval and prepare for commercialization of selinexor ~~and~~in additional indications or for our other ~~drug candidates. In addition,~~product candidates, if ~~we obtain marketing approval for any of our drug candidates, we expect to incur significant commercialization expenses related to drug sales, marketing, manufacturing and distribution~~approved, to the extent that such ~~sales, marketing, manufacturing and distribution~~functions are not the responsibility of ~~any collaborator that we may have at such time for any such drug.~~a collaborator. Furthermore, we will continue to incur additional costs associated with operating as a public ~~company. Accordingly, we will need to obtain substantial~~company, hiring additional ~~funding~~personnel and expanding our geographical reach. Although currently XPOVIO is commercially available in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and drug development programs or commercialization efforts.

We expect that our existing cash, cash equivalents, restricted cash and investments will enable us to fund our current operating plan and capital expenditure requirements into 2019 while we are preparing to establish a commercial infrastructure for a potential launch of selinexor in North America and Western Europe. Our future capital requirements will depend on many factors, including:

~~the progress and results of our current and planned clinical trials of selinexor;~~

~~the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our other drug candidates;~~

•

~~the costs, timing and outcome of regulatory review of our drug candidates;~~

~~our ability to establish and maintain collaborations on favorable terms, if at all;~~

~~the success of any collaborations that we may enter into with third parties;~~

~~the extent to which we acquire or in-license other drugs and technologies;~~

~~the amount of revenue, if any, received from commercial sales of our drug candidates, should any of our drug candidates receive marketing approval; and~~

~~the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.~~

Identifying potential drug candidates and conducting preclinical studies and clinical trials is a time-consuming, expensive and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain marketing approval and achieve drug sales. In addition, our drug candidates, if approved, may not achieve commercial success. Our commercial revenues, if any, will be derived from sales of drugs thatthree indications, we do not ~~expect~~anticipate that our revenue from product sales of XPOVIO or any funds we may receive from our collaborators will be sufficient for us to ~~be commercially available~~become profitable for ~~many~~several years, if at all. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. ~~Adequate~~

As of March 31, 2023, we believe that our existing cash, cash equivalents and investments will enable us to fund our current operating and capital expenditure plans for at least twelve months from the date of issuance of the financial statements contained in this Quarterly Report on Form 10-Q. The amount and timing of our future capital requirements will depend on many factors, including, but not limited to:

•

the scope, progress, results, timing and costs of our current and planned development efforts and regulatory review of our product candidates;

•

the amount and timing of revenues from sales of XPOVIO, or any product candidate that we develop or acquire;

•

the cost of, and our ability to expand and maintain, the commercial infrastructure required to support the commercialization of XPOVIO and any other product for which we receive marketing approval, including medical affairs, manufacturing, marketing and distribution functions;

•

our ability to establish and maintain collaboration, partnership, licensing, marketing, distribution or other arrangements on favorable terms and the level and timing of success of these arrangements;

•

the extent to which we acquire or in-license other products, product candidates and technologies; and

•

the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.

In addition, the terms of any financing may adversely affect the holdings or the rights of our stockholders. If we raise additional funds by issuing equity securities, dilution to our existing stockholders will result. In addition, as a condition to providing additional funding to us, future investors may demand, and may be granted, rights superior to those of existing stockholders. Moreover, any debt financing, if available, may involve restrictive covenants that could limit our flexibility in conducting future business activities and, in

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the event of insolvency, would be paid before holders of equity securities received any distribution of corporate assets. Our ability to satisfy and meet any future debt service obligations will depend upon our future performance, which will be subject to financial, business and other factors affecting our operations, many of which are beyond our control.

Even if we believe we have sufficient funds for our current or future operating plans, we may seek additional capital due to favorable market conditions or strategic considerations. Any future fundraising efforts could divert our management’s attention away from their day-to-day activities. Further, adequate additional financing may not be available to us on acceptable terms, or at all. In addition, raising funds in the current economic environment may present additional challenges. For example, any sustained disruption in the capital markets from adverse macroeconomic conditions, such as the disruption and uncertainty caused by the COVID-19 pandemic, rising inflation, increasing interest rates and slower economic growth or recession, could negatively impact our ability to raise capital and we cannot predict the extent or duration of such macro-economic disruptions. Moreover, there has been recent turmoil in the global banking system, which could result in a situation where we lose our deposits, or access to our deposits, and are unable to obtain financing from other sources. If adequate funds are not available to us on a timely basis or on attractive terms, we may ~~seek~~be required to delay, reduce or eliminate our research and development programs or any current or future commercialization efforts for one or more of our products or product candidates, any of which could have a material adverse effect on our business, operating results and prospects.

Our Revenue Interest Agreement with HCR, as amended, contains various covenants and other provisions, which, if violated, could result in the acceleration of payments due under such agreement or the foreclosure on the pledged collateral, including all of our present and future assets relating to selinexor.

In September 2019, we entered into the Revenue Interest Financing Agreement (the “Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”) and which was amended in June 2021 (the “Amended Revenue Interest Agreement”). Pursuant to the Amended Revenue Interest Agreement, we are required to comply with various covenants relating to the conduct of our business and the commercialization of XPOVIO, including obligations to use commercially reasonable efforts to commercialize our products. In addition, the Amended Revenue Interest Agreement limits our ability to incur or prepay indebtedness, create or incur liens, pay dividends on or repurchase outstanding shares of our capital stock or dispose of assets. The Amended Revenue Interest Agreement also includes customary events of default upon the occurrence of enumerated events, including non-payment of revenue interests, failure to perform certain covenants and the occurrence of insolvency proceedings, specified judgments, specified cross-defaults or specified revocations, or withdrawals or cancellations of regulatory approval for XPOVIO. Upon the occurrence of an event of default and in the event of a change of control, HCR may accelerate payments due under the Amended Revenue Interest Agreement up to $249.8 million, less the aggregate of all of the payments previously paid to HCR. Upon the occurrence of specified material adverse events or the material breach of specified representations and warranties, which will not be considered events of default, HCR may elect to terminate the Amended Revenue Interest Agreement and require us to make payments necessary for HCR to receive $135.0 million, less the aggregate of all of the payments made to date, plus a specified annual rate of return. In the event that we are unable to make such payment, HCR may be able to foreclose on the collateral that was pledged to HCR, which consists of all of our present and future assets relating to selinexor. Any such foreclosure remedy would significantly and adversely affect us and could result in us losing our interest in such assets, which would have an adverse material impact on our business.

Our indebtedness could limit cash flow available for our operations, expose us to risks that could adversely affect our business, financial condition and results of operations and impair our ability to satisfy our obligations under the Convertible Senior Notes due 2025 (the “Notes”).

We incurred $172.5 million of indebtedness as a result of the sale of the Notes, $75.0 million as a result of the initial closing pursuant to the Revenue Interest Agreement and $60.0 million following the closing of the Amended Revenue Interest Agreement. We may also incur additional indebtedness to meet future financing needs. Our indebtedness could have significant negative consequences for our security holders and our business, results of operations and financial condition by, among other things:

•

increasing our vulnerability to adverse economic and industry conditions;

•

limiting our ability to obtain additional financing;

•

requiring the dedication of a substantial portion of our cash flow from operations to service our indebtedness, which would reduce the amount of cash available for other purposes;

•

limiting our flexibility to plan for, or react to, changes in our business;

•

diluting the interests of our existing stockholders as a result of issuing shares of our common stock upon conversion of the Notes; and

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•

placing us at a possible competitive disadvantage with competitors that are less leveraged than us or have better access to capital.

Our ability to pay the principal of or interest on the Notes or to make cash payments in connection with any conversion of the Notes depends on our future performance, which is subject, in part, to economic, financial, competitive and other factors beyond our control. Our business may not generate cash flow from operations in the future sufficient to service the Notes or other future indebtedness and make necessary capital expenditures.

We may not have the ability to raise the funds necessary to settle conversions of the Notes in cash, to repurchase the Notes for cash upon a fundamental change, to pay the redemption price for any Notes we redeem or to refinance the Notes, and any future debt we incur may contain limitations on our ability to pay cash upon conversion or repurchase of the Notes.

Holders may require us to repurchase their Notes following a fundamental change at a cash repurchase price generally equal to the principal amount of the Notes to be repurchased, plus accrued and unpaid interest. In addition, upon conversion, unless we elect to deliver solely shares of our common stock to settle conversions (other than paying cash in lieu of delivering any fractional share), we must satisfy the conversion in cash. If we do not have enough available cash at the time we are required to repurchase the Notes, pay cash amounts due upon conversion or redemption of the Notes or refinance the Notes, we may be required to ~~favorable market conditions~~adopt one or ~~strategic considerations, even~~more alternatives, such as selling assets, restructuring indebtedness or obtaining additional debt financing or equity capital on terms that may be onerous or highly dilutive. Our ability to refinance the Notes or other future indebtedness will depend on the capital markets, our financial condition at such time and our obligations under any other existing indebtedness in effect at such time. We may not be able to engage in any of these activities on desirable terms, or at all, which could result in a default on our debt obligations, including the Notes. In addition, our ability to repurchase the Notes, to pay cash upon conversion or redemption of the Notes or to refinance the Notes may be limited by law, regulatory authority or agreements governing any future indebtedness that we may incur. Our failure to repurchase the Notes at a time when the repurchase is required by the indenture governing the Notes or to pay cash upon conversion of the Notes as required by the indenture would constitute a default under the indenture. A default under the indenture or the fundamental change itself could also lead to a default under agreements governing our future indebtedness, if any. Moreover, the occurrence of a fundamental change under the indenture could constitute an event of default under any such agreements. If the repayment of the related indebtedness were to be accelerated after any applicable notice or grace periods, we ~~believe we~~may not have sufficient funds to repay the indebtedness and repurchase the Notes or to pay cash upon conversion of the Notes.

The conditional conversion feature of the Notes, if triggered, may adversely affect our financial condition and operating results.

In the event the conditional conversion feature of the Notes is triggered, holders of Notes will be entitled to convert the Notes at any time during specified periods at their option. If one or more holders elect to convert their Notes, unless we elect to satisfy our conversion obligation by delivering solely shares of our common stock (other than paying cash in lieu of delivering any fractional share), we would be required to settle a portion or all of our conversion obligation in cash, which could adversely affect our liquidity. In addition, even if holders do not elect to convert their Notes, we could be required under applicable accounting rules to reclassify all or a portion of the outstanding principal amount of the Notes as a current rather than long-term liability, which would result in a material reduction of our net working capital.

The accounting method for convertible debt securities that may be settled in cash, such as the Notes, could have a material effect on our ~~current~~reported financial results.

The Notes may be settled in cash or ~~future operating plans.~~shares, or a combination of cash and shares. Under the if-converted method, the maximum potential dilutive impact of the conversion of the Notes is assumed when calculating diluted earnings per share during periods of net income. This could result in a material impact to diluted earnings per share. Diluted earnings per share is not impacted by the Notes during periods of net loss.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our ~~drug~~product candidates.

Until such time, if ever, as we can generate substantial revenues from the sale of ~~drugs,~~our products, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and/or licensing arrangements. We do not have any committed external source of funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interests of stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of common stockholders. Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends. For example, during the term of the Amended Revenue Interest Agreement, we cannot

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make any voluntary or optional cash payment or prepayment on our existing convertible debt and cannot enter into any new debt without the consent of HCR.

If we raise additional funds through further collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our future revenue streams, research programs or ~~drug~~product candidates or to grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our research and drug development or current or future commercialization efforts or grant rights to develop and market ~~drug~~product candidates that we would otherwise prefer to develop and market ourselves.

Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and stock price.

Global credit and financial markets have experienced extreme disruptions over ~~some of~~ the past several years. Such disruptions have resulted, and could in the future result, in diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. ~~There can be no assurance that any deterioration in credit and financial markets and confidence in economic conditions will not occur.~~ Our general business strategy may be compromised by economic downturns, a volatile business environment and unpredictable and unstable market ~~conditions.~~conditions, such as the current global situation resulting from the COVID-19 pandemic, the ongoing conflict between Russia and Ukraine, rising inflation, failures and instability in U.S. and international banking systems, increasing interest rates and slower economic growth or recession. If the equity and credit markets deteriorate, it may make any necessary equity or debt financing more difficult to secure, more costly or more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could harm our growth strategy, financial performance and stock price and could require us to delay or abandon plans with respect to our business, including clinical development plans. Further, recent developments in the banking industry could adversely affect our business. If the financial institutions with which we do business enter receivership or become insolvent in the future, there is no guarantee that the Department of the Treasury, the Federal Reserve and the FDIC will intercede to provide us and other depositors with access to balances in excess of the $250,000 FDIC insurance limit, that we would be able to access our existing cash, cash equivalents and investments, that we would be able to maintain any required letters of credit or other credit support arrangements, or that we would be able to adequately fund our business for a prolonged period of time or at all, any of which could have a material adverse effect on our business, financial condition and results of operations. We cannot predict the impact that the high market volatility and instability of the banking sector more broadly could have on economic activity and our business in particular. In addition, there is a risk that one or more of our current service providers, manufacturers or other third parties with which we conduct business may not survive difficult economic times, including the current global situation resulting from the COVID-19 pandemic, the ongoing conflict between Russia and Ukraine, the instability of the banking sector, and the uncertainty associated with current worldwide economic conditions, which could directly affect our ability to attain our operating goals on schedule and on budget.

Risks Related to Our Dependence on Third Parties

We depend on collaborations with third parties for certain aspects of the development, marketing and/or commercialization of XPOVIO and/or our ~~drug candidates, and plan to enter into additional collaborations.~~product candidates. If those collaborations are not successful, or if we are not able to maintain our existing collaborations or establish additional collaborations, we may have to alter our development and commercialization plans and may not be able to capitalize on the market potential of ~~these~~XPOVIO or our product candidates.

Our drug ~~candidates.~~

development programs and the commercialization of our products and product candidates, if approved, require local expertise and substantial additional cash to fund expenses. We ~~intend~~expect to maintain our existing collaborations and ~~will continue to seek~~collaborate with additional ~~third-party collaborators~~pharmaceutical and biotechnology companies for certain aspects of the development, marketing and/or commercialization of our ~~drug~~products and product candidates. For example, ~~while~~ we ~~currently plan~~are parties to license arrangements with Antengene and Menarini and distribution agreements with Promedico Ltd. and FORUS Therapeutics Inc. for the development, marketing and/or commercialization of selinexor in certain geographies outside of the U.S., and we expect to rely on additional partners to develop and ~~seek approval~~commercialize our products outside of ~~selinexor in North America and Western Europe with respect to~~ the potential approval of selinexor without a collaborator, we have entered into a collaboration with Ono Pharmaceutical Co., Ltd., and will continue to seek to enter into additional collaborations, for marketing and commercialization of selinexor for other geographies.U.S. In addition, we intend to seek one or more collaborators to aid in the further development, marketing and/or commercialization of selinexor and our other ~~SINE~~ compounds for ~~inflammatory, autoimmune and/or neurological conditions~~indications both within and ~~viral indications. Our likely~~outside of oncology. All of the risks relating to product development, regulatory approval and commercialization described in this Quarterly Report on Form 10-Q also apply to the activities of our collaborators.

Potential collaborators ~~for any collaboration arrangements~~ include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology ~~companies.~~companies and we face significant competition in seeking appropriate collaborators, including as a result of a significant number of recent business combinations among large pharmaceutical companies that have reduced the number of potential collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon the assessment of the potential collaborator’s expertise, its current and expected resources and competing priorities, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or foreign regulatory authorities, the potential market for the product or

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product candidate, the costs and complexities of manufacturing and delivering such product or product candidate to patients, the potential of competing products, the existence of uncertainty with respect to our ownership of intellectual property, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. A potential collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us.

Collaborations are complex and time-consuming to negotiate, document and manage. We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all, or we may be restricted under then-existing collaboration agreements from entering into future agreements on certain terms with potential collaborators. If we are unable to maintain our current collaboration agreements or enter into new collaboration agreements, we may have to curtail, reduce or delay the development or commercialization programs for our products or product candidates, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund and undertake development or commercialization activities on our own, we may need to obtain additional expertise and additional capital, which may not be available to us on acceptable terms, or at all. If we do not have sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop our product candidates or bring them to market and generate product revenue.

Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements, and our collaboration agreements may not lead to the development or commercialization of our products or product candidates in the most efficient manner, or at all, and may result in lower product revenues or profitability to us than if we were to market and sell these products ourselves. In connection with any such arrangements with third parties, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development, marketing and/or commercialization of our ~~drug~~products or product candidates. ~~Our ability~~Further, if our collaborations do not result in the successful development and commercialization of our products or product candidates or if any one of our collaborators terminates its agreement with us, we may not receive any future milestone or royalty payments under the collaboration. If we do not receive the funding we expect under these agreements, the development and commercialization of our products or product candidates could be delayed and we may need additional resources to ~~generate revenues from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements.~~develop product candidates.

Collaborations involving our ~~drug~~products and product candidates pose the following risks to us:

•

collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;

•

collaborators may not perform their obligations as expected or in compliance with applicable local and national laws and regulatory requirements;

•

collaborators may not pursue development, marketing and/or commercialization of our ~~drug~~products or product candidates or may elect not to continue or renew development, marketing or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities;

•

collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a ~~drug~~product candidate, repeat or conduct new clinical trials or require a new formulation of a ~~drug~~product candidate for clinical testing;

•

collaborators could independently develop, or develop with third parties, ~~drugs~~products that compete directly or indirectly with our ~~drugs~~products or ~~drug~~product candidates if the collaborators believe that competitive ~~drugs~~products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

•

a collaborator with marketing and distribution rights to one or more ~~drugs~~products or product candidates may not commit sufficient resources to the marketing and distribution of ~~such drug~~our products or ~~drugs;~~

product candidates;

•

disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development or commercialization, might cause delays or termination of the research, development or commercialization of products or product candidates, might lead to additional responsibilities for us with respect to our products or product candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive;

•

collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

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•

collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability;

•

disputes may arise between the collaborators and us that result in the delay or termination of the research, development or commercialization of our drugs or drug candidates or that result in costly litigation or arbitration that diverts management’s attention and resources of the company;

we may lose certain valuable rights under circumstances identified in any collaboration arrangement that we enter into, such as if we undergo a change of control;

•

collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development, marketing and/or commercialization of the applicable ~~drug candidates;~~

products or product candidates or to enter into new collaboration agreements;

•

collaborators may learn about our discoveries and use this knowledge to compete with us in the future; and

•

the number and type of our collaborations could adversely affect our attractiveness to other collaborators or acquirers.

~~Collaboration agreements may not lead to development or commercialization~~If any of ~~drug candidates in~~these events occurs, the ~~most efficient manner, or at all. If our collaborations do not result in the successful development and commercialization of products or if one~~market potential of our collaborators terminates its agreement with us, we may not receive any future milestone or royalty payments under the collaboration. If we do not receive the funding we expect under these agreements, our development of ourproducts and product candidates, if approved, could be ~~delayed~~reduced, and we may need additional resources to develop product candidates. All of the risks relating to product development, regulatory approval and commercialization described in this Quarterly Report on Form 10-Q also apply to the activities of our ~~collaborators.~~business could be materially harmed.

If we are ~~not able~~unable to establish and maintain our ~~existing collaborations or establish additional collaborations as~~agreements with third parties to distribute XPOVIO to patients, our results of operations and business could be adversely affected.

We rely on third parties to commercially distribute XPOVIO to patients. For example, we ~~currently plan, we may~~ have ~~to alter our development and commercialization plans.~~

Our drug development programs and the potential commercialization of our drug candidates will require substantial additional cash to fund expenses. As noted above, we expect to maintain our existing collaborations and collaboratecontracted with ~~additional pharmaceutical and biotechnology companies for the development and/or commercialization of our drug candidates.~~

~~We face significant competition in seeking appropriate collaborators. Whether we reach~~ a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of alimited number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside of the United States, the potential market for the subject drug candidate, the costs and complexities of manufacturing and delivering such drug candidatespecialty pharmacies, which sell XPOVIO directly to patients, and specialty distributors, which sell XPOVIO to healthcare entities who then resell XPOVIO to patients. While we have entered into agreements with each of these pharmacies and distributors to distribute XPOVIO in the ~~potential of competing drugs, the existence of uncertainty~~U.S., they may not perform as agreed or they may terminate their agreements with respect to our ownership of intellectual property, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. The collaborator may also consider alternative drug candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for our drug candidate.

us. We may also ~~be restricted under then-existing collaboration~~need to enter into agreements ~~from entering into future agreements on certain terms~~ with ~~potential collaborators.~~

~~Collaborations are complex~~additional pharmacies or distributors, and ~~time-consuming to negotiate and document. In addition,~~ there ~~have been a significant number of recent business combinations among large pharmaceutical companies~~is no guarantee that ~~have resulted in a reduced number of potential future collaborators.~~

~~We may not~~we will be able to ~~negotiate collaborations~~do so on a timely basis, ~~on acceptable~~at commercially reasonable terms, or at all. If we are unable to ~~do so,~~maintain and, if needed, expand, our network of specialty pharmacies and specialty distributors, we ~~may have~~would be exposed to ~~curtail~~substantial distribution risk.

The use of specialty pharmacies and specialty distributors involves certain risks, including, but not limited to, risks that these organizations will:

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not provide us accurate or timely information regarding their inventories, the ~~development~~number of ~~such drug candidate,~~ patients who are using XPOVIO or serious adverse reactions, events and/or product complaints regarding XPOVIO;

•

not effectively sell or support XPOVIO or communicate publicly concerning XPOVIO in a manner that is contrary to FDA rules and regulations;

•

reduce their efforts or ~~delay its development program~~discontinue to sell or ~~one~~support, or ~~more of our other development programs, delay its potential commercialization~~otherwise not effectively sell or ~~reduce~~support, XPOVIO;

•

not devote the ~~scope of any sales or marketing activities, or increase our expenditures~~resources necessary to sell XPOVIO in the volumes and ~~undertake development or commercialization activities at our own expense. If~~within the time frames that we ~~elect~~expect;

•

be unable to ~~increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available~~satisfy financial obligations to us ~~on acceptable terms,~~ or ~~at all. If we do not have sufficient funds, we~~others; or

•

cease operations.

Any such events may ~~not be able to further develop~~result in decreased product sales, which would harm our ~~drug candidates or bring them to market~~results of operations and ~~generate revenue from sales of drugs.~~business.

We rely on third parties toas we conduct our clinical trials and some aspects of our research and preclinical studies, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials, research or testing.

We rely on third parties, such as ~~contract research organizations,~~CROs, clinical data management organizations, medical institutions and clinical investigators, toas we conduct our clinical trials. We currently rely and expect to continue to rely on third parties to conduct some aspects of our research and preclinical studies. Any of these third parties may terminate their engagements with us at any time. If we need to enter into alternative arrangements, it would delay our drug development activities.

Our reliance on these third parties for research and development activities ~~will reduce~~reduces our control over these activities but ~~will~~does not relieve us of our responsibilities. For example, we ~~will~~ remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the trial. Moreover, the FDA requires us to comply with GCP standards ~~commonly referred to as Good Clinical Practices, for~~when conducting, recording and reporting the results of clinical trials to ~~assure~~ensure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected. The ~~European Medicines Agency~~EMA also requires us to comply with comparable standards. Regulatory authorities ensure compliance with these requirements through periodic inspections of trial sponsors, principal investigators and trial sites. If we or any of the third parties that we rely on in connection with our clinical trials fail

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to comply with applicable requirements, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, EMA or other comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with such requirements. We also are required to register ongoing clinical trials and post the results of completed clinical trials on a government-sponsored database, such as ClinicalTrials.gov, within certain timeframes. Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.

Furthermore, these third parties may also have relationships with other entities, some of which may be our competitors. If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our clinical trials in accordance with regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for our ~~drug~~product candidates and will not be able to, or may be delayed in our efforts to, successfully commercialize our ~~drug candidates.~~products. In such an event, our financial results and the commercial prospects for our products or product candidates, if approved, could be harmed, our costs could increase and our ability to generate revenues could be delayed, impaired or foreclosed.

We also expect to rely on other third parties to store and distribute drug supplies for our clinical trials. Any performance failure on the part of such third parties could delay clinical development or marketing approval of our ~~drug~~product candidates or commercialization of our ~~drugs,~~products, producing additional losses and depriving us of potential ~~revenue from sales~~product revenue.

In addition, as discussed above, the third parties upon whom we rely to conduct our clinical trials could be negatively impacted as a result of ~~drugs.~~disruptions caused by the COVID-19 pandemic, including difficulties in initiating clinical sites or enrolling participants, travel or quarantine policies, and other factors. If these third parties are so affected, our business prospects and results of operations could be severely adversely impacted.

We rely on third parties to conduct investigator-sponsored clinical trials of selinexor and our other ~~drug~~product candidates. Any failure by a third party to meet its obligations with respect to the clinical development of our ~~drug~~product candidates may delay or impair our ability to obtain regulatory approval for selinexor and our other ~~drug~~product candidates.

We rely on academic and private non-academic institutions to conduct and sponsor clinical trials relating to selinexor and our other ~~drug~~product candidates. We do not control the design or conduct of the investigator-sponsored trials, and it is possible that the FDA or ~~non-U.S.~~foreign regulatory authorities will not view these investigator-sponsored trials as providing adequate support for future clinical trials, whether controlled by us or third parties, for any one or more reasons, including elements of the design, or execution of the trials, or safety concerns or other trial results.

Such arrangements will provide us certain information rights with respect to the investigator-sponsored trials, ~~including~~such as access to and the ability to use and reference the data, including for our own regulatory filings, resulting from the investigator-sponsored trials. However, we do not have control over the timing and reporting of the data from investigator-sponsored trials, nor do we own the data from the investigator-sponsored trials. If we are unable to confirm or replicate the results from the investigator-sponsored trials or if negative results are obtained, we would likely be further delayed or prevented from advancing ~~further~~ clinical development of our ~~drug~~product candidates. Further, if investigators or institutions breach their obligations with respect to the clinical development of our ~~drug~~product candidates, or if the data proves to be inadequate compared to the first-hand knowledge we might have gained had the investigator-sponsored trials been sponsored and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.

Additionally, the FDA or ~~non-U.S.~~foreign regulatory authorities may disagree with the sufficiency of our right ofto reference to the preclinical, manufacturing or clinical data generated by these investigator-sponsored trials, or our interpretation of preclinical, manufacturing or clinical data from these investigator-sponsored trials. If so, the FDA or ~~other non-U.S.~~foreign regulatory authorities may require us to obtain and submit additional preclinical, manufacturing, or clinical data before we may initiate our planned trials and/or may not accept such additional data as adequate to initiate our planned trials.

We ~~contract with~~are completely dependent on third parties for the manufacture of our ~~drug~~products and product candidates ~~for preclinical studies~~ and ~~clinical trials~~any difficulties, disruptions, delays or unexpected costs, or the need to find alternative sources, could adversely affect our results of operations, profitability and expect to continue to do so for clinical trials and ultimately for commercialization. This reliance on third parties increases the risk that we will not have sufficient quantities of our drug candidates or drugs or such quantities at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts.future business prospects.

We do not own or operate, and currently have no plans to establish, any manufacturing facilities for our products or ~~personnel.~~product candidates. We currently rely, and expect to continue to rely, on third-party contract manufacturers to manufacture our products and product candidates for our commercial and clinical use.

Facilities used by our third-party manufacturers may be inspected by the FDA after we submit a marketing application and before potential approval of the product candidate and are also subject to ongoing periodic unannounced inspections by the FDA for

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compliance with cGMP and other regulatory requirements following approval. Similar regulations apply to manufacturers of our product candidates for use or sale in foreign countries. We do not control the manufacturing processes of, and are completely dependent on, our third-party manufacturers for compliance with the applicable regulatory requirements for the manufacture of our ~~drug candidates for preclinical studies~~products and ~~clinical trials under the guidance of members of our organization. We have engaged third-party manufacturers for drug substance and drug~~ product ~~(fill-and-finish) services. We do not have a long term supply agreement with any of these third-party manufacturers, and we purchase our required drug supplies on a purchase order basis.~~

We expect to rely on third-party manufacturers or third-party collaborators for the manufacture of our drug candidates for clinical trials and ultimately for commercial supply of any of these drug candidates for which we or any of our collaborators obtain marketing approval. We may be unable to establish any agreements with third-party manufacturers or to do so on acceptable terms. Even if we are able to establish agreements with third-party manufacturers, reliance on third-party manufacturers entails additional risks, including:

~~reliance on the third party for regulatory compliance and quality assurance;~~

~~the possible breach of the manufacturing agreement by the third party;~~

~~the possible failure of the third party to manufacture our drug candidate according to our specifications;~~

~~the possible failure of the third party to manufacture our drug candidate according to our schedule, or at all;~~

•

~~the possible misappropriation or disclosure by the third party or others of our proprietary information, including our trade secrets and know-how; and~~

~~the possible termination or nonrenewal of the agreement by the third party at a time that is costly or inconvenient for us.~~

candidates. Third-party manufacturers may not be able to comply with ~~current Good Manufacturing Practices, or~~ cGMP regulations or similar regulatory requirements outside of the ~~United States. Our failure,~~ U.S. If our manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA and any applicable foreign regulatory authority, they will not be able to secure and/or ~~the failure~~maintain regulatory approval for their manufacturing facilities. If these facilities are not approved for commercial manufacture or are not able to maintain approval, we may need to find alternative manufacturing facilities, which could significantly impact our ability to develop, obtain regulatory approval for or market our products or product candidates as alternative qualified manufacturing facilities may not be available on a timely or cost-efficient basis, or at all. Failure by any of our ~~third-party~~ manufacturers to comply with applicable cGMP regulations or other regulatory requirements could result in sanctions being imposed on us or the contract manufacturer, including fines, injunctions, civil penalties, delays, ~~suspension~~suspensions or ~~withdrawal~~withdrawals of approvals, ~~license revocation, seizures or recalls of drug candidates or drugs,~~ operating restrictions, interruptions in supply and criminal prosecutions, any of which could significantly and adversely affect supplies of our ~~drugs~~products or product candidates and ~~harm~~have a material adverse impact on our business, financial condition and results of operations.

~~Any drugs~~We currently have long-term supply agreements with our third-party contract manufacturers to manufacture the clinical and commercial supplies of the drug product for XPOVIO. Our ability to have our products manufactured in sufficient quantities and at acceptable costs to meet our commercial demand and clinical development needs is dependent on the uninterrupted and efficient operation of our third-party contract manufacturers’ facilities. Reliance on third-party manufacturers entails risks, including:

•

reliance on the third party for regulatory compliance and quality assurance;

•

the possible breach, termination or nonrenewal of a manufacturing agreement by the third party, including at a time that ~~we may develop may compete~~is costly or inconvenient to us;

•

the possible failure of the third party to manufacture our products or product candidates according to our schedule, or at all, including if the third-party manufacturer gives greater priority to the supply of other products over our products and product candidates, or otherwise does not satisfactorily perform according to the terms of the manufacturing agreement;

•

equipment malfunctions, power outages or other general disruptions experienced by our third-party manufacturers to their respective operations and other general problems with ~~other~~a multi-step manufacturing process; and

•

the possible misappropriation or disclosure by the third party or others of our proprietary information, including our trade secrets and know-how.

We currently rely on a single source supplier for our active pharmaceutical ingredient and our drug ~~candidates and drugs for access to~~product manufacturing ~~facilities. There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for us.~~

requirements. Any performance failure on the part of our existing or future manufacturers could delay clinical development, marketing approval or ~~marketing approval.~~commercialization of our products or product candidates. If our suppliers or contract manufacturers are so affected, our supply chain could be disrupted, our product shipments could be delayed, our costs could be increased and our business could be adversely affected. If our current contract manufacturers cannot perform as agreed, we may be required to replace those manufacturers. Although we believe that there are several potential alternative manufacturers who could manufacture our ~~drug~~products and product candidates, we ~~may~~could incur added costs and delays in identifying and qualifying any such replacement. Consequently, we may not be able to reach agreement with third-party manufacturers on satisfactory terms, which could negatively impact our XPOVIO revenues or delay commercialization of any product candidates that are subsequently approved.

~~Our current and anticipated future dependence upon others for~~If, because of the ~~manufacture of~~factors discussed above, we are unable to have our ~~drug candidates or drugs may adversely affect our future profit margins and our ability to commercialize any drugs that receive marketing approval~~products manufactured on a timely or sufficient basis, we may not be able to meet clinical development needs or commercial demand for our products or product candidates or we may not be able to manufacture our products in a cost-effective manner. As a result, we may lose sales, fail to generate projected revenues or suffer development or regulatory setbacks, any of which could have an adverse impact on our profitability and ~~competitive basis.~~future business prospects.

Risks Related to Our Intellectual Property

If we are unable to obtain and maintain patent protection for our ~~drug~~products or product candidates and other discoveries, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize drugs and other discoveries similar or identical to ours, and our ability to successfully commercialize our ~~drug~~products or product candidates and other discoveries may be adversely affected.

Our success depends in large part on our ability to obtain and maintain patent protection in the ~~United States~~U.S. and other countries with respect to our proprietary ~~drug~~products and product candidates and other discoveries. We seek to protect our proprietary position by filing patent applications in the ~~United States~~U.S. and abroad related to our novel ~~drug~~products and product candidates and other discoveries that are

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important to our business. ~~To date, 42~~As of April 28, 2023, 106 patents ~~have issued~~were in force that relate to ~~XPO1~~exportin 1 inhibitors, including composition of matter patents for selinexor, verdinexor ~~KPT-8602~~ and ~~KPT-350~~eltanexor in the ~~United States,~~U.S., and their use in targeted therapeutics. In addition, 30 patents were in force that relate to our PAK4/NAMPT inhibitors, including three composition of matter patents for KPT-9274 in the U.S. and its use in targeted therapeutics. With respect to our KPT-1200 program, as of April 28, 2023, 22 patents were in force, 10 of which are exclusively licensed to Karyopharm by the University of Southern California, that relate to IL-12 compositions and uses of IL-12 in targeted therapeutics. We cannot be certain that any other patents will issue with claims that cover any of our key ~~drug~~products, product candidates or other ~~discoveries or drug candidates.~~discoveries.

The patent prosecution process is expensive and time-consuming, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation. As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may not result in patents being issued which protect our ~~drug~~product candidates or other discoveries, or which effectively prevent others from commercializing competitive drugs and discoveries. Changes in either the patent laws or interpretation of the patent laws in the ~~United States~~U.S. and other countries may diminish the value of our patents or narrow the scope of our patent protection.

The laws of foreign countries may not protect our rights to the same extent as the laws of the ~~United States.~~U.S. For example, in some foreign jurisdictions, our ability to secure patents based on our filings in the ~~United States~~U.S. may depend, in part, on our ability to timely obtain assignment of rights to the invention from the employees and consultants who invented the technology. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the ~~United States~~U.S. and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all. Therefore, we cannot be certain that we were the first to make the inventions claimed in our patents or pending patent applications, or that we were the first to file for patent protection of such inventions.

Assuming the other requirements for patentability are met, prior to March 2013, in the ~~United States,~~U.S., the first to invent the claimed invention was entitled to the patent, while outside of the ~~United States,~~U.S., the first to file a patent application is entitled to the patent. In March 2013, the ~~United States~~U.S. transitioned to a first-inventor-to-file system in which, assuming the other requirements for patentability are met, the first inventor to file a patent application is entitled to the patent. We may be subject to a third-party preissuance submission of prior art to the U.S. Patent and Trademark Office (“USPTO”) or become involved in opposition, derivation, revocation, reexamination, or post-grant or inter partes review or interference proceedings challenging our patent rights or the patent rights of others. An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our discoveries or drugs and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing third-party patent rights.

Even if our patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our patents by developing similar or alternative discoveries or drugs in a non-infringing manner.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our patents may be challenged in the courts or patent offices in the ~~United States~~U.S. and abroad. Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, which could limit our ability to stop others from using or commercializing similar or identical discoveries and drugs, or limit the duration of the patent protection of our ~~discoveries~~products, product candidates and ~~drug candidates.~~discoveries. Given the amount of time required for the development, testing and regulatory review of new ~~drug~~product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our patent portfolio may not provide us with sufficient rights to exclude others from commercializing drugs similar or identical to ours.

We may become involved in lawsuits to protect or enforce our patents and other intellectual property rights, which could be expensive, time-consuming and unsuccessful.

Competitors or commercial supply companies or others may infringe our patents and other intellectual property rights. For example, we are aware of a third ~~party~~parties selling a version of our lead product candidate for research purposes, which may infringe our intellectual property rights. To counter such infringement, we may advise such companies of our intellectual property rights, including, in some cases, intellectual property rights that provide protection for our lead product candidates, and demand that they stop infringing those rights. Such demand may provide such companies the opportunity to challenge the validity of certain of our intellectual property rights, or the opportunity to seek a finding that their activities do not infringe our intellectual property rights. We may also be required to file infringement actions, which can be expensive and time-consuming. In an infringement proceeding, a

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defendant may assert and a court may agree with a defendant that a patent of ours is invalid or unenforceable, or may refuse to stop the other party from using the intellectual property at issue. An adverse result in any litigation could put one or more of our patents at risk of being invalidated or interpreted narrowly. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.

Our commercial success depends upon our ability and the ability of any current and future collaborators to develop, manufacture, market and sell XPOVIO and our ~~drug~~product candidates and use our proprietary technologies without infringing the proprietary rights of third parties. We may become party to, or threatened with, future adversarial proceedings or litigation regarding intellectual property rights with respect to our ~~drug~~products or product candidates and technology, including interference proceedings before the ~~U.S. Patent and Trademark Office.~~USPTO. Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future. No litigation asserting such infringement claims is currently pending against us, and we have not been found by a court of competent jurisdiction to have infringed a third party’s intellectual property rights. If we are found to infringe or think there is a risk we may be found to infringe, a third party’s intellectual property rights, we could be required or choose to obtain a license from such third party to continue developing, marketing and ~~marketing~~selling our ~~drug~~products, product candidates and ~~using our~~ technology. However, we may not be able to obtain any required license on commercially reasonable terms, or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same intellectual property licensed to us. We could be forced, including by court order, to cease commercializing the infringing intellectual property or ~~drug~~product or to cease using the infringing technology. In addition, we could be found liable for monetary damages. A finding of infringement could prevent us from commercializing our ~~drug~~products or product candidates or force us to cease some of our business operations, which could materially harm our business. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.

We may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.

Many of our employees were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although we try to ensure that our employees do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these employees have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer. Although we have no knowledge of any such claims being alleged to date, if such claims were to arise, litigation may be necessary to defend against any such claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

Intellectual property litigation could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of our common stock. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities. We may not have sufficient financial or other resources to adequately conduct such litigation or proceedings. Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.

Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications will be due to the ~~United States Patent and Trademark Office, or~~ USPTO and various foreign patent offices at various points over the lifetime of the patents and/or applications. We have systems in place to remind us to pay these fees, and we rely on our outside counsel to pay these fees when due. Additionally, the USPTO and various foreign patent offices require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. We employ reputable law firms and other professionals to help us comply

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with such provisions, and in many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with rules applicable to the particular jurisdiction. However, there are situations in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. If such an event were to occur, it could have a material adverse effect on our business.

If our product candidates or any of our future product candidates obtain regulatory approval, additional competitors could enter the market with generic versions of such products, which may result in a material decline in sales of our competing products.

Under the Drug Price Competition and Patent Term Restoration Act of 1984 (the “Hatch-Waxman Amendments”) to the FDCA, a company may file an ANDA, seeking approval of a generic version of an approved innovator product. Under the Hatch-Waxman Amendments, a company may also submit an NDA under section 505(b)(2) of the FDCA that references the FDA’s prior approval of the innovator product or preclinical studies and/or clinical trials that were not conducted by, or for, the sponsor and for which the sponsor has not obtained a right of reference. A 505(b)(2) NDA product may be for a new or improved version of the original innovator product. The Hatch-Waxman Amendments also provide for certain periods of regulatory exclusivity, which preclude FDA approval (or in some circumstances, FDA filing and review) of an ANDA or 505(b)(2) NDA.

In certain circumstances, third parties may file an ANDA or NDA under Section 505(b)(2) as early as the so-called “NCE-1” date that is one year before the expiry of the five-year period of New Chemical Entity exclusivity or more generally four years after NDA approval. The third parties are allowed to rely on the safety and efficacy data of the innovator’s product, may not need to conduct clinical trials and can market a competing version of a product after the expiration or loss of patent exclusivity or the expiration or loss of regulatory exclusivity and often charge significantly lower prices. Upon the expiration or loss of patent protection or the expiration or loss of regulatory exclusivity for a product, the major portion of revenues for that product may be dramatically reduced in a very short period of time. If we are not successful in defending our patents and regulatory exclusivities, we will not derive the expected benefit from them. For example, the NCE-1 date for selinexor is July 3, 2023 after which a third party could be positioned to market an ANDA or Section 505(b)(2) product that competes with selinexor prior to the expiry of our patents if the third party successfully challenged the validity of our patents protecting the product.

In addition to the benefits of regulatory exclusivity, an innovator NDA holder may have patents claiming the active ingredient, product formulation or an approved use of the drug, which would be listed with the product in the FDA publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” known as the Orange Book. If there are patents listed in the Orange Book for the applicable, approved innovator product, a generic or 505(b)(2) sponsor that seeks to market its product before expiration of the patents must include in their applications what is known as a “Paragraph IV” certification, challenging the validity or enforceability, or claiming non-infringement, of the listed patent or patents. Notice of the certification must be given to the patent owner and NDA holder and if, within 45 days of receiving notice, either the patent owner or NDA holder sues for patent infringement, approval of the ANDA or 505(b)(2) NDA is stayed for up to 30 months.

Accordingly, if any of our product candidates that are regulated as drugs are approved, competitors could file ANDAs for generic versions of these products or 505(b)(2) NDAs that reference our products. If there are patents listed for such drug products in the Orange Book, those ANDAs and 505(b)(2) NDAs would be required to include a certification as to each listed patent indicating whether the ANDA sponsor does or does not intend to challenge the patent. We cannot predict which, if any, patents in our current portfolio or patents we may obtain in the future will be eligible for listing in the Orange Book, how any generic competitor would address such patents, whether we would sue on any such patents or the outcome of any such suit.

If we do not successfully extend the term of patents covering our ~~drug~~product candidates under the Hatch-Waxman Amendments and similar foreign legislation, our business may be materially harmed.

Depending upon the timing, duration and conditions of FDA marketing approval, if any, of our ~~drug~~products or product candidates, one or more of our U.S. patents may be eligible for patent term extension under ~~the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as~~ the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent term extension of up to five years for one patent covering an approved product as compensation for effective patent term lost during product development and the FDA regulatory review process. However, we may not receive an extension if we fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. The total patent term, including the extension period, may not exceed 14 years following FDA approval. Accordingly, the length of the extension, or the ability to even obtain an extension, depends on many factors.

In the ~~United States,~~U.S., only a single patent can be extended for each qualifying FDA approval, and any patent can be extended only once and only for a single product. Laws governing analogous patent term extensions in foreign jurisdictions vary widely, as do laws governing the ability to obtain multiple patents from a single patent family. Because both selinexor and verdinexor are protected by a

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single family of patents and applications, we may not be able to secure patent term extensions for both of these ~~drug~~product candidates in all jurisdictions where these ~~drug~~product candidates are ~~approved, if ever.~~approved.

If we are unable to obtain a patent term extension for a ~~drug~~product or product candidate or the term of any such extension is less than we request, the period during which we can enforce our patent rights for that ~~drug~~product or product candidate, if any, in that jurisdiction will be shortened and our competitors may obtain approval to market competing products sooner. As a result, our revenue could be materially reduced.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to seeking patents for our ~~drug~~products, product candidates and other discoveries, we also rely on trade secrets, including unpatented know-how, technology and other proprietary information, to maintain our competitive position. We seek to protect these trade secrets, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, outside scientific collaborators, ~~contract research organizations,~~CROs, contract manufacturers, consultants, advisors and other third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. To the extent that we are unable to timely enter into confidentiality and invention or patent assignment agreements with our employees and consultants, our ability to protect our business through trade secrets and patents may be harmed. Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, some courts inside and outside of the ~~United States~~U.S. are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them from using that technology or information to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor, our competitive position would be harmed. To the extent inventions are made by a third party under an agreement that does not grant us an assignment of their rights in inventions, we may choose or be required to obtain a license.

Not all of our trademarks are registered. Failure to secure those registrations could adversely affect our business.

~~Four~~As of ~~our trademarks are registered~~April 28, 2023, we have trademark registrations in the ~~United States.~~U.S. for KARYOPHARM THERAPEUTICS, our color logo, and a combination of the two, XPOVIO, PORE for our online research portal, and KARYFORWARD and our KARYFORWARD logo for our financial aid and charitable services. We also have ~~six~~ pending ~~intent-to-use~~ applications ~~that we filed in 2014, which have been allowed, meaning that we can perfect our registrations when we have commenced use in commerce. Outside the United States, we have five registrations~~ in the ~~European Union,~~U.S. to register KARYOPHARM alone, and ~~we filed two~~our logo in greyscale, for pharmaceuticals. Outside of the U.S., XPOVIO is registered or pending in 46 additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan. KARYOPHARM, the greyscale logo, KARYOPHARM THERAPEUTICS with the color logo, and the KARYFORWARD logo are each registered or pending in four jurisdictions outside of the U.S. We also have registrations or applications ~~each~~for eight additional possible drug names in ~~14 other~~numerous foreign jurisdictions. ~~Several of those have proceeded to registration.~~ If we do not secure registrations for our trademarks, we may encounter more difficulty in enforcing them against third parties than we otherwise would, which could adversely affect our business. During trademark registration proceedings in the ~~United States~~U.S. and foreign jurisdictions, we may receive rejections. We are given an opportunity to respond to those rejections, but we may not be able to overcome such rejections. In addition, in the USPTO and in comparable agencies in many foreign jurisdictions, third parties are given an opportunity to oppose pending trademark applications and to seek to cancel registered trademarks. Opposition or cancellation proceedings may be filed against our trademarks, and our trademarks may not survive such proceedings.

In addition, any proprietary name we propose to use with our key ~~drug~~product candidates in the ~~United States~~U.S. must be approved by the FDA, regardless of whether we have registered it, or applied to register it, as a trademark. The FDA typically conducts a review of proposed drug names, including an evaluation of potential for confusion with other drug names. If the FDA objects to any of our proposed proprietary drug names for any of our ~~drug~~product candidates, if approved, we may be required to expend significant additional resources in an effort to identify a suitable proprietary drug name that would qualify under applicable trademark laws, not infringe the existing rights of third parties and be acceptable to the FDA.

~~Risks Related to Regulatory Approval and Marketing of Our Product Candidates and Other Legal Compliance Matters~~

Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of some or all of our drug candidates. As a result, we cannot predict when or if we or any of our collaborators will obtain marketing approval to commercialize a drug candidate.

The research, testing, manufacturing, labeling, approval, selling, marketing, promotion and distribution of drugs are subject to extensive regulation by the FDA and comparable foreign regulatory authorities, whose laws and regulations may differ from country to country. We are not permitted to market our drug candidates in the United States or in other countries until we or any of our collaborators receive approval of an NDA from the FDA or marketing approval from applicable regulatory authorities outside of the United States. Our drug candidates are in early stages of development and are subject to the risks of failure inherent in drug development. We have not submitted an application for or received marketing approval for any of our drug candidates in the United States or in any other jurisdiction. We have limited experience in conducting and managing the clinical trials necessary to obtain marketing approvals, including FDA approval of an NDA.

The process of obtaining marketing approvals, both in the United States and abroad, is a lengthy, expensive and uncertain process. It may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the drug candidates involved.

In addition, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted drug application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional preclinical studies, clinical trials or other studies and testing. In addition, varying interpretations of the data obtained from preclinical studies and clinical trials could delay, limit or prevent marketing approval of a drug candidate. Any marketing approval we or any of our collaborators ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable.

Any delay in obtaining or failure to obtain required approvals could materially adversely affect our ability or that of any of our collaborators to generate revenue from the particular drug candidate, which likely would result in significant harm to our financial position and adversely impact our stock price.

Our failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being marketed abroad, and any approval we are granted for our product candidates in the United States would not assure approval of product candidates in foreign jurisdictions.

In order to market and sell our drugs in the European Union and many other jurisdictions, we and our collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The marketing approval process outside of the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside of the United States, it is required that the drug be approved for reimbursement before the drug can be approved for sale in that country. We and our collaborators may not obtain approvals from regulatory authorities outside of the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside of the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.

Additionally, on June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union, commonly referred to as Brexit. On March 29, 2017, the country formally notified the European Union of its intention to withdraw pursuant to Article 50 of the Lisbon Treaty. Since a significant proportion of the regulatory framework in the United Kingdom is derived from European Union directives and regulations, the referendum could materially impact the regulatory regime with respect to the approval of our product candidates in the United Kingdom or the European Union. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing our product candidates in the United Kingdom and/or the European Union and restrict our ability to generate revenue and achieve and sustain profitability. If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European Union for our product candidates, which could significantly and materially harm our business.

~~We may not be able to obtain orphan drug exclusivity for our product candidates.~~

Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs and biologics for relatively small patient populations as orphan drugs. Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals annually in the United States.

Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same product for that time period. The applicable period is seven years in the United States and ten years in Europe. The European exclusivity period can be reduced to six years if a product no longer meets the criteria for orphan drug designation or if the product is sufficiently profitable so that market exclusivity is no longer justified. Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.

Even if we obtain orphan drug exclusivity from the FDA for a product, as we have for selinexor in AML, diffuse large B-cell lymphoma, or DLBCL, and multiple myeloma, that exclusivity may not effectively protect the product from competition because different products can be approved for the same condition. Even after an orphan drug is approved, the FDA can subsequently approve a different product for the same condition if the FDA concludes that the later product is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

On August 3, 2017, Congress passed the FDA Reauthorization Act of 2017 (FDARA). FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity. The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority. The FDA may further reevaluate the Orphan Drug Act and its regulations and policies. We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business. Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.

A fast track designation, grant of priority review status or breakthrough therapy status by the FDA is not assured and, in any event, may not actually lead to a faster development or regulatory review or approval process and, moreover, would not assure FDA approval of our product candidates.

We may be eligible for fast track designation, priority review or breakthrough therapy status for product candidates that we develop. If a product is intended for the treatment of a serious or life-threatening disease or condition and the product demonstrates the potential to address unmet medical needs for this disease or condition, the product sponsor may apply for FDA fast track designation. If a product offers major advances in treatment, the product sponsor may apply for FDA priority review status. Additionally, a product candidate may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The FDA has broad discretion whether or not to grant these designations, so even if we believe a particular product candidate is eligible for such designation or status, the FDA could decide not to grant it. Moreover, even if we do receive such a designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures and there is no assurance that our product candidate will be approved by the FDA.

Even if we or any of our collaborators obtain marketing approvals for our drug candidates, the terms of approvals and ongoing regulation of our drugs may limit how we, or they, manufacture and market our drugs, which could materially impair our ability to generate revenue.

Once marketing approval has been granted, an approved drug and its manufacturer and marketer are subject to ongoing review and extensive regulation. We and our collaborators must therefore comply with requirements concerning advertising and promotion for any of our drug candidates for which we or they obtain marketing approval. Promotional communications with respect to prescription drugs are subject to a variety of legal and regulatory restrictions and must be consistent with the information in the drug’s approved labeling. Thus, we and our collaborators may not be able to promote any drugs we develop for indications or uses for which they are not approved.

In addition, manufacturers of approved drugs and those manufacturers’ facilities are required to comply with extensive FDA requirements, including ensuring that quality control and manufacturing procedures conform to cGMPs, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation and reporting requirements. We, our contract manufacturers, our collaborators and their contract manufacturers could be subject to periodic unannounced inspections by the FDA to monitor and ensure compliance with cGMPs.

Accordingly, assuming we or our collaborators receive marketing approval for one or more of our drug candidates, we, and our collaborators, and our and their contract manufacturers will continue to expend time, money and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance and quality control.

If we and our collaborators are not able to comply with post-approval regulatory requirements, we and our collaborators could have the marketing approvals for our drugs withdrawn by regulatory authorities, and our or our collaborators’ ability to market any future drugs could be limited, which could adversely affect our ability to achieve or sustain profitability. Further, the cost of compliance with post-approval regulations may have a negative effect on our operating results and financial condition.

Any of our drug candidates for which we or our collaborators obtain marketing approval in the future could be subject to post-marketing restrictions or withdrawal from the market, and we and our collaborators may be subject to substantial penalties if we, or they, fail to comply with regulatory requirements or if we, or they, experience unanticipated problems with our drugs following approval.

Any of our drug candidates for which we or our collaborators obtain marketing approval in the future, as well as the manufacturing processes, post-approval studies and measures, labeling, advertising and promotional activities for such drug, among other things, will be subject to continual requirements of and review by the FDA and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and recordkeeping. Even if marketing approval of a drug candidate is granted, the approval may be subject to limitations on the indicated uses for which the drug may be marketed or to the conditions of approval, including the requirement to implement a Risk Evaluation and Mitigation Strategy, which could include requirements for a restricted distribution system.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of a drug. The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of drugs to ensure that they are manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label use, and if we or our collaborators do not market any of our drug candidates for which we, or they, receive marketing approval for only their approved indications, we, or they, may be subject to warnings or enforcement action for off-label marketing. Violation of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations or allegations of violations of federal and state health care fraud and abuse laws and state consumer protection laws.

In addition, later discovery of previously unknown AEs or other problems with our drugs or their manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including:

~~litigation involving patients taking our drug;~~

~~restrictions on such drugs, manufacturers or manufacturing processes;~~

~~restrictions on the labeling or marketing of a drug;~~

~~restrictions on drug distribution or use;~~

~~requirements to conduct post-marketing studies or clinical trials;~~

~~warning letters or untitled letters;~~

~~withdrawal of the drugs from the market;~~

~~refusal to approve pending applications or supplements to approved applications that we submit;~~

~~recall of drugs;~~

~~fines, restitution or disgorgement of profits or revenues;~~

~~suspension or withdrawal of marketing approvals;~~

~~damage to relationships with any potential collaborators;~~

~~unfavorable press coverage and damage to our reputation;~~

~~refusal to permit the import or export of drugs;~~

~~drug seizure; or~~

~~injunctions or the imposition of civil or criminal penalties.~~

The efforts of the Administration to pursue regulatory reform may limit FDA’s ability to engage in oversight and implementation activities in the normal course, and that could negatively impact our business.

The Trump Administration has taken several executive actions, including the issuance of a number of executive orders, that could impose significant burdens on, or otherwise materially delay, the FDA’s ability to engage in routine regulatory and oversight activities such as implementing statutes through rulemaking, issuance of guidance, and review and approval of marketing applications. On January 30, 2017, President Trump issued an executive order, applicable to all executive agencies, including the FDA, that requires that for each notice of proposed rulemaking or final regulation to be issued in fiscal year 2017, the agency shall identify at least two existing regulations to be repealed, unless prohibited by law. These requirements are referred to as the “two-for-one” provisions. This executive order includes a budget neutrality provision that requires the total incremental cost of all new regulations in the 2017 fiscal year, including repealed regulations, to be no greater than zero, except in limited circumstances. For fiscal years 2018 and beyond, the executive order requires agencies to identify regulations to offset any incremental cost of a new regulation. In interim guidance issued by the Office of Information and Regulatory Affairs within OMB on February 2, 2017, the administration indicates that the “two-for-one” provisions may apply not only to agency regulations, but also to significant agency guidance documents. It is difficult to predict how these requirements will be implemented, and the extent to which they will impact the FDA’s ability to exercise its regulatory authority. If these executive actions impose constraints on FDA’s ability to engage in oversight and implementation activities in the normal course, our business may be negatively impacted.

Current and future legislation may increase the difficulty and cost for us and any collaborators to obtain marketing approval of and commercialize our product candidates and affect the prices we, or they, may obtain.

In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates for which we obtain marketing approval. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.

In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or collectively the ACA. Among the provisions of the ACA of potential importance to our business and our product candidates are the following:

~~an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription products and biologic agents;~~

~~an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;~~

~~a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for products that are inhaled, infused, instilled, implanted or injected;~~

~~expansion of healthcare fraud and abuse laws, including the civil False Claims Act and the federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;~~

a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated prices of applicable brand products to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient products to be covered under Medicare Part D;

~~extension of manufacturers’ Medicaid rebate liability to individuals enrolled in Medicaid managed care organizations;~~

~~expansion of eligibility criteria for Medicaid programs;~~

~~expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;~~

~~new requirements to report certain financial arrangements with physicians and teaching hospitals;~~

~~a new requirement to annually report product samples that manufacturers and distributors provide to physicians;~~

~~a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;~~

a new Independent Payment Advisory Board, or IPAB, which has authority to recommend certain changes to the Medicare program to reduce expenditures by the program that could result in reduced payments for prescription products; and

~~established the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service delivery models.~~

In addition, other legislative changes have been proposed and adopted since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2024 unless additional Congressional action is taken. The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

We expect that the ACA, as well as other healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new payment methodologies and additional downward pressure on the price that we receive for any approved product and/or the level of reimbursement physicians receive for administering any approved product we might bring to market. Reductions in reimbursement levels may negatively impact the prices we receive or the frequency with which our products are prescribed or administered. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.

Since enactment of the ACA, there have been numerous legal challenges and Congressional actions to repeal provisions of the ACA. In January 2017, President Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices. The U.S. House of Representatives passed legislation known as the American Health Care Act of 2017 in May 2017. More recently, the Senate Republicans introduced and then updated a bill to replace the ACA known as the Better Care Reconciliation Act of 2017. The Senate Republicans also introduced legislation to repeal the ACA without companion legislation to replace it, and a “skinny” version of the Better Care Reconciliation Act of 2017. Each of these measures was rejected by the full U.S. Senate. Congress will likely consider other legislation to replace elements of the ACA. We continue to evaluate the effect that the ACA and its possible repeal and replacement could have on our business. Such reforms could have an adverse effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain marketing approval and may affect our overall financial condition and ability to develop or commercialize product candidates.

The costs of prescription pharmaceuticals in the United States has also been the subject of considerable discussion in the United States, and members of Congress and the Administration have stated that they will address such costs through new legislative and administrative measures. The pricing of prescription pharmaceuticals is also subject to governmental control outside the United States. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidates to other available therapies. If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate revenues and become profitable could be impaired.

Our relationships with healthcare providers and physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third party payors will play a primary role in the recommendation and prescription of any drugs for which we obtain marketing approval. Our future arrangements with third party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any drugs for which we obtain marketing approval. These include the following:

~~Anti-Kickback Statute~~—the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

•

~~False Claims Act~~—the federal False Claims Act imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties, currently set at $5,500 to $11,000 per false claim;

~~HIPAA~~—the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters, and, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and transmission of individually identifiable health information;

~~Transparency Requirements—federal laws require applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals; and~~

~~Analogous State and Foreign Laws~~—analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, can apply to sales or marketing arrangements and claims involving healthcare items or services and are generally broad and are enforced by many different federal and state agencies as well as through private actions.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures. State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations. If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union. The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of European Union Member States, such as the UK Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment.

Payments made to physicians in certain European Union Member States must be publicly disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual European Union Member States. These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the European Union Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

The collection and use of personal health data in the European Union is governed by the provisions of the Data Protection Directive. This directive imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, notification of data processing obligations to the competent national data protection authorities and the security and confidentiality of the personal data. The Data Protection Directive also imposes strict rules on the transfer of personal data out of the European Union to the United States. Failure to comply with the requirements of the Data Protection Directive and the related national data protection laws of the European Union Member States may result in fines and other administrative penalties. The draft Data Protection Regulation currently going through the adoption process is expected to introduce new data protection requirements in the European Union and substantial fines for breaches of the data protection rules. If the draft Data Protection Regulation is adopted in its current form it may increase our responsibility and liability in relation to personal data that we process and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules. This may be onerous and adversely affect our business, financial condition, results of operations and prospects.

Our employees may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements, which could cause significant liability for us and harm our reputation.

We are exposed to the risk of employee fraud or other misconduct, including intentional failures to comply with FDA regulations or similar regulations of comparable foreign regulatory authorities, provide accurate information to the FDA or comparable foreign regulatory authorities, comply with manufacturing standards we have established, comply with federal and state healthcare fraud and abuse laws and regulations and similar laws and regulations established and enforced by comparable foreign regulatory authorities, report financial information or data accurately or disclose unauthorized activities to us. Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. It is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and results of operations, including the imposition of significant fines or other sanctions.

~~If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on our business.~~

Laws and regulations governing any international operations we may have in the future may preclude us from developing, manufacturing and selling certain drug candidates outside of the United States and require us to develop and implement costly compliance programs.

We are subject to numerous laws and regulations in each jurisdiction outside the United States in which we operate. The creation, implementation and maintenance of international business practices compliance programs is costly and such programs are difficult to enforce, particularly where reliance on third parties is required.

The FCPA prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations. The anti-bribery provisions of the FCPA are enforced primarily by the DOJ. The Securities and Exchange Commission, or SEC, is involved with enforcement of the books and records provisions of the FCPA.

Various laws, regulations and executive orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. Our expansion outside of the United States, has required, and will continue to require, us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain drugs and drug candidates outside of the United States, which could limit our growth potential and increase our development costs. The failure to comply with laws governing international business practices may result in substantial penalties, including suspension or debarment from government contracting. Violation of the FCPA can result in significant civil and criminal penalties. Indictment alone under the FCPA can lead to suspension of the right to do business with the U.S. government until the pending claims are resolved. Conviction of a violation of the FCPA can result in long-term disqualification as a government contractor. The termination of a government contract or relationship as a result of our failure to satisfy any of our obligations under laws governing international business practices would have a negative impact on our operations and harm our reputation and ability to procure government contracts. The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions.

~~Governments outside of the United States tend to impose strict price controls, which may adversely affect our revenues from the sales of drugs, if any.~~

In some countries, particularly the countries of the European Union, the pricing of prescription pharmaceuticals is subject to governmental control. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a drug. To obtain reimbursement or pricing approval in some countries, we or our collaborators may be required to conduct a clinical trial that compares the cost-effectiveness of our drug to other available therapies. If reimbursement of our drugs is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be materially harmed.

Risks Related to Employee Matters and Managing Growth

Our future success depends on our ability to retain key members of our ~~Chief Executive Officer, our President and Chief Scientific Officer and other key executives~~management team and to attract, retain and motivate qualified personnel.

We are highly dependent on ~~Michael Kauffman, M.D., Ph.D., our Chief Executive Officer,~~the management, technical and ~~Sharon Shacham, Ph.D., M.B.A., our President and Chief Scientific Officer, as well as the other~~scientific expertise of principal members of our management and scientific ~~teams.~~teams, including our President and Chief Executive Officer. Although we have entered into formal employment agreements with ~~Drs. Kauffman and Shacham,~~our executive officers, these agreements do not prevent them from terminating their employment with us at any time. We do not maintain “key person” insurance for any of our executives or other employees. The loss of the services of any of our key employees could impede the achievement of our research, development, commercialization and other business objectives.

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Recruiting and retaining qualified scientific, clinical, manufacturing and sales and marketing personnel ~~will also be~~is critical to our success. We may not be able to attract and retain these personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions. In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization ~~strategy.~~strategies. Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.

~~Drs. Kauffman and Shacham are married to each other. The separation or divorce of the couple in the future could adversely affect our business.~~

Dr. Kauffman, our Chief Executive Officer and member of our board of directors, and Dr. Shacham, our President and Chief Scientific Officer, are married to each other. They are two of our executive officers and are a vital part of our operations. If they were to become separated or divorced or could otherwise not amicably work with each other, one of them may decide to cease his or her employment with us or it could negatively impact our working environment. Alternatively, their work performance may not be satisfactory if they become preoccupied with issues relating to their personal situation. In these cases, our business could be materially harmed.

~~We expect to expand our development, regulatory and future sales and marketing capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.~~

We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug development, regulatory affairs and, potentially, sales and marketing. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel. Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel. The physical expansion of our operations may lead to significant costs and may divert our management and business development resources. Any inability to manage growth could delay the execution of our business plans or disrupt our operations.

Our business and operations may be materially adversely affected in the event of ~~computer~~information technology system failures or security ~~breaches.~~breaches, and the costs and consequences of implementing data protection measures could be significant.

Despite the implementation of security measures, our internal computer systems, and those of our ~~contract research organizations~~CROs and other third parties on which we rely, are vulnerable to damage from computer viruses, unauthorized access, ~~cyber attacks,~~ natural disasters, fire, terrorism, war and telecommunication and electrical failures. Such systems are also vulnerable to service interruptions or to security breaches from inadvertent or intentional actions by our employees, third-party vendors and/or business partners, or from cyber incidents initiated by malicious third parties. Cyber incidents are increasing in their frequency, sophistication and intensity, and have become increasingly difficult to detect, respond to and recover from. Cyber incidents could include the deployment of harmful malware, ransomware, denial-of-service attacks, unauthorized access to or deletion of files, social engineering and other means to affect service reliability and threaten the confidentiality, integrity and availability of information. Cyber incidents also could include phishing attempts or e-mail fraud to cause payments or information to be transmitted to an unintended recipient. We could be subject to risks caused by misappropriation, misuse, leakage, falsification or intentional or accidental release or loss of information maintained in the information systems and networks of our company, including personal data of our employees. In addition, we face other kinds of risks related to our commercial and personal data, including lost or stolen devices or other systems (including paper records) that collect and store our personal and commercial information.

If such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our ~~drug~~ development ~~programs.~~and commercialization programs and our business operations, whether due to a loss of our trade secrets or other proprietary information or other similar disruptions. For example, the loss of clinical trial data from completed, ongoing or planned clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach ~~results~~were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our reputation or competitive position could be damaged, and the further development and commercialization of our ~~drug~~products or product candidates could be ~~delayed. We~~delayed or halted. In addition, we may ~~also~~in certain instances be ~~vulnerable~~required to ~~cyber attacks by hackers,~~provide notification to individuals or ~~other malfeasance. This type~~others in connection with the loss of their personal or commercial information.

If a material breach of our ~~cybersecurity may compromise~~security or that of our vendors occurs, our financial or other confidential information ~~and/or our financial information~~could be compromised and could adversely affect our business or result in legal proceedings. In addition, the cost and operational consequences of implementing further data protection measures could be significant. The development and maintenance of these systems, controls and processes is costly and requires ongoing monitoring and updating as technologies change and efforts to overcome security measures become more sophisticated. Moreover, the possibility of these events occurring cannot be eliminated entirely.

Risks Related to Our Common Stock

~~Our executive officers, directors and principal stockholders maintain the ability to control all matters submitted to stockholders for approval.~~

As of September 30, 2017, our executive officers, directors and a small number of stockholders own more than a majority of our outstanding common stock. As a result, if these stockholders were to choose to act together, they would be able to control all matters submitted to our stockholders for approval, as well as our management and affairs. For example, these persons, if they choose to act together, would control the election of directors and approval of any merger, consolidation or sale of all or substantially all of our assets. This concentration of voting power could delay or prevent an acquisition of our company on terms that other stockholders may desire.

Provisions in our corporate charter documents and under Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current management.

Provisions in our corporate charter and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of us that stockholders may consider favorable, including transactions in which stockholders might otherwise receive a premium for their shares. These provisions could also limit the price that investors might be willing to pay in the future for shares of our common stock, thereby depressing the market price of our common stock. In addition, because our board of directors is responsible for appointing the members of our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our board of directors. Among other things, these provisions:

•

establish a classified board of directors such that not all members of the board are elected at one time;

•

allow the authorized number of our directors to be changed only by resolution of our board of directors;

•

limit the manner in which stockholders can remove directors from the board;

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•

establish advance notice requirements for stockholder proposals that can be acted on at stockholder meetings and nominations to our board of directors;

•

require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent;

•

limit who may call stockholder meetings;

•

authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and

•

require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.

Moreover, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which prohibits a person who owns in excess of 15% of our outstanding voting stock from merging or combining with us for a period of three years after the date of the transaction in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or combination is approved in a prescribed manner.

~~An active trading~~The price of our common stock has been and may continue to be volatile and your investment in our stock could decline in value or fluctuate significantly, including as a result of analysts’ activities.

Our stock price has been, and may continue to be, volatile, and your investment in our stock could decline or fluctuate significantly. Our common stock price has ranged from $2.48 to $6.74 in the 52-week period ended April 28, 2023. On April 28, 2023, the closing sale price of our common stock on the Nasdaq Global Select Market was $3.58 per share. The stock market in general and the market for pharmaceutical and biotechnology companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies, such as the response to world-wide economic disruptions related to the ongoing COVID-19 pandemic, the conflict between Russia and Ukraine, rising inflation and increasing interest rates. The market price for our common stock may ~~not~~ be ~~sustained.~~influenced by many factors, including:

~~Although~~

•

our ~~common stock is listed~~failure to successfully execute on ~~The NASDAQ Global Select Market, an active trading market~~our commercialization strategy for XPOVIO or our product candidates, if approved;

•

the level of success of competitive products or technologies;

•

results, delays in, or the halting of our clinical trials or those of our competitors, including reports of AEs related to the use of our products;

•

announcements by us or our competitors of new products or data, significant mergers, acquisitions, licenses or joint ventures;

•

commencement or termination of collaborations for our ~~shares may not be sustained. If an active~~ development programs and the commercialization of our products;

•

adverse regulatory or legal developments in the U.S. and other countries;

•

developments or disputes concerning patent applications, issued patents or other proprietary rights;

•

additions or departures of key personnel;

•

the level of expenses related to the commercialization of XPOVIO and clinical development programs for any of our product candidates;

•

the results of our efforts to discover, develop, acquire or in-license additional products or product candidates;

•

actual or anticipated changes in estimates of financial results or guidance, development timelines or recommendations by securities analysts;

•

actual or anticipated fluctuations in our quarterly or annual financial results;

•

changes in healthcare laws affecting pricing, reimbursement or access;

•

market ~~for~~ conditions in the pharmaceutical and biotechnology sectors, including as the result of uncertainties due to or impacts from the ongoing COVID-19 pandemic;

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•

general economic, industry and market conditions, such as those caused by the COVID-19 pandemic, the ongoing conflict between Russia and Ukraine, inflation and fluctuations in interest rates;

•

our ~~common stock does not continue, it may be difficult for you~~ability to ~~sell shares~~raise additional capital and the terms on which we can raise it;

•

sales of large blocks of our common stock, ~~without depressing~~including by our executive officers, directors and significant stockholders, or substantial changes in short interest in our common stock; and

•

the other risks and uncertainties described in this “Risk Factors” section.

The COVID-19 pandemic has caused significant disruptions in the financial markets, and may continue to cause such disruptions, and has also impacted, and may continue to impact, the volatility of our stock price and trading in our stock. In addition, U.S. and global markets are experiencing volatility and disruption following the escalation of geopolitical tensions and the ongoing conflict between Russia and Ukraine, rising inflation and increasing interest rates. A continuation or worsening of the levels of market disruption and volatility could have an adverse effect on the market price ~~for the shares, or at all. An inactive trading market for~~of our common stock may also impair our ability to raise capital to continue to fund our operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.

~~If securities analysts do not continue to publish research or reports about our business or if they publish negative evaluations of our stock,~~stock. Furthermore, the ~~price of our stock could decline.~~

~~The~~ trading market for our common stock relies, in part, on the research and reports that industry or financial analysts publish about us or our business. ~~There can be no assurance that analysts will provide favorable coverage~~Our stock price could decline significantly if we fail to meet or ~~continue to cover us. If~~exceed analysts’ forecasts and expectations or if one or more of the analysts covering our business downgrade their evaluations of our ~~stock, the price of our stock could decline. If~~stock. Further, if one or more of these analysts cease to cover our stock, we could lose visibility in the market for our stock, which in turn could cause our stock price to decline.

~~The price of our common stock has been~~Securities or other litigation could result in substantial costs and may ~~be volatile in the future~~divert management’s time and ~~fluctuate substantially.~~attention from our business.

Our stock price has been and is likely to be volatile and may fluctuate substantially. For example, since January 1, 2015, our common stock has traded at prices per share as high as $38.47 and as low as $4.83. The stock market in general and the market for pharmaceutical and biotechnology companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. The market price for our common stock may be influenced by many factors, including:

~~the success of competitive drugs or technologies;~~

~~results of clinical trials of our drug candidates or those of our competitors;~~

~~regulatory or legal developments in the United States and other countries;~~

~~developments or disputes concerning patent applications, issued patents or other proprietary rights;~~

~~the recruitment or departure of key personnel;~~

~~the level of expenses related to any of our drug candidates or clinical development programs;~~

~~the results of our efforts to discover, develop, acquire or in-license additional drug candidates or drugs;~~

~~actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;~~

~~variations in our financial results or those of companies that are perceived to be similar to us;~~

~~changes in the structure of healthcare payment systems;~~

~~market conditions in the pharmaceutical and biotechnology sectors;~~

~~general economic, industry and market conditions; and~~

~~the other factors described in this “Risk Factors” section.~~

~~We could be subject to securities class action litigation.~~

~~In the past, securities~~Securities class action litigation ~~has~~is often ~~been~~ brought against a company following a decline or periods of volatility in the market price of its securities. This risk is especially relevant for us because pharmaceutical companies have experienced significant stock price volatility in recent ~~years. If~~years, including as a result of the COVID-19 pandemic, and we are therefore a target of this type of litigation. For example, we were subject to a class action lawsuit and a shareholder derivative lawsuit alleging federal securities laws violations, both of which have been dismissed. We may face additional securities class action litigation or other litigation in the future, including if we fail to successfully commercialize XPOVIO, or if we cannot obtain regulatory approvals for, or if we otherwise fail to successfully commercialize and launch, our product candidates.

The outcome of litigation is necessarily uncertain, and we could be forced to expend significant resources in the defense of such suits, and we may not prevail. Monitoring and defending against legal actions is time-consuming for our management and detracts from our ability to fully focus our internal resources on our business activities. In addition, we may incur substantial legal fees and costs in connection with any such litigation. We have not established any reserves for any potential liability relating to any such potential lawsuits. It is possible that we could, in the future, incur judgments or enter into settlements of claims for monetary damages. We currently maintain insurance coverage for some of these potential liabilities. Other potential liabilities may not be covered by insurance, insurers may dispute coverage or the amount of insurance may not be enough to cover damages awarded. In addition, certain types of damages may not be covered by insurance, and insurance coverage for all or certain forms of liability may become unavailable or prohibitively expensive in the future. A decision adverse to our interests on one or more legal matters or litigation it could result in the payment of substantial ~~costs~~damages, or possibly fines, and could have a ~~diversion~~material adverse effect on our reputation, financial condition and results of ~~management’s attention and our resources, which could harm our business.~~operations.

We have broad discretion in the use of our cash, ~~and~~ cash equivalents and investments and may not use them effectively.

Our management has broad discretion to use our cash, ~~and~~ cash equivalents and investments to fund our operations and could spend these funds in ways that do not improve our results of operations or enhance the value of our common stock. The failure by our management to apply these funds effectively could result in financial losses that could have a material adverse effect on our business, cause the price of our common stock to decline and delay the development of our ~~drug~~product candidates. Pending their use to fund our operations, we may invest our cash and cash equivalents in a manner that does not produce income or that loses value.

~~We are~~If we identify a material weakness in our internal control over financial reporting, it could have an ~~“emerging growth company,”~~adverse effect on our business and financial results and our ability to meet our reporting obligations could be negatively affected, each of which could negatively affect the ~~reduced disclosure requirements applicable to emerging growth companies may make~~trading price of our common ~~stock less attractive to investors.~~stock.

A material weakness is a deficiency, or a combination of deficiencies, in internal control over financial reporting, such that there is a reasonable possibility that a material misstatement of our annual or interim financial statements will not be prevented or detected on a timely basis. Accordingly, a material weakness increases the risk that the financial information we report contains material errors.

We ~~are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act,~~regularly review and ~~may remain an emerging growth company through 2018. For so long as we remain an emerging growth company,~~update our internal controls, disclosure controls and procedures, and corporate governance policies. In addition, we are ~~permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include not being~~ required ~~to comply with the auditor attestation requirements of Section 404 of~~under the Sarbanes-Oxley Act of 2002 ~~or Section 404, not being required~~ to ~~comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s~~ report providing additional information about the audit and the financial statements, reduced disclosure obligations regarding executive compensation and exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and shareholder approval of any golden parachute payments not previously approved. We cannot predict whether investors will find our common stock less attractive if we rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be more volatile.

In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards. This allows an emerging growth company to delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have irrevocably elected not to avail ourselves of this exemption from new or revised accounting standards and, therefore, we will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

We will continue to incur increased costs as a result of operating as a public company, and our management will need to continue to devote substantial time to compliance initiatives and corporate governance practices.

As a public company, and particularly after we are no longer an “emerging growth company,” we will incur significant legal, accounting and other expenses. In addition, the Sarbanes-Oxley Act of 2002 and rules subsequently implemented by the SEC and NASDAQ have imposed various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our management and other personnel will need to continue to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations will increase our legal and financial compliance costs and will make some activities more time-consuming and costly.

We cannot predict with certainty the amount of additional costs we may incur to continue to operate as a public company, nor can we predict the timing of such costs. In addition, the rules and regulations applicable to public companies are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies which could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.

~~Pursuant to Section 404, we are required to furnish a report by our management~~annually on our internal control over financial reporting. ~~However, while~~

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Any system of internal controls, however well designed and operated, is based in part on certain assumptions and can provide only reasonable, not absolute, assurances that the objectives of the system are met. If we, ~~remain an emerging growth company, we are not required to include an attestation report on internal control over financial reporting issued by~~or our independent registered public accounting ~~firm. To achieve compliance with Section 404 within~~firm, determine that our internal control over our financial reporting is not effective, or we discover areas that need improvement in the ~~prescribed period,~~future, or we ~~are engaged~~experience high turnover of our personnel in ~~a process~~our financial reporting functions, these shortcomings could have an adverse effect on our business and financial results, and the price of our common stock could be negatively affected.

If we cannot conclude that we have effective internal control over our financial reporting, or if our independent registered public accounting firm is unable to ~~document and evaluate~~provide an unqualified opinion regarding the effectiveness of our internal control over financial reporting, which is both costly and challenging. In this regard, we will need to continue to dedicate internal resources, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as documented and implement a

continuous reporting and improvement process for internal control over financial reporting. There is a risk that neither we nor our independent registered public accounting firm will be able to conclude within the prescribed timeframe that our internal control over financial reporting is effective as required by Section 404. Thisinvestors could ~~result in an adverse reaction in the financial markets due to a loss of~~lose confidence in the reliability of our financial ~~statements. In addition,~~statements, which could lead to a decline in our stock price. Failure to comply with reporting requirements could also subject us to sanctions and/or investigations by the SEC, the Nasdaq Stock Market or other regulatory authorities.

If the estimates we make, or the assumptions on which we rely, in preparing our consolidated financial statements, our projected guidance and/or our projected market opportunities prove inaccurate, our actual results may vary from those reflected in our projections and accruals.

Our consolidated financial statements have been prepared in accordance with accounting principles generally accepted in the United States of America (“GAAP”). The preparation of these consolidated financial statements requires us to make estimates and judgments that affect the reported amounts of our assets, liabilities, revenues and expenses, the amounts of charges accrued by us and related disclosure of contingent assets and liabilities. We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances.

We cannot assure you, however, that our estimates, or the assumptions underlying them, will be correct. Further, from time to time we issue guidance on our expected financial performance for future periods, such as our expectations regarding our revenue, non-GAAP research and development and selling, general and administrative expenses, and cash, cash equivalents and investments available for operations, which guidance is based on estimates and the judgment of management. If, for any reason, our actual results differ materially from our guidance, we may have to adjust our publicly announced financial guidance. If we fail to meet, or if we ~~identify one~~are required to change or ~~more material weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability~~update any element of, our publicly disclosed financial ~~statements.~~guidance or other expectations about our business, our stock price could decline.

~~Because we do not anticipate paying any cash dividends~~Further our estimates of the potential market opportunities for XPOVIO and our product candidates include several key assumptions based on our ~~capital stock in~~industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, these assumptions involve the ~~foreseeable future, capital appreciation, if~~exercise of significant judgment on the part of our management, are inherently uncertain and the reasonableness of these assumptions has not been assessed by an independent source. If any of our ~~common stock will~~assumptions or estimates, or these publications, research, surveys or studies prove to be inaccurate, then the ~~sole source of gain~~actual market for ~~our stockholders.~~

~~We have never declared~~XPOVIO or ~~paid cash dividends on our capital stock. We currently intend to retain all of our future earnings, if~~ any ~~to finance the growth~~other products or product candidates may be smaller than we expect, and ~~development of our business. In addition, the terms of any future debt agreements may preclude us from paying dividends. As~~as a result ~~capital appreciation, if any, of~~ our ~~common stock will be the sole source of gain for our stockholders for the foreseeable future.~~

~~A significant portion of our total outstanding shares are restricted from immediate resale but~~product revenue may be ~~sold into the market in the near future, which could cause the market price of our common stock to drop significantly, even if our business is doing well.~~

Sales of a substantial number of shares of our common stock in the public market could occur at any time. These sales, or the perception in the market that the holders of a large number of shares intend to sell shares, could reduce the market price of our common stock. We had 47,154,204 shares outstanding as of September 30, 2017. Of such shares, at least 11.6 million shares are eligiblelimited and it may be more difficult for sale in the public market under Rule 144 of the Securities Act of 1933, as amended, or the Securities Act, subject to the volume limitations and other conditions of Rule 144. The holders of these shares may at any time decide to sell their shares in the public market.

~~Moreover, holders of an aggregate of approximately 11.7 million shares of our common stock as of September 30, 2017 have rights, subject to some conditions, to require~~ us to file registration statements covering their shares or to include their shares in registration statements that we may file for ourselves or other stockholders. We have also registered all shares of common stock that we may issue under our equity compensation plans. As a result, these shares can be freely sold in the public market upon issuance, subject to volume limitations applicable to affiliates, to the extent applicable.achieve profitability.

Our ability to use our net operating loss carryforwards and tax credit carryforwards to offset future taxable income may be subject to certain limitations.

Under the provisions of the Internal Revenue Code of 1986, as amended ~~or the Code,~~(the “Code”), our net operating loss and tax credit carryforwards are subject to review and possible adjustment by the Internal Revenue Service (and state tax authorities under relevant state tax rules). ~~The~~In addition, as described below in “Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition,” the TCJA, as amended by the CARES Act, includes changes to U.S. federal tax rates and the rules governing net operating loss carryforwards that may significantly impact our ability to utilize our net operating losses to offset taxable income in the future. Furthermore, the use of net operating loss and tax credit carryforwards may become subject to an annual limitation under Sections 382 and 383 of the Code, respectively, and similar state provisions in the event of certain cumulative changes in the ownership interest of significant ~~shareholders~~stockholders in excess of 50 percent over a three-year period. This could limit the amount of tax attributes that can be utilized annually to offset future taxable income or tax liabilities. The amount of the annual limitation is determined based on the value of a company immediately prior to the ownership change. Subsequent ownership changes may further affect the limitation in future years. Our company has completed several financings since its inception which resulted in an ownership change under Sections 382 and 383 of the Code. In addition, future changes in our stock ownership, some of which are outside of our control, could result in ownership changes in the future. For these reasons, we may not be able to use some or all of our net operating loss and tax credit carryforwards, even if we attain ~~profitability prior~~profitability.

Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.

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Changes in tax law may adversely affect our business or financial condition. The TCJA, as amended by the CARES Act, significantly revises the Code. The TCJA, among other things, contains significant changes to corporate taxation, including reduction of the corporate tax rate from a top marginal rate of 35% to a flat rate of 21% and limitation of the deduction for net operating losses to 80% of current year taxable income for losses arising in taxable years beginning after December 31, 2017 (though any such net operating losses may be carried forward indefinitely). In addition, beginning in 2022, the TCJA eliminates the option to deduct research and development expenditures currently and requires corporations to capitalize and amortize them over five years.

In addition to the ~~expiration~~CARES Act, as part of Congress’ response to the COVID-19 pandemic, economic relief legislation was enacted in 2020 and 2021 containing tax provisions. The IRA was also signed into law in August 2022. The IRA introduced new tax provisions, including a one percent excise tax imposed on certain stock repurchases by publicly traded companies. The one percent excise tax generally applies to any acquisition of stock by the publicly traded company (or certain of its affiliates) from a stockholder of the company in exchange for money or other property (other than stock of the company itself), subject to a de minimis exception. Thus, the excise tax could apply to certain transactions that are not traditional stock repurchases. Regulatory guidance under the TCJA and such additional legislation is and continues to be forthcoming, and such guidance could ultimately increase or lessen their impact on our ~~net operating loss~~business and financial condition. In addition, it is uncertain if and to what extent various states will conform to the TCJA and additional tax ~~credit carryforwards.~~legislation.

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Item 6. Exhibits.


~~Item 6.~~Exhibit Number		Description of Exhibit

10.1*		Form of Restricted Stock Agreement (Performance Vested) under 2022 Equity Incentive Plan (incorporated by reference to Exhibit 10.1 to the Registrant’s Current Report on Form 8-K (File No. 001-36167) filed with the Commission on February 15, 2023.

10.2*		Amendment No. 2 to 2022 Inducement Stock Incentive Plan (incorporated by reference to Exhibit 10.20 to the Registrant’s Annual Report on Form 10-K (File No. 001-36167) filed with the Commission on February 17, 2023.

10.3		Amendment No. 1 to License Agreement, dated May 19, 2022, by and between the Registrant and Berlin-Chemie AG.~~Exhibits.~~

10.4		Amendment No. 2 to License Agreement, dated March 14, 2023, by and between the Registrant and Berlin-Chemie AG.

10.5*		Promotion Letter, dated as of August 5, 2022, between the Registrant and Stuart Poulton.

10.6*		Offer Letter, dated as of January 13, 2022, between the Registrant and Stuart Poulton.

10.7*		Promotion Letter, dated as of December 31, 2021, between the Registrant and Sohanya Cheng.

10.8*		Offer Letter, dated as of June 1, 2021, between the Registrant and Sohanya Cheng.

10.9*		Offer Letter, dated as of November 24, 2020, between the Registrant and Michael Mano.

31.1		Certification of principal executive officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

31.2		Certification of principal financial officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

32.1		Certification of principal executive officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

32.2		Certification of principal financial officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

101.INS		Inline XBRL Instance Document. The instance document does not appear in the Interactive Data File because its XBRL tags are embedded within the Inline XBRL document.

101.SCH		Inline XBRL Taxonomy Extension Schema Document.

101.CAL		Inline XBRL Taxonomy Extension Calculation Linkbase Document.

101.DEF		Inline XBRL Taxonomy Extension Definition Linkbase Document.

101.LAB		Inline XBRL Taxonomy Extension Label Linkbase Document.

101.PRE		Inline XBRL Taxonomy Extension Presentation Linkbase Document.

104		Cover Page Interactive Data File (formatted as inline XBRL with applicable taxonomy extension information contained in Exhibits 101)

Exhibit

Form

Incorporated by Reference

Filed
Number

Description of Exhibit

File Number

Date of Filing

Exhibit Number

Herewith

  10.1

Letter Agreement, dated September 9, 2017, by and between the Registrant and Michael Falvey.

8-K

001-36167

09/12/2017

10.1

  10.2

Nonstatutory Stock Option Agreement, dated September 11, 2017, by and between the Registrant and Michael Falvey.

8-K

001-36167

09/12/2017

10.2

  31.1

Certification of principal executive officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

X

  31.2

Certification of principal financial officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

X

  32.1

Certification of principal executive officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

X

  32.2

Certification of principal financial officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

X

101.INS

Instance Document

X

101.SCH

Scheme Document

X

101.CAL

Calculation Linkbase Document

X

101.DEF

Definition Linkbase Document

X

101.LAB

Labels Linkbase Document

X

101.PRE

Presentation Linkbase Document

X

* Indicates a management contract or compensatory plan or arrangement.

Table of Contents ~~SIGNATURES~~

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.


	KARYOPHARM THERAPEUTICS INC.

Date: ~~November 2, 2017~~May 4, 2023	By:	/s/ ~~MICHAEL KAUFFMAN~~Richard Paulson
		~~Michael Kauffman, M.D., Ph.D.~~Richard Paulson
		President and Chief Executive Officer
		(Principal executive officer)

Date: ~~November 2, 2017~~May 4, 2023	By:	/s/ ~~MICHAEL F. FALVEY~~Michael Mason
		Michael ~~F. Falvey~~Mason
		Executive Vice President, Chief Financial Officer and Treasurer
		(Principal financial and accounting officer)

5769


Delaware		26-3931704
(State or other jurisdiction of incorporation or organization)		(I.R.S. Employer Identification Number)

85 Wells Avenue, 2nd Floor Newton, MA		02459
(Address of principal executive offices)		(Zip Code)


Large accelerated filer	☐	Accelerated filer	~~Accelerated filer~~	☒
~~Non-accelerated filer~~	☐	~~(Do not check if a smaller reporting company)~~	~~Smaller reporting company~~	☐
Non-accelerated filer	☐	Smaller reporting company	☐

		Emerging growth company	☒☐


	September 30, 2017			December 31, 2016			March 31, 2023			December 31, 2022
Assets
Current assets:
Cash and cash equivalents	$	54,450		$	49,663		$	84,062		$	135,188
Short-term investments		64,956			79,889
Investments								176,322			142,779
Accounts receivable, net								35,200			47,086
Inventory								3,827			4,224
Prepaid expenses and other current assets								18,284			19,821
Restricted cash		200			—			846			1,064
Prepaid expenses and other current assets		2,076			2,084
Total current assets		121,682			131,636			318,541			350,162
Property and equipment, net		2,304			2,836			849			1,139
Long-term investments		39,498			45,434
Operating lease right-of-use assets								5,776			6,238
Restricted cash		289			479			634			633
Total assets	$	163,773		$	180,385		$	325,800		$	358,172
Liabilities and stockholders’ equity
Liabilities and stockholders’ deficit
Current liabilities:
Accounts payable	$	1,890		$	4,751		$	9,045		$	2,773
Accrued expenses		17,715			11,362			47,032			58,415
Deferred revenue		1,050			—
Deferred rent		298			280
Operating lease liabilities								2,977			2,872
Other current liabilities		202			83			2,501			1,848
Total current liabilities		21,155			16,476			61,555			65,908
Deferred rent, net of current portion		1,441			1,666
Convertible senior notes								170,306			170,105
Deferred royalty obligation								132,718			132,718
Operating lease liabilities, net of current portion								5,310			6,097
Other liabilities								1,085			—
Total liabilities		22,596			18,142			370,974			374,828
Stockholders’ equity:
Preferred stock, $0.0001 par value; 5,000,000 shares authorized; none issued and outstanding		—			—
Common stock, $0.0001 par value; 100,000,000 shares authorized; 47,154,204 and 41,887,829 shares issued and outstanding at September 30, 2017 and December 31, 2016, respectively		5			4
Stockholders’ deficit:
Preferred stock, $0.0001 par value; 5,000 shares authorized; none issued and outstanding								—			—
Common stock, $0.0001 par value; 200,000 shares authorized; 113,971 and 113,213 shares issued and outstanding at March 31, 2023 and December 31, 2022, respectively								12			12
Additional paid-in capital		597,562			528,617			1,333,298			1,327,909
Accumulated other comprehensive loss		(90	)		(274	)		(419	)		(638	)
Accumulated deficit		(456,300	)		(366,104	)		(1,378,065	)		(1,343,939	)
Total stockholders’ equity		141,177			162,243
Total liabilities and stockholders’ equity	$	163,773		$	180,385
Total stockholders’ deficit								(45,174	)		(16,656	)
Total liabilities and stockholders’ deficit							$	325,800		$	358,172


	Nine Months Ended September 30,						For the Three Months Ended March 31,
	2017			2016			2023			2022
Operating activities
Net loss	$	(89,944	)	$	(82,642	)	$	(34,126	)	$	(41,399	)
Adjustments to reconcile net loss to net cash used in operating activities:
Stock-based compensation expense								5,389			7,336
Depreciation and amortization		539			537			290			177
Amortization of debt issuance costs								201			198
Net amortization of premiums and discounts on investments		903			839			(1,126	)		45
Stock-based compensation expense		15,906			17,157
Other								4			(2	)
Changes in operating assets and liabilities:
Prepaid expenses and other current assets		18			412
Accounts receivable, net								11,886			(2,495	)
Inventory								397			232
Prepaid expenses and other assets								1,537			(15,600	)
Operating lease right-of-use assets								462			397
Accounts payable		(2,867	)		(1,659	)		6,272			1,837
Accrued expenses and other liabilities		6,423			1,101			(9,414	)		(9,387	)
Deferred revenue		1,050			—
Deferred rent		(207	)		(138	)
Operating lease liabilities								(682	)		(536	)
Net cash used in operating activities		(68,179	)		(64,393	)		(18,910	)		(59,197	)
Investing activities
Purchases of property and equipment		(7	)		(45	)		—			(79	)
Proceeds from maturities of investments		94,033			140,719
Proceeds from sales and maturities of investments								27,944			21,584
Purchases of investments		(74,017	)		(122,681	)		(60,332	)		(35,540	)
Net cash provided by investing activities		20,009			17,993
Net cash used in investing activities								(32,388	)		(14,035	)
Financing activities
Proceeds from the issuance of common stock, net of issuance costs		52,323			31,463
Proceeds from the exercise of stock options and shares issued under employee stock purchase plan		463			452
Proceeds from issuance of common stock, net of issuance costs								—			29,316
Proceeds from the exercise of stock options								—			1,467
Net cash provided by financing activities		52,786			31,915			—			30,783
Effect of exchange rate on cash		171			35
Net increase (decrease) in cash and cash equivalents		4,787			(14,450	)
Cash and cash equivalents at beginning of period		49,663			58,358
Cash and cash equivalents at end of period	$	54,450		$	43,908
Supplemental disclosure of non-cash financing activity
Deferred financing costs included in accounts payable	$	—		$	40
Deferred financing costs included in accrued expenses	$	—		$	258
Deferred financing costs included in other current assets	$	16		$	1,883
Effect of exchange rate on cash, cash equivalents and restricted cash								(45	)		(90	)
Net decrease in cash, cash equivalents and restricted cash								(51,343	)		(42,539	)
Cash, cash equivalents and restricted cash at beginning of period								136,885			197,445
Cash, cash equivalents and restricted cash at end of period							$	85,542		$	154,906
Reconciliation of cash, cash equivalents and restricted cash reported within the condensed consolidated balance sheets
Cash and cash equivalents							$	84,062		$	153,256
Short-term restricted cash								846			1,014
Long-term restricted cash								634			636
Total cash, cash equivalents and restricted cash							$	85,542		$	154,906
Supplemental disclosures:
Cash paid for amounts included in the measurement of operating lease liabilities							$	923		$	841
Cash paid for interest on deferred royalty obligation							$	4,076		$	15,784


	For the Three Months Ended March 31,
	2023			2022
Gross product revenue	$	37,065		$	34,910
Provisions for product revenue		(8,777	)		(6,610	)
Total product revenue, net	$	28,288		$	28,300


	PART I - FINANCIAL INFORMATION	3
	~~PART I—FINANCIAL INFORMATION~~	3
Item 1.
~~Item 1.~~	Condensed Consolidated Financial Statements (Unaudited)	3
	Condensed Consolidated Balance Sheets	3
	Condensed Consolidated Statements of Operations	4
	Condensed Consolidated Statements of Comprehensive Loss	5
	Condensed Consolidated Statements of Cash Flows	6
	Condensed Consolidated Statements of Stockholders’ Deficit	7
	Notes to Condensed Consolidated Financial Statements	78
Item 2.	Management’s Discussion and Analysis of Financial Condition and Results of Operations	17
Item 3.	Quantitative and Qualitative Disclosures About Market Risk	23
Item 4.	Controls and Procedures	23

	PART ~~II—~~II - OTHER INFORMATION	24

Item 1A.	Risk Factors	24
Item 6.	Exhibits	5668
	Signatures	5769

	Three Months Ended September 30,						Nine Months Ended September 30,
	2017			2016			2017			2016			For the Three Months Ended March 31,
Contract and grant revenue	$	—		$	48		$	71		$	107
													2023			2022
Revenues:
Product revenue, net													$	28,288		$	28,300
License and other revenue														10,410			19,370
Total revenue														38,698			47,670
Operating expenses:
Cost of sales														1,351			1,426
Research and development		25,237			19,893			72,440			66,267			32,339			42,062
General and administrative		5,818			5,897			18,717			17,407
Selling, general and administrative														35,907			38,768
Total operating expenses		31,055			25,790			91,157			83,674			69,597			82,256
Loss from operations		(31,055	)		(25,742	)		(91,086	)		(83,567	)		(30,899	)		(34,586	)
Other income (expense):
Interest income		454			311			1,266			926			2,849			74
Other income (expense)		(26	)		6			(70	)		(1	)
Total other income (expense), net		428			317			1,196			925
Interest expense														(5,758	)		(6,684	)
Other expense, net														(264	)		(73	)
Total other expense, net														(3,173	)		(6,683	)
Loss before income taxes		(30,627	)		(25,425	)		(89,890	)		(82,642	)		(34,072	)		(41,269	)
Provision for income taxes		(13	)		—			(54	)		—
Income tax provision														(54	)		(130	)
Net loss	$	(30,640	)	$	(25,425	)	$	(89,944	)	$	(82,642	)	$	(34,126	)	$	(41,399	)
Net loss per share—basic and diluted	$	(0.65	)	$	(0.69	)	$	(2.00	)	$	(2.28	)	$	(0.30	)	$	(0.53	)
Weighted-average number of common shares outstanding used in net loss per share—basic and diluted		47,141,146			36,819,329			44,974,945			36,223,324
Weighted-average number of common shares outstanding used to compute net loss per share—basic and diluted														113,481			77,570


	Common Shares				Additional Paid-In Capital		Accumulated Other Comprehensive (Loss) Income			Accumulated Deficit			Total Stockholders’ (Deficit) Equity
	Shares		Amount
Balance at December 31, 2022		113,213	$	12	$	1,327,909	$	(638	)	$	(1,343,939	)	$	(16,656	)
Vesting of restricted stock		758		—		—		—			—			—
Stock-based compensation expense		—		—		5,389		—			—			5,389
Unrealized gain on investments		—		—		—		33			—			33
Foreign currency translation adjustment		—		—		—		186			—			186
Net loss		—		—		—		—			(34,126	)		(34,126	)
Balance at March 31, 2023		113,971	$	12	$	1,333,298	$	(419	)	$	(1,378,065	)	$	(45,174	)

Balance at December 31, 2021		75,746	$	8	$	1,098,776	$	191		$	(1,178,648	)	$	(79,673	)
Vesting of restricted stock		565		—		—		—			—			—
Exercise of stock options and shares issued under the employee stock purchase plan		167		—		1,467		—			—			1,467
Stock-based compensation expense		—		—		7,336		—			—			7,336
Issuance of common stock, net of issuance costs		2,941		—		29,294		—			—			29,294
Unrealized loss on investments		—		—		—		(14	)		—			(14	)
Foreign currency translation adjustment		—		—		—		(90	)		—			(90	)
Net loss		—		—		—		—			(41,399	)		(41,399	)
Balance at March 31, 2022		79,419	$	8	$	1,136,873	$	87		$	(1,220,047	)	$	(83,079	)


	As of March 31, 2023		As of December 31, 2022
Raw materials	$	1,124	$	1,370
Work in process		1,767		1,878
Finished goods		936		976
Total inventory	$	3,827	$	4,224


Description	As of March 31, 2023		Quoted Prices in Active Markets for Identical Assets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Financial assets
Cash equivalents:
Money market funds	$	72,491	$	72,491	$	—	$	—
U.S. government and agency securities		4,973		—		4,973		—
Investments:
Corporate debt securities		95,255		—		95,255		—
Commercial paper		43,648		—		43,648		—
U.S. government and agency securities		37,419		—		37,419		—
	$	253,786	$	72,491	$	181,295	$	—
Financial liability
Embedded derivative liability	$	2,800	$	—	$	—	$	2,800

Description	Total		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Financial assets
Cash equivalents:
Money market funds	$	29,038	$	29,038	$	—	$	—
Investments:
Current:
Corporate debt securities		58,462		—		58,462		—
Commercial paper		1,996		—		1,996		—
U.S. government and agency securities		4,498		—		4,498		—
Non-current:
Corporate debt securities (one to two year maturity)		34,498		—		34,498		—
Certificates of deposit (one to two year maturity)		2,500		—		2,500		—
U.S. government and agency securities		2,500		—		2,500		—
	$	133,492	$	29,038	$	104,454	$	—


	As of March 31, 2023
	Amortized Cost		Total Unrealized Gains		Total Unrealized Loss			Aggregate Fair Value
Corporate debt securities	$	95,496	$	13	$	(254	)	$	95,255
Commercial paper		43,683		1		(36	)		43,648
U.S. government and agency securities		37,457		6		(44	)		37,419
Total	$	176,636	$	20	$	(334	)	$	176,322

	Amortized Cost		Gross Unrealized Gains		Gross Unrealized Loss			Fair Value
Current:
Corporate debt securities	$	58,533	$	2	$	(73	)	$	58,462
Commercial paper		1,996		—		—			1,996
U.S. government and agency securities		4,500		—		(2	)		4,498
Non-current:
Corporate debt securities (one to two year maturity)		34,530		8		(40	)		34,498
Certificates of deposit (one to two year maturity)		2,500		—		—			2,500
U.S. government and agency securities		2,500							2,500
	$	104,559	$	10	$	(115	)	$	104,454

	Estimated Useful Life Years	September 30, 2017			December 31, 2016
Laboratory equipment	4	$	538		$	538
Furniture and fixtures	5		381			381
Office and computer equipment	3		378			371
Leasehold improvements	Lesser of useful life or lease term		3,391			3,391
			4,688			4,681
Less accumulated depreciation and amortization			(2,384	)		(1,845	)
		$	2,304		$	2,836


	As of March 31, 2023
	Less than 12 Months					12 Months or Longer				Total
	Aggregate Related Fair Value		Unrealized Losses			Aggregate Related Fair Value		Unrealized Losses		Aggregate Related Fair Value		Unrealized Losses
Corporate debt securities	$	79,249	$	(254	)	$	—	$	—	$	79,249	$	(254	)
Commercial paper		42,687		(36	)		—		—		42,687		(36	)
U.S. government and agency securities		27,756		(44	)		—		—		27,756		(44	)
Total	$	149,692	$	(334	)	$	—	$	—	$	149,692	$	(334	)

	Shares			Weighted- Average Exercise Price Per Share		Weighted- Average Remaining Contractual Term (years)		Aggregate Intrinsic Value (in thousands)
Outstanding at December 31, 2016		5,574,179		$	16.55		7.7	$	12,178
Granted		2,443,200			10.13
Exercised		(46,995	)		5.24
Canceled		(921,377	)		20.88
Outstanding at September 30, 2017		7,049,007		$	13.83		7.7	$	17,456
Exercisable at September 30, 2017		3,580,821		$	15.41		6.4	$	12,884

	Number of Shares Underlying RSUs			Weighted- Average Grant Date Fair Value
Unvested at December 31, 2016		214,300		$	17.91
Granted		298,800			10.26
Forfeited		(81,950	)		12.93
Vested		(5,300	)		17.91
Unvested at September 30, 2017		425,850		$	13.19

	September 30, 2017		December 31, 2016
Research and development costs	$	13,328	$	6,855
Payroll and employee-related costs		3,129		3,476
Professional fees		955		480
Other		303		551
	$	17,715	$	11,362


	As of March 31,
	2023		2022
Outstanding stock options		11,851		13,477
Unvested restricted stock units		8,085		3,798

	Three and Nine Months Ended September 30,
	2017		2016
Outstanding stock options		7,049,007		5,557,752
Unvested restricted stock units		425,850		451,600


	As of March 31, 2023			As of December 31, 2022
Principal	$	172,500		$	172,500
Less: debt issuance costs		(2,194	)		(2,395	)
Net carrying amount	$	170,306		$	170,105


Years ended December 31,	Future Minimum Payments
2023	$	5,175
2024		5,175
2025		177,675
Total minimum payments	$	188,025
Less: interest expense and issuance costs		(17,719	)
Convertible senior notes	$	170,306

	Three Months Ended September 30,
	2017			2016			$ Change			% Change
	(in thousands)
Contract and grant revenue	$	—		$	48		$	(48	)		(100	)%
Operating expenses:
Research and development		25,237			19,893			5,344			27	%
General and administrative		5,818			5,897			(79	)		(1	)%
Loss from operations		(31,055	)		(25,742	)		(5,313	)		21	%
Other income, net	428				317			111			35	%
Loss before income taxes		(30,627	)		(25,425	)		(5,202	)		21	%
Provision for income taxes		(13	)		—			(13	)		—
Net loss	$	(30,640	)	$	(25,425	)	$	(5,215	)		21	%

	Nine Months Ended September 30,
	2017			2016				$ Change			% Change
	(in thousands)
Contract and grant revenue	$	71		$	107			$	(36	)		(34	)%
Operating expenses:
Research and development		72,440			66,267				6,173			9	%
General and administrative		18,717			17,407				1,310			8	%
Loss from operations		(91,086	)		(83,567	)			(7,519	)		9	%
Other income, net		1,196			925				271			29	%
Loss before income taxes		(89,890	)		(82,642	)			(7,248	)		9	%
Provision for income taxes		(54	)		—		��		(54	)		—
Net loss	$	(89,944	)	$	(82,642	)		$	(7,302	)		9	%