UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

SCHEDULE 14A

Proxy Statement Pursuant to Section 14(a) of the

Securities Exchange Act of 1934

(Amendment No.    )

Filed by the Registrant  ☒                             Filed by a party other than the Registrant  ☐

Check the appropriate box:

Karyopharm Therapeutics Inc.

(Name of Registrant as Specified In Its Charter)

(Name of Person(s) Filing Proxy Statement, if other than the Registrant)

Payment of Filing Fee (Check the appropriate box):

85 Wells Avenue, Newton, Massachusetts 02459

NOTICE OF ANNUAL MEETING OF STOCKHOLDERS

TO BE HELD ON TUESDAY,THURSDAY, JUNE 19, 20186, 2019

Dear Stockholder:

You are cordially invited to our 20182019 Annual Meeting of Stockholders (the “Annual Meeting”) on Tuesday,Thursday, June 19, 2018,6, 2019, beginning at 8:00 a.m., Eastern time, at our headquarters, 85 Wells Avenue, Newton, Massachusetts 02459, for the following purposes:

1. To elect onethree Class II directorIII directors to serve for a three-year term to expire at the 20212022 annual meeting of stockholders;

2. To approve, on anon-binding advisory basis, the compensation of our named executive officers, as described in the “Compensation Discussion and Analysis,” executive compensation tables and accompanying narrative disclosures in this proxy statement;

3. To recommend, on anon-binding advisory basis, the frequency of future advisory votes on the compensation of our named executive officers;

4. To consider and vote upon the ratification of the selection of Ernst & Young LLP as our independent registered public accounting firm for the fiscal year ending December 31, 2018;2019;

5. To approve an amendment to our Restated Certificate of Incorporation to increase the number of authorized shares of common stock from 100,000,000 to 200,000,000; and

3.6. To consider and vote upon such other business as may be properly brought before the meeting or any adjournment or postponement thereof.

Instead of mailing a printed copy of our proxy materials to all of our stockholders, we provide access to these materials via the Internet. This reduces the amount of paper necessary to produce these materials as well as the costs associated with mailing these materials to all stockholders. Accordingly, on or about April 27, 2018,19, 2019, we will begin mailing a Notice of Internet Availability of Proxy Materials, or Notice, to stockholders and will post our proxy materials on the website referenced in the Notice. As more fully described in the Notice, stockholders may choose to access our proxy materials on the website referred to in the Notice or may request to receive a printed set of our proxy materials. In addition, the Notice and website provide information regarding how you may request to receive proxy materials in printed form by mail, or electronically by email, on an ongoing basis.

If you are a stockholder of record, you may vote in one of the following ways:

If your shares are held in “street name,” meaning that they are held for your account by a broker or other nominee, you will receive instructions from the holder of record that you must follow for your shares to be voted.

Our Board of Directors has fixed the close of business on April 23, 201812, 2019 as the record date for the determination of stockholders entitled to notice of, and to vote at, the Annual Meeting and any adjournment or postponement thereof.

Whether or not you plan to attend the Annual Meeting in person, we urge you to take the time to vote your shares.

By Order of the Board of Directors,

Michael G. Kauffman, M.D., Ph.D.

Chief Executive Officer

Newton, Massachusetts

April 27, 201819, 2019

TABLE OF CONTENTS

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85 Wells Avenue, Newton, Massachusetts 02459

PROXY STATEMENT FOR THE 20182019 ANNUAL MEETING OF STOCKHOLDERS

TO BE HELD ON TUESDAY,THURSDAY, JUNE 19, 20186, 2019

The board of directors of Karyopharm Therapeutics Inc. (which we also refer to as “Karyopharm” or “the Company”company”) is soliciting proxies for use at the 20182019 annual meeting of stockholders, or the Annual Meeting, to be held at our headquarters, 85 Wells Avenue, Newton, Massachusetts 02459, on Thursday, June 19, 20186, 2019 at 8:00 a.m., Eastern time.

Important Notice Regarding the Availability of Proxy Materials for the Annual Meeting of

Stockholders to be Held on Thursday, June 19, 2018:6, 2019:

This proxy statement and our annual report are available electronically at www.proxyvote.com.

On or about April 27, 2018,19, 2019, we began mailing a Notice of Internet Availability of Proxy Materials, or Notice, to our stockholders (other than those who previously requested electronic or paper delivery of proxy materials), directing stockholders to a website where they can access our proxy materials, including this proxy statement and our Annual Report on Form10-K, and view instructions on how to vote online or by telephone. If you would prefer to receive a paper copy of our proxy materials, please follow the instructions included in the Notice. If you have previously elected to receive our proxy materials electronically, you will continue to receive access to those materials viae-mail unless you elect otherwise.

EXPLANATORY NOTE

We are an “emerging growth company” under applicable federal securities laws and therefore permitted to take advantage of certain reduced public company reporting requirements. As an emerging growth company, we provide in this proxy statement the scaled disclosure permitted under the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, including the compensation disclosures required of a “smaller reporting company,” as that term is defined in Rule12b-2 promulgated under the Securities Exchange Act of 1934, as amended, or the Exchange Act. In addition, as an emerging growth company, we are not required to conduct votes seeking approval, on an advisory basis, of the compensation of our named executive officers or the frequency with which such votes must be conducted. We will remain an “emerging growth company” until the earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) December 31, 2018; (iii) the date on which we have issued more than $1 billion in nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the Securities and Exchange Commission, or SEC.

GENERAL INFORMATION ABOUT THE ANNUAL MEETING AND VOTING

Why did you send me these proxy materials?

We are providing these proxy materials because our board of directors is soliciting your proxy to vote at the Annual Meeting. This proxy statement summarizes information related to your vote at the Annual Meeting. All

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What is the purpose of the Annual Meeting?

At the Annual Meeting, stockholders will consider and vote on the following matters:

How many votes do I have?

Each share of our common stock that you own as of April 23, 201812, 2019 entitles you to one vote.

How do I vote?

If you are the “record holder” of your shares,meaning that you own your shares in your own name and not through a bank, brokerage firm or other nominee, you may vote:

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If your shares are held in“street name,” meaning they are held for your account by a bank, brokerage firm, or other nominee, you may vote:

If you hold your shares of our common stock in multiple accounts, you should vote your shares as described above for each account.

Can I revoke or change my vote?

If your shares are registered directly in your name, you may revoke your proxy and change your vote at any time before the Annual Meeting. To do so, you must do one of the following:

If your shares are held in “street name,” you may submit new voting instructions with a later date by contacting your bank, brokerage firm, or other nominee. You may also vote in person at the Annual Meeting, which will have the effect of revoking any previously submitted voting instructions, if you obtain a legal proxy as described in the answer to the question “How do I vote?” above.

Will my shares be voted if I do not return my proxy or do not provide specific voting instructions in the proxy card or voting instruction form that I submit?

If your shares are registered directly in your name,your shares will not be voted if you do not vote over the Internet, by telephone, by returning your proxy by mail, or by ballot at the Annual Meeting. If you submit a proxy card without giving specific voting instructions on one or more matters listed in the notice for the Annual

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Proposal 1 election(election of director, is adirectors), Proposal 2 (thenon-binding advisory vote on the compensation of our named executive officers) and Proposal 3 (thenon-binding advisory vote on the frequency of future votes on the compensation of our named executive officers) arenon-discretionary mattermatters.If you do not instruct your brokerage firm how to vote with respect to this proposal,any of these proposals, your brokerage firm may not vote with respect to thissuch proposal or proposals, and those shares that would have otherwise been entitled to be voted will be counted as“brokernon-votes.” “Brokernon-votes” are shares that are held in “street name” by a brokerage firm that indicates on its proxy that it does not have or did not exercise discretionary authority to vote on a particular matter. Proposal 2, ratification4 (ratification of the selection of our independent registered public accounting firm, isfirm) and Proposal 5 (amendment to our Restated Certificate of Incorporation) are considered a discretionary matter,matters, and your brokerage firm will be able to vote on this proposalthese proposals even if it does not timely receive instructions from you, so long as it holds your shares in its name. We encourage you to timely provide voting instructions to your brokerage firm or other nominee. This ensures that your shares will be voted at the Annual Meeting according to your instructions. You should receive directions from your brokerage firm or other nominee about how to submit your voting instructions to them.

How many shares must be represented to hold the Annual Meeting?

A majority in voting power of our shares of common stock outstanding at the record date must be present in person or represented by proxy to hold the Annual Meeting and conduct business. This is called a quorum. For purposes of determining whether a quorum exists, we count as present any shares that are voted over the Internet, by telephone, by completing and submitting a proxy by mail, or that are represented in person at the meeting. Further, for purposes of establishing a quorum, we will count as present shares that a stockholder holds even if the stockholder votes to abstain or only votes on one of the proposals. In addition, we will count as present shares held in “street name” by banks, brokerage firms, or nominees who indicate on their proxies that they do not have discretionary authority to vote those shares on ProposalProposals 1, 2 and 3, or brokernon-votes. If a quorum is not present, we expect to adjourn the Annual Meeting until we obtain a quorum.

The presence at the Annual Meeting, in person or by proxy, of holders representing a majority of our outstanding common stock as of April 23, 2018,12, 2019, or 49,691,32830,432,223 shares, constitutes a quorum at the Annual Meeting, permitting us to conduct the business of the Annual Meeting.

What vote is required to approve each matter and how are votes counted?

Proposal 1—Election of DirectorDirectors

The nomineethree nominees for director to receive the highest number of votes FOR election will be elected as a Class II director.III directors. This is called a plurality.Proposal 1 is anon-discretionary matter. Therefore, if your shares are held by your brokerage firm in “street name” and you do not timely provide voting instructions with respect to your shares, your brokerage firm cannot vote your shares on Proposal 1. Shares held in “street name” by banks, brokerage firms, or nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 1 will not be counted as votes FOR or WITHHELD from the nominee. As a result, such “brokernon-votes” will have no effect on the voting on Proposal 1. You may:

and Analysis,” executive compensation tables and accompanying narrative disclosures in this proxy statement.Proposal 2 is anon-discretionary matter. Therefore, if your shares are held by your bank, broker or other nominee in “street name” and you do not vote your shares, your bank, broker or other nominee cannot vote your shares on Proposal 2, and yournon-vote will have no effect on the outcome of this proposal. If you vote to ABSTAIN on Proposal 2, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 2. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 2.

As an advisory vote, this proposal is not binding. The outcome of this advisory vote will not overrule any decision by us or our board of directors (or any committee thereof). However, our compensation committee and our board of directors value the opinions expressed by our stockholders in their vote on this proposal and will consider the outcome of the vote when making future compensation decisions for our named executive officers.

Proposal3—Non-binding Advisory Vote on the Frequency of Future Advisory Votes on the Compensation of Our Named Executive Officers

To recommend the frequency of future advisory votes on the compensation of our named executive officers, you may:

The frequency choice that receives the highest numbers of votes cast will be considered to be the preferred frequency of our stockholders with which we are to hold futurenon-binding stockholder advisory“say-on-pay” votes on the compensation of our named executive officers.Proposal 3 is anon-discretionary matter. Therefore, if your shares are held by your bank, broker or other nominee in “street name” and you do not vote your shares, your bank, broker or other nominee cannot vote your shares on Proposal 3, and yournon-vote will have no effect on the outcome of this proposal. If you vote to ABSTAIN on Proposal 3, your shares will not be voted FOR any of the frequency choices and will also not be counted as votes cast or shares voting on Proposal 3. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 3.

As an advisory vote, this proposal is not binding. Our board of directors will take into consideration the outcome of this vote in determining the frequency of futurenon-binding advisory votes on the compensation of our named executive officers. However, because this vote is advisory andnon-binding, our board of directors may decide that it is in our best interests and those of our stockholders to hold the advisory vote to approve the compensation of our named executive officers more or less frequently.

Proposal 4—Ratification of Selection of Independent Registered Public Accounting Firm

To approve Proposal 4, stockholders holding a majority of the votes cast on the matter must vote FOR the proposal.Proposal 24 is considered a discretionary matter. If your shares are held by your brokerage firmbank, broker or other nominee in “street name” and you do not timely provide voting instructions with respect to your shares, your brokeragebank, broker or other nominee firm may vote your unvoted shares on Proposal 2.4. If you ABSTAIN from voting on Proposal 2,4, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on the proposal. As a result, voting to ABSTAIN will have no effect on the outcome of Proposal 2.4.

Although stockholder ratification of our audit committee’s selection of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 20182019 is not required, we believe

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that it is advisable to give stockholders an opportunity to ratify this selection. If this proposal is not approved at the Annual Meeting, our audit committee will reconsider its selection of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2018.2019.

Proposal 5—Approval of an Amendment to our Restated Certificate of Incorporation to Increase the Number of Authorized Shares of Common Stock

To approve Proposal 5, stockholders holding a majority of the shares of our common stock issued and outstanding and entitled to vote at the Annual Meeting must vote FOR the approval of the amendment to our restated certificate of incorporation to increase the number of authorized shares of common stock.Proposal 5 is a discretionary matter. Therefore, if your shares are held by your bank, broker or other nominee in “street name” and you do not vote your shares, your bank, broker or other nominee may vote your shares on Proposal 5. If you ABSTAIN from voting on Proposal 5, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 5. Because Proposal 5 requires the affirmative vote of the holders of a majority of the shares of our common stock issued and outstanding and entitled to vote at the Annual Meeting, a vote to ABSTAIN will have the same effect as a vote AGAINST Proposal 5.

How does the board of directors recommend that I vote on the proposals?

Our board of directors recommends that you vote:

Are there other matters to be voted on at the Annual Meeting?

We do not know of any matters that may come before the Annual Meeting other than the election of one member of our board of directorsProposals 1, 2, 3, 4 and the ratification of the selection of our independent registered public accounting firm.5. If any other matters are properly presented at the Annual Meeting, the persons named in the accompanying proxy intend to vote, or otherwise act, in accordance with their judgment on the matter.

Who is paying the costs of soliciting these proxies?

We will pay all of the costs of soliciting proxies. Our directors, officers, and other employees may solicit proxies in person or by mail, telephone, fax or email. We will pay our directors, officers, and other employees no additional compensation for these services. We do not currently plan to hire a proxy solicitor to help us solicit proxies, although we reserve the right to do so. We will ask banks, brokerage firms, and other nominees to forward these proxy materials to their principals and to obtain authority to execute proxies. We will then reimburse them for their expenses. Our costs for forwarding proxy materials will not be significant.

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How do I obtain an Annual Report on Form10-K?

If you would like a copy of our Annual Report on Form10-K for the year ended

December 31, 20172018 that we filed with the Securities and Exchange Commission, or SEC, we will send you one without charge. Please

write to:

Karyopharm Therapeutics Inc.

85 Wells Avenue

Newton, Massachusetts 02459

Attn: Investor Relations

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Information Regarding Directors

The information set forth below as to the directors and nominee for director has been furnished to us by the directors and nominee for director:

Nominee for Election to the Board of Directors

For a Three-Year Term Expiring at the

2021 Annual Meeting of Stockholders (Class II)

Deepika R. Pakianathan, Ph.D.Dr. Pakianathan has served as a member of our board of directors since April 2013. Since 2001, Dr. Pakianathan has been a Managing Member at Delphi Ventures, a venture capital firm focused on biotechnology and medical device investments, and leads the firm’s biotechnology investment activities. From 1998 to 2001, Dr. Pakianathan was a senior biotechnology banker at JPMorgan, a global investment bank, from 1997 to 1998, she was a Research analyst covering biotech at Genesis Merchant Group and from 1993 to 1997 she was a post-doctoral research scientist at Genentech. Dr. Pakianathan serves on the boards of directors of Alder Biopharmaceuticals, Inc., a public biopharmaceutical company, where she serves as a member of its compensation committee, OncoMed Pharmaceuticals, Inc., a public biopharmaceutical company, where she serves as a member of its audit and compensation committees and Calithera Biosciences, Inc., a public biopharmaceutical company, where she serves as the lead independent director and is a member of its compensation committee and chair of its nominating and governance committee. From 2004 to 2016, Dr. Pakianathan served on the board of directors of Alexza Pharmaceuticals, Inc., from 2009 to February 2013, Dr. Pakianathan served on the board of directors of PTC Therapeutics, Inc., and from 2007 to 2012, Dr. Pakianathan served on the board of directors of Relypsa, Inc., each a public biopharmaceutical company. Dr. Pakianathan received a B.Sc. from the University of Bombay, India, a M.Sc. from The Cancer Research Institute at the University of Bombay, India, and an M.S. and Ph.D. from Wake Forest University. We believe Dr. Pakianathan’s qualifications to serve on our board of directors include her experience as a venture capital investor in, and director of, multiple biotechnology companies, as well as her experience as a biotechnology investment banker, research analyst and research scientist.

Members of the Board of Directors Continuing in Office

Term Expiring at the

20192022 Annual Meeting of Stockholders (Class III)

Garen G. Bohlin.Mr. Bohlin has served as a member of our board of directors since October 2013. Since April 2012, Mr. Bohlin has focused exclusively on service on boards of directors and consulting. From January2010 until his retirement in April 2012, he served as Executive Vice President of Constellation Pharmaceuticals, Inc., a biopharmaceutical company, where he served as a part-time business partner with the Chief Executive Officer. Prior to Constellation Pharmaceuticals, Mr. Bohlin served as Chief Operating Officer of Sirtris Pharmaceuticals, Inc., a biotechnology company, from January 2006 to December 2009, where he played key roles in the overall management of Sirtris, its initial public offering and the sale of the company to

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Dr. Sharon Shacham in 2008 and served as our President from January 2011 to December 2013 and as Chief Medical Officer from December 2012 to December 2013. Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc., a biopharmaceutical company, from November 2009 to December 2010. From November 2008 to November 2009, Dr. Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx Pharmaceuticals. At Proteolix, he led the development of Kyprolis^® (carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the Food and Drug Administration in July 2012. Dr. Kauffman was an operating partner at Bessemer Venture Partners from 2006 to 2008, where he led investments in biotechnology companies. From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc., a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. Dr. Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc., a private biopharmaceutical company focused on G protein-coupled receptors (GPCR), from 2002 until its merger into Epix Pharmaceuticals in 2006. In that role, he led the merger of Predix Pharmaceuticals and Epix Pharmaceuticals, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline. From March 2000 to September 2002, Dr. Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc., a biopharmaceutical company, where he led the Velcade^® development program. From September 1997 to March 2000, Dr. Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium Pharmaceuticals, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb. From August 1995 to September 1997, Dr. Kauffman held a number of senior positions at Biogen Idec, Inc., a biopharmaceutical company, where he led the clinical

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Commercial Officer from October 2014 to April 2017. Prior to Relypsa, Mr. Garland served as Executive Vice President and Chief Commercial Officer of Exelixis, Inc., a biopharmaceutical company focused on developing and commercializing cancer treatments, from October 2011 to October 2014. Prior to joining Exelixis, from April 2002 to October 2011, Mr. Garland held positions at Genentech, Inc., most recently serving as Vice President of Genentech’s Avastin^® franchise, where he led the U.S. sales and marketing efforts for the drug. Prior to that position, he served as Vice President, Hematology Marketing and Sales, overseeing the Rituxan^® franchise and as a Director on the Tarceva^® franchise. From July 1997 to April 2002, Mr. Garland held several positions within the sales and marketing division of Amgen, Inc. and from July 1991 to July 1995, he served as a professional sales representative at Merck & Co., Inc. Mr. Garland has an M.B.A. from Duke University’s Fuqua School of Business and a B.A. from California Polytechnic University (San Luis Obispo). We believe Mr. Garland’s qualifications to serve on our board of directors include his more than 20 years of sales, marketing and commercialization experience in the pharmaceutical and biopharmaceutical industry as well as his extensive management experience at publicly-traded biopharmaceutical companies.

Barry E. Greene.Mr. Greene has served as a member of our board of directors since January 2013 and as our Lead Independent Director since January 2015. Mr. Greene has served as President of Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company, since 2007, and served as its Chief Operating Officer from 2003 to 2016. Mr. Greene joined Alnylam in 2003, bringing over 15 years of experience in the healthcare industry and in consulting. Prior to Alnylam, he was General Manager of Oncology at Millennium Pharmaceuticals, Inc., a biopharmaceutical company, where he led the company’s global strategy and execution for its oncology business, including strategic business direction and execution, culminating in the successful Food and Drug Administration approval and launch of VELCADE^® (bortezomib) inmid-2003. Prior to joining Millennium in 2001, Mr. Greene served as Executive Vice President and Chief Business Officer for Mediconsult.com, a healthcare consulting company. Prior to Mediconsult.com, Mr. Greene’s experience included serving as Vice President of Marketing and Customer Services for AstraZeneca (formerly AstraMerck), a biopharmaceutical company; Vice President, Strategic Integration with responsibility for the AstraZeneca North American post-merger integration; and a partner of Andersen Consulting, a consulting company, where he was responsible for the pharmaceutical/biotechnology marketing and sales practice. Mr. Greene currently is a member of the board of directors of Acorda Therapeutics, Inc., a public biopharmaceutical company, where he

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European Network of Gynecologic Oncology Trials Group, faculty member of the European Society of Medical Oncology and of the International Gynecologic Cancer Society. He also serves on the board of directors of Sera Prognostics, Inc., a private biopharmaceutical company. He has multiple publications in high-impact journals like the New England Journal of Medicine. He holds a M.D., Diploma in Surgery and Diploma in Clinical Oncology from the Pirogov Moscow State Medical Institute as well as post-graduate education and certification in radiation and medical oncology from the University of Southern Denmark. We believe Dr. Mirza’s qualifications to serve on our board of directors include his position as an expert in thenon-surgical treatment of cancer, and gynecologic cancers in particular, and his knowledge of our company and its business through service on our board since October 2010.

Term Expiring at the

2021 Annual Meeting of Stockholders (Class II)

Deepika R. Pakianathan, Ph.D.Dr. Pakianathan has served as a member of our board of directors since April 2013. Since 2001, Dr. Pakianathan has been a Managing Member at Delphi Ventures, a venture capital firm focused on biotechnology and medical device investments, and leads the firm’s biotechnology investment activities. From 1998 to 2001, Dr. Pakianathan was a senior biotechnology banker at JPMorgan, a global investment bank, from 1997 to 1998, she was a Research analyst covering biotech at Genesis Merchant Group and from 1993 to 1997 she was a post-doctoral research scientist at Genentech. Dr. Pakianathan serves on the boards of directors of Alder Biopharmaceuticals, Inc., a public biopharmaceutical company, where she serves as a member of its compensation committee, OncoMed Pharmaceuticals, Inc., a public biopharmaceutical company, where she serves as a member of its audit and compensation committees and Calithera Biosciences, Inc., a public biopharmaceutical company, where she serves as the lead independent director and is a member of its compensation committee and chair of its nominating and governance committee. From 2004 to 2016, Dr. Pakianathan served on the board of directors of Alexza Pharmaceuticals, Inc., from 2009 to February 2013, Dr. Pakianathan served on the board of directors of PTC Therapeutics, Inc., and from 2007 to 2012, Dr. Pakianathan served on the board of directors of Relypsa, Inc., each a public biopharmaceutical company. Dr. Pakianathan received a B.Sc. from the University of Bombay, India, a M.Sc. from The Cancer Research Institute at the University of Bombay, India, and an M.S. and Ph.D. from Wake Forest University. We believe Dr. Pakianathan’s qualifications to serve on our board of directors include her experience as a venture capital investor in, and director of, multiple biotechnology companies, as well as her experience as a biotechnology investment banker, research analyst and research scientist.

Recommendation of the Board of Directors

OUR BOARD OF DIRECTORS UNANIMOUSLY RECOMMENDS THAT THE STOCKHOLDERS VOTE FOR THE ELECTION OF EACH OF MR. GAREN G. BOHLIN, DR. DEEPIKA R. PAKIANATHANMIKAEL DOLSTEN AND DR. MICHAEL G. KAUFFMAN AS A CLASS IIIII DIRECTOR.

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CORPORATE GOVERNANCE

General

We believe that good corporate governance is important to ensure that Karyopharm Therapeutics Inc. is managed for the long-term benefit of our stockholders. This section describes key corporate governance practices that we have adopted. We have adopted a Code of Business Conduct and Ethics, which applies to all of our officers, directors and employees, Corporate Governance Guidelines, and charters for our audit committee, our compensation committee and our nominating and corporate governance committee. We have posted copies of our Code of Business Conduct and Ethics and Corporate Governance Guidelines, as well as each of our committee charters, on the Corporate Governance page of the Investors section of our website, www.karyopharm.com, which you can access free of charge. Information contained on the website is not incorporated by reference in, or considered part of, this proxy statement. We intend to disclose on our website any amendments to, or waivers from, our Code of Business Conduct and Ethics that are required to be disclosed by law or Nasdaq listing standards. We will also provide copies of these documents as well as our other corporate governance documents, free of charge, to any stockholder upon written request to Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459, Attn: Investor Relations.

Director Independence

Rule 5605 of the Nasdaq Listing Rules requires a majority of a listed company’s board of directors to be comprised of independent directors within one year of listing. In addition, the Nasdaq Listing Rules require that, subject to specified exceptions, each member of a listed company’s audit, compensation and nominating and corporate governance committees be independent and that audit committee members also satisfy independence criteria set forth in Rule10A-3 under the Exchange Act.

Under Rule 5605(a)(2) of the Nasdaq Listing Rules, a director will only qualify as an “independent director” if, in the opinion of our board of directors, that person does not have a relationship that would interfere with the exercise of independent judgment in carrying out the responsibilities of a director. In order to be considered independent for purposes of Rule10A-3 of the Exchange Act, a member of an audit committee of a listed company may not, other than in his or her capacity as a member of the audit committee, the board of directors, or any other board committee, accept, directly or indirectly, any consulting, advisory, or other compensatory fee from the listed company or any of its subsidiaries or otherwise be an affiliated person of the listed company or any of its subsidiaries.

In addition, in affirmatively determining the independence of any director who will serve on a company’s compensation committee, Rule10C-1 under the Exchange Act requires that a company’s board of directors consider all factors specifically relevant to determining whether a director has a relationship to such company which is material to that director’s ability to be independent from management in connection with the duties of a compensation committee member, including, but not limited to: (i) the source of compensation of the director, including any consulting, advisory or other compensatory fee paid by such company to the director; and (ii) whether the director is affiliated with the company or any of its subsidiaries or affiliates.

Our board of directors has undertaken a review of the composition of our board of directors and its committees and the independence of each director. Based upon information requested from and provided by each director concerning his background, employment and affiliations, including family relationships, our board of directors has determined that each of our directors, with the exception of Drs. Kauffman and Mirza, is an “independent director” as defined under Rule 5605(a)(2) of the Nasdaq Listing Rules. Our board of directors also determined that Messrs. Bohlin and Garland and Dr. Pakianathan, who currently comprise our audit committee, Messrs. Greene and Weg and Dr. Pakianathan and Mr. Greene, who comprise our compensation committee, and Messrs. BohlinGreene and WegBohlin and Dr. Dolsten, who currently comprise our nominating and corporate governance committee, satisfy the independence standards for such committees established by the SEC and the Nasdaq Listing Rules, as applicable.

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In addition, our board of directors also determined that Kenneth E. Weg, who served as a member of our board of directors from February 2013 until the annual meeting of stockholders on June 19, 2018 and served as a member of the nominating and corporate governance committee and compensation committee during 2018 from January 1, 2018 until June 19, 2018, and F. Carsten Thiel, Ph.D., who served as a member of our board of directors from August 31, 2018 until his resignation on November 27, 2018, and served as a member of the compensation committee from October 11, 2018 until November 27, 2018, satisfied the independence standards for such committees established by the SEC and the Nasdaq Listing Rules, as applicable. In making such determinations, our board of directors considered the relationships that each suchnon-employee director has with our company and all other facts and circumstances our board of directors deemed relevant in determining independence, including the beneficial ownership of our capital stock by eachnon-employee director.

There are no family relationships among any of our directors or executive officers, except that Dr. Kauffman, our Chief Executive Officer and a director, is married to Dr. Shacham, our President and Chief Scientific Officer.

Board Leadership Structure

Our bylaws and Corporate Governance Guidelines provide our board of directors with flexibility to combine or separate the positions of Chairman of the Board and Chief Executive Officer and/or to implement the role of Lead Independent Director in accordance with its determination that utilizing one or the other structure would be in the best interests of our company.

At this time, we do not have a Chairman of the Board, though our board of directors appointed Mr. Greene to serve as Lead Independent Director in January 2015. While our board of directors believes that oversight of our company is the responsibility of our board of directors as a whole, and this responsibility can be properly discharged without a Chairman or Lead Independent Director, our board of directors determined that appointing Mr. Greene as Lead Independent Director would facilitate interactions between Dr. Kauffman, our Chief Executive Officer, and the other independent directors and would enable the board of directors and the Companycompany to utilize Mr. Greene’s breadth of experience across many strategic and operational matters in development stage biotechnology companies.

Mr. Greene serves as a liaison between our Chief Executive Officer and our independent directors. Mr. Greene meets regularly and communicates directly with the independent directors outside the presence of management and reports any comments and concerns of the independent directors to our Chief Executive Officer. He also meets regularly with our senior management to discuss operational and strategic matters. Mr. Greene presides over executive sessions of the board of directors and provides our Chief Executive Officer with a formalan annual review, as well as regular informal feedback, based on the consensus views collected from members of our board of directors.

While Dr. Kauffman facilitates communications between members of our board of directors and works with management in the preparation of the agenda for each meeting of the board of directors, Mr. Greene also has an important role in establishing the agenda, determining what information is provided to our board of directors and coordinating with management to ensure that sufficient meeting time is allocated to each agenda item. Additionally, all of our directors are encouraged to make suggestions for agenda items orpre-meeting materials for meetings of our board of directors.

Our board of directors has concluded that the current leadership structure described above is appropriate at this time. However, our board of directors will continue to periodically review our leadership structure and may make such changes in the future, as it deems appropriate.

The Board’s Role in Risk Oversight

Our board of directors has responsibility for the oversight of the Company’scompany’s risk management processes and, either as a whole or through its committees, regularly discusses with management our major risk exposures, the

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potential impact of these risks on our business and the steps we take to manage them. The risk oversight process includes receiving regular reports from board committees and members of senior management to enable our board of directors to understand the Company’scompany’s risk identification, risk management and risk mitigation strategies with respect to areas of potential material risk, including operations, finance, legal, regulatory, strategic and reputational risk.

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assist in its evaluation of executive and director compensation, including the authority to approve the consultant’s reasonable fees and other retention terms.

During 2017, In addition, under its charter, the compensation committee engaged Arnosti Consulting, Inc., or Arnosti, an independent compensation consultant, to provide comparative data on executivemay form, and board compensation practices in our industry and to advise on our executive compensation program generally. The Company pays the cost for Arnosti’s services. However, the compensation committee retains the soledelegate authority to, direct, terminate, or engage Arnosti’s services. Other than the services provided to the compensation committee, Arnosti provided advice to the Company with respect to compensation for employees at the Vice President level. The decision to use Arnosti for advice regarding compensation for employees at the levelsubcommittees, consisting of Vice President was made by management. Compensation for all services provided to the Company by ACI did not exceed $120,000 during 2017.independent directors, as it deems appropriate.

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Compensation Committee Interlocks and Insider Participation

During 2017, the members of our compensation committee were2018, Drs. Pakianathan and Thiel and Messrs. Greene and Weg and Dr. Pakianathan. Mr. Greene is the chairserved as members of our compensation committee. None of our executive officers served as a director or a member of a compensation committee (or other committee serving an equivalent function) of any other entity, whose executive officers served as a member of our board of directors or our compensation committee during 2017.2018. During 2017,2018, no member of our compensation committee was a current or former officer or employee of Karyopharm or had any related person transaction involving Karyopharm.

Code of Business Conduct and Ethics

We have adopted a written Code of Business Conduct and Ethics that applies to our directors, officers and employees, including our principal executive officer, principal financial officer, principal accounting officer or controller, or persons performing similar functions. We have posted on our website, www.karyopharm.com, a current copy of the Code of Business Conduct and Ethics and all disclosures that are required by law or Nasdaq listing standards concerning any amendments to, or waivers from, any provision of the Code of Business Conduct and Ethics. Information contained on the website is not incorporated by reference in, or considered part of, this proxy statement.

Director Nomination Process

Director Qualifications

In evaluating director nominees, the nominating and corporate governance committee will consider, among other things, the following factors:

The nominating and corporate governance committee’s goal is to assemble a board of directors that brings to the Companycompany a variety of perspectives and skills derived from high quality business and professional experience. Moreover, the nominating and corporate governance committee believes that the background and

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The nominating and corporate governance committee has not adopted a formal policy with respect to a fixed set of specific minimum qualifications for its candidates for membership on the board of directors. The committee considers such factors, including those set forth above, as it may deem are in the best interests of our company and its stockholders. The committee further believes it is appropriate for at least one member of our board of directors to meet the criteria for an “audit committee financial expert” as that phrase is defined under the regulations promulgated by the SEC, and that a majority of the members of our board of directors be independent as required under the Nasdaq qualification standards. The committee believes it is appropriate for our Chief Executive Officer to serve as a member of our board of directors. Our directors’ performance and qualification criteria are reviewed periodically by the nominating and corporate governance committee.

Identification and Evaluation of Nominees for Directors

The nominating and corporate governance committee identifies nominees for director by first evaluating the current members of our board of directors willing to continue in service. Current members with qualifications and skills that are consistent with the nominating and corporate governance committee’s criteria for board of directorsdirectors’ service and who are willing to continue in service are considered forre-nomination, balancing the value of continuity of service by existing members of our board of directors with that of obtaining a new perspective or expertise.

If any member of our board of directors does not wish to continue in service or if our board of directors decides not tore-nominate a member forre-election, and our board seeks to fill such vacancy, the nominating and corporate governance committee identifies a new nominee that meets the criteria above. The committee generally inquires of our board of directors and members of management for their recommendations. The committee may also review the composition and qualification of the boards of directors of our competitors and may seek input from industry experts or analysts. The nominating and corporate governance committee reviews the qualifications, experience, and background of suggested candidates. Final candidates, if other than our current directors, would be interviewed by the members of the nominating and corporate governance committee and by certain of our other independent directors and executive management. In making its determinations, the nominating and corporate governance committee evaluates each individual in the context of our board of directors as a whole, with the objective of assembling a group that can best contribute to the success of our company and represent stockholder interests through the exercise of sound judgment. After review and deliberation of all feedback and data, the nominating and corporate governance committee makes its recommendation to our board of directors. The nominating and corporate governance committee has previously engaged a search firm to conduct a search for additional directors with extensive development or commercialization expertise to join our board of directors. The nominating and corporate governance committee may in the future engage additional third-party search firms in those situations where particular qualifications are required or where existing contacts are not sufficient to identify an appropriate candidate.

We have not received director candidate recommendations from our stockholders and do not have a formal policy regarding consideration of such recommendations. However, any recommendations received from stockholders will be evaluated in the same manner that potential nominees suggested by board members, management, or other parties are evaluated. We do not intend to treat stockholder recommendations in any manner different from other recommendations.

Stockholders wishing to recommend a director candidate for consideration by our nominating and corporate governance committee must write to our Corporate Secretary. Recommendation of director candidates must be received by our Corporate Secretary at our principal executive offices. Such submissions must state the

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Stockholders also have the right under our bylaws to directly nominate director candidates, without any action or recommendation on the part of the nominating and corporate governance committee or the board of directors, by following the procedures set forth under “Stockholder Proposals.” If our board of directors determines to nominate a stockholder-recommended candidate and recommends his or her election, then his or her name will be included in our proxy statement and proxy card for the next annual meeting of stockholders. Otherwise, candidates nominated by stockholders in accordance with the procedures set forth in the bylaws will not be included in our proxy statement and proxy card for the next annual meeting.

Director Attendance at Annual Meetings

We do not have a formal policy regarding attendance by members of our board of directors at our annual meeting of stockholders. Three members of our board of directors serving at the time attended our 20172018 annual meeting of stockholders held on June 15, 201719, 2018 in person or by teleconference.

Communications with Our Board of Directors

Stockholders seeking to communicate with our board of directors must submit their written comments to our Corporate Secretary, Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459. The Corporate Secretary will forward such communications to each member of our board of directors; provided that, if in the opinion of our Corporate Secretary it would be inappropriate to send a particular stockholder communication to a specific director, such communication will only be sent to the remaining directors (subject to the remaining directors concurring with such opinion).

Director Compensation

We compensatenon-employee members of our board of directors for their service using a combination of cash and equity compensation. Directors who are also employees do not receive any compensation for service on the board of directors in addition to compensation payable for their service as our employees. Thenon-employee members of our board of directors are also reimbursed for travel, lodging, and other reasonable expenses incurred in attending board of directors or committee meetings.

Our compensation committee periodically reviews the compensationDuring 2018, we paycompensated ournon-employee directors with input from its independentbased on the following compensation consultants, and makes recommendations to our board of directors. In January 2017,guidelines established by our board of directors, upon the recommendation of our compensation committee, revised the compensation guidelines fornon-employee directors, to become effective upon the adjournment of the 2017 annual meeting of stockholders.committee:

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The table below reflects the changes to compensation guidelines fornon-employee directors that became effective upon the adjournment of the 2017 annual meeting of stockholders. Increases in fees werepro-rated for 2017 based on the effective date of the changes.

The stock options granted to ournon-employee directors for service on our board of directors or its committees have an exercise price equal to the fair market value of our common stock on the date of grant, expire ten years after the date of grant, and are subject to the director’s continued service on our board of directors.

To the extent that anon-employee director has other responsibilities to our company in addition to service on our board of directors, such director may receive additional compensation to the extent as deemed appropriate by our board of directors.

Following the formation of the compliance committee,In February 2019, our board of directors, upon the recommendation of our compensation committee, approvedrevised the followingcompensation guidelinesfor non-employee directors, to become effective upon the adjournment of the Annual Meeting. The changes to the compensation guidelines for compliance committee members effective January 1, 2018:are as follows:

All other elements of the compensation guidelines fornon-employee directors remain unchanged.

Dr. Mirza serves as a clinical consultant to us pursuant to a consulting agreement with an entity wholly-owned by Dr. Mirza, for which he was paid (through such entity) a consulting fee of $135,000$114,000 for 2017.2018. See “Certain Relationships and Related Person Transactions—Consulting Arrangements.”

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2018 Director Compensation

Limitation of Liability and Indemnification

Our certificate of incorporation limits the personal liability of directors for breach of fiduciary duty to the maximum extent permitted by the Delaware General Corporation Law and provides that no director will have personal liability to us or to our stockholders for monetary damages for any breach of fiduciary duty as a director. However, these provisions do not eliminate or limit the liability of any of our directors:

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Report of the Audit Committee of the Board of Directors

The audit committee oversees the Company’scompany’s financial reporting process on behalf of the board of directors. We have reviewed the Company’scompany’s audited consolidated financial statements for the fiscal year ended December 31, 20172018 and discussed them with Company management and Ernst & Young LLP, the Company’scompany’s independent registered public accounting firm for the fiscal year ended December 31, 2017.2018.

We have received from, and discussed with, Ernst & Young LLP, which is responsible for expressing an opinion on the conformity of the Company’scompany’s audited consolidated financial statements with accounting principles generally accepted in the United States, its judgments as to the quality, not just the acceptability, of the Company’scompany’s accounting principles and such other matters as are required to be discussed with the audit committee under generally accepted auditing standards, including the matters to be discussed as required by AS 1301: Communications with Audit Committees, as adopted by the Public Company Accounting Oversight Board (the “PCAOB”) and all other communications required under the standards of the PCAOB. In addition, we have discussed with Ernst & Young LLP its independence from management and the Company,company, have received from Ernst & Young LLP the written disclosures and the letter required by applicable requirements of the PCAOB regarding its communications with us concerning independence, and have considered the compatibility ofnon-audit services with the auditors’ independence.

Based on the review and discussions referred to above, we recommended to the board of directors that the audited consolidated financial statements be included in the Company’scompany’s Annual Report on Form10-K for the year ended December 31, 2017.2018.

This report of the audit committee is not “soliciting material,” shall not be deemed “filed” with the SEC and shall not be incorporated by reference by any general statement incorporating by reference this proxy statement into any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing, except to the extent that we specifically incorporate this information by reference, and shall not otherwise be deemed filed under such acts.

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INFORMATION ABOUT EXECUTIVE OFFICER COMPENSATION

This section discussesCompensation Discussion and Analysis

Our compensation committee is responsible for overseeing the material elementstotal compensation of our senior management team, which is comprised of our executive officers and certain other senior managers. In this capacity, our compensation committee designs, implements, reviews and approves all compensation for named executive officers (NEOs), except that in the case of Michael G. Kauffman, M.D., Ph.D., our Chief Executive Officer, and Sharon Shacham, Ph.D., M.B.A., our President and Chief Scientific Officer, our compensation committee designs, implements, reviews and recommends, and the board of directors reviews and approves, all compensation for Drs. Kauffman and Shacham. This Compensation Discussion and Analysis describes the principles underlying our policies and importantdecisions with respect to the compensation of our NEOs who are named in the Summary Compensation Table below, and all material factors relevant to an analysis of these policies. It provides qualitative information regardingpolicies and decisions. Our NEOs for the manner and context in which compensation is awarded to and earned by our executive officers named in the “Summary Compensation Table” below and is intended to place in perspective the information presented in the following tables and the corresponding narrative.

Summary Compensation Table

The following table sets forth information regarding compensation earned by each of our named executive officers during each of the fiscal yearsyear ended December 31, 2016 and 2017. Our named executive officers for 2017 are Dr. 2018 are:

Executive Compensation Program Best Practices

Our compensation committee believes that a strong foundation for our compensation program is necessary to execute our executive compensation philosophy effectively. The following best practices serve as the foundation for our executive compensation program:

Select Business Highlights for 2018

We are a clinical-stage pharmaceutical company focused on the discovery, development and subsequent commercialization of novel,first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Our scientific expertise is focused on understanding the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing wholly-owned, novel, small molecule Selective Inhibitor of Nuclear Export (SINE) compounds that inhibit the nuclear export protein 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 unmet medical need.

During 2018, we achieved a number of milestones and made significant progress on our clinical development and business goals. Our clinical development achievements for 2018 include announcing positive topline results from our Phase 2b STORM study and Phase 2b SADAL study, completing the enrollment in our Phase 3 BOSTON study and completing the rolling submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) with a request for accelerated approval for selinexor as a new treatment for patients based on the results of the STORM study. In addition, we also achieved goals relating to business development, financial performance and employee retention.

Compensation Philosophy and Core Objectives

The objective of our executive compensation program is to align management interests with the drivers of value creation for our stockholders and support achievement of our strategic goals and objectives. We are committed to our compensation philosophy which incorporates the following principles:

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Narrative Disclosure to SummaryDetermining and Setting Executive Compensation Table

OurWe develop our compensation committee makesprograms after reviewing publicly-available compensation decisions regardingdata and subscription survey data for our named executive officers or makes recommendations concerning executivepeer group, provided by an independent compensation toconsulting firm engaged by our board of directors. In May 2013,compensation committee. For setting 2018 compensation, our compensation committee engaged Arnosti Consulting, Inc., or Arnosti, an (Arnosti) as its independent compensation consultant, to provide expertise-based advice, research and analytical services relating to peer group composition and trends and comparative dataadvise on executive compensation matters including: overall compensation program design, peer group development and updates, and benchmarking executive officer and director compensation programs. Our compensation committee assessed the independence of Arnosti consistent with Nasdaq listing standards and concluded that the engagement of Arnosti did not raise any conflict of interest. The company paid the cost for Arnosti’s services; however, the compensation committee retained the sole authority to direct, terminate, or engage Arnosti’s services and Arnosti reported directly to the compensation committee. In addition to the services provided to the compensation committee, Arnosti provided advice to management with respect to compensation for employees at or above the Vice President level and information to management with respect to planning for the 2019 equity incentive compensation program. The decision to use Arnosti for advice regarding compensation for employees at or above the level of Vice President was made by management and approved by the compensation committee. Compensation for all services provided to the company by Arnosti did not exceed $120,000 during 2018.

In October 2018, Compensia, Inc. (Compensia) was appointed by the compensation committee as a compensation advisor to the compensation committee. Our compensation committee assessed the independence of Compensia consistent with Nasdaq listing standards and concluded that the engagement of Compensia did not raise any conflict of interest. We pay the cost for Compensia’s services; however, the compensation committee retains the sole authority to direct, terminate, or engage Compensia’s services and Compensia reports directly to the compensation committee. Compensia performed no other work for the company. Compensation for all services provided to the company by Compensia did not exceed $120,000 during 2018.

Defining and Comparing Compensation to Market Benchmarks

In evaluating the total compensation of our named executive officers, our compensation committee, using information provided by Arnosti, established a peer group of publicly-traded companies in the biopharmaceutical and biotechnology industries that was selected based on a balance of the following criteria:

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Based on these criteria, our peer group for 2018, referred to as our 2018 peer group, as approved by our compensation committee, was comprised of the 25 companies listed below.

We believe that the compensation practices of our 2018 peer group provided us with appropriate compensation benchmarks for evaluating the compensation of our named executive officers during 2018. Notwithstanding the similarities of the 2018 peer group to our company, due to the nature of our business, we compete for executive talent with many public companies that are larger and more established than we are or that possess greater resources than we do, and with smaller private companies that may be able to offer greater equity compensation potential. Accordingly, in 2018, our compensation committee generally targeted compensation for our executive officers (other than Drs. Kauffman and Shacham) as follows:

In determining the annual equity incentive awards for each executive officer (other than Drs. Kauffman and Shacham) in 2018, the equity incentive compensation was targeted at the 65th percentile of equity compensation awarded to similarly situated executives of the companies whom we consider peers in termsour 2018 peer group. The target amounts for each of market capitalization, development stagethose executive officers were then aggregated (subject to adjustment) and sizeour compensation committee allocated such aggregate amount among the executive officers (other than Drs. Kauffman and Shacham) based a number of criteria, including the executive officer’s performance against established company goals, long-term expected individual contributions and any promotions.

Because Drs. Kauffman and Shacham are married, their aggregate compensation is considered. In 2018, our compensation committee generally targeted compensation for Drs. Kauffman and Shacham as follows:

In determining the annual equity incentive awards for each of Drs. Kauffman and Shacham in 2018, the equity incentive compensation was targeted at the 65th percentile of equity compensation awarded to advise onsimilarly situated executives of the companies in our executive compensation program generally. Arnosti provided these consulting services throughout 20162018 peer group. The target amounts for Drs. Kauffman and 2017. Although ourShacham were then aggregated (subject to adjustment) and the board of directors (based on the recommendation of the compensation committee) allocated 50% of such aggregate amount to each of Drs. Kauffman and Shacham.

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In addition, our compensation committee may consider other criteria, including market factors, the adviceexperience level of the executive and recommendationthe executive’s performance against established company goals, in determining variations to the general target ranges.

Other Key Performance Factors in Determining Executive Compensation

As the biopharmaceutical industry is characterized by a long product development cycle, including a lengthy research and development period and a rigorous approval phase involving clinical studies that must precede any governmental regulatory approval, many of any independentthe traditional benchmarking metrics, such as product sales, revenues and profits are inappropriate for a development-stage biopharmaceutical company such as us. Instead, the specific performance factors our compensation consultants as tocommittee considers when determining the compensation of our named executive officers include:

These performance factors were considered by our compensation program,committee in determining awards for our executives under our annual performance-based cash incentive and equity incentive programs.

Annual Compensation Review Process

Throughout each calendar year, the board of directors and the compensation committee ultimatelydiscuss each executive officer’s performance with input from our Chief Executive Officer and President and Chief Scientific Officer. This process leads to a recommendation by our Chief Executive Officer and President and Chief Scientific Officer, at the end of each calendar year, to our compensation committee with respect to each executive officer other than themselves as to:

These recommendations are considered by our compensation committee when they make their own decisions about thesedeterminations on all such matters.

Base SalaryComponents of Executive Compensation

Base salariesThe primary elements of our executive compensation program are:

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The value of our variable, performance-based compensation is allocated between short-term compensation in the form of a cash bonus and long-term compensation in the form of stock option awards that vest over time from the date of grant of the option awards. The annual cash bonus is intended to provide an incentive to our executives to achieve short-term operational objectives. The stock option award is intended to provide an incentive for our executives to achieve longer-term strategic business goals, which should lead to higher stock prices and increased stockholder value. We have not had any formal or informal policy or target for allocating compensation between long-term and short-term compensation, between cash andnon-cash compensation, or among the different forms ofnon-cash compensation. Instead, the compensation committee, after reviewing industry information and our cash and equity resources, determines subjectively what it believes to be the appropriate level and mix of the various compensation components.

We do not have any defined benefit pension plans or anynon-qualified deferred compensation plans.

We are usedparty to recognize the experience, skills, knowledge and responsibilities requiredemployment agreements with each of our named executive officers. Historically, base salaries forEmployment agreements with our named executive officers are described below under the caption“Executive Compensation –Employment Agreements, Severance and Change in Control Arrangements.”

Base Salaries

We provide base salaries to our named executive officers to compensate them with a fair and competitive base level of compensation for services rendered during the year. Base salaries for our NEOs typically have beenare established through arm’s lengtharm’s-length negotiation at the time the named executive officer is appointed,hired, taking into account responsibilities, experience, internal equity and peer company data. On an annual basis, our compensation committee reviews and evaluates, with input from our Chief Executive Officer and President and Chief Scientific Officer, for executives other than themselves, the positionneed for whichadjustment of the named executive officer is being considered and the named executive officer’s qualifications, prior experience and prior salary. Nonebase salaries of our namedNEOs based on changes and expected changes in the scope of an NEO’s responsibilities.

The compensation committee also considers promotions, the individual contributions made by, and performance of, the executive during the prior year, the executive’s performance over a period of years, overall labor market conditions, the relative ease or difficulty of replacing the executive with a well-qualified person, our overall growth and development as a company, general salary trends in our industry and among our peer group and where the executive’s salary falls in the salary range presented by that data. We do not provide for any formulaic base salary increases for our NEOs and none of our executive officers is currently party to an employment agreement or other service agreement that provides for automatic or scheduled increases in base salary. However, on an annual basis,Our compensation committee believes our base salaries for our executives (other than Drs. Kauffman and Shacham) should be targeted at the 50th percentiles of the salaries in the peer group and base salaries for Drs. Kauffman and Shacham should be targeted at the 35th and 80th percentiles, respectively, of the salaries in the peer group.

Merit-based increases in base salary for all of our executive officers (other than Drs. Kauffman and Shacham) are determined by our compensation committee reviews and evaluatesmerit-based increases in base salary for Drs. Kauffman and Shacham are determined by our board of directors based on the advisabilityrecommendation of any adjustmentour compensation committee.

As part of our 2017 annual compensation review, the compensation committee approved (and, in the case of Drs. Kauffman and Shacham, the compensation committee recommended, and the board of directors approved) annual base salaries offor our executive officers for 2018 (other than for Mr. Varadan). In determining and recommending these annual base salaries, the compensation committee reviewed the market compensation data presented by Arnosti and considered each executive officer’s performance. The table below sets forth the

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adjustments to base salary, in dollars and as a percentage, for each of our named executive officers includingserving at the beginning of 2018:

Under the 2018 annual performance-based cash incentive which we refer to as an annual cash incentive, in an amount corresponding toprogram, awards were determined by first establishing a percentage of his or her base salary.bonus pool. The target amount ofbonus pool was calculated by aggregating the annual cash incentive is determined, prior to the applicable fiscal year,maximum awards for all eligible participants and then multiplying that sum by a modifier established by our compensation committee withbased on our performance as measured against the actual payment2018 corporate goals. Under the 2018 annual performance-based cash incentive program, the corporate performance level on which such modifier was based could range from 0% to be based upon136.25%. In addition, our compensation committee had the accomplishment of certain objectivediscretion to adjust upward or downward any award and/or the pool as it deemed appropriate.

In making its determination regarding awards under the 2018 annual performance-based cash incentive program, our compensation committee considered our success against our 2018 corporate milestones forgoals. The 2018 corporate goals approved by our board and compensation committee, the applicable fiscal year. The amountrelative weightings assigned to each goal at the beginning of the annual cash incentive paid toyear, our named executive officers is determinedactual achievement during the performance period as a percentage of target and the weighted performance against these corporate goals for 2018, as approved by our compensation committee, upon a considerationwere as follows:

Based on our overall performance during 2018, our compensation committee determined that we achieved 126.25% of our corporate goals for 2018, which allows us to focus our development efforts and further advance our programs and business goals in 2019. Given the strong contributions of each named executive officer to the achievement of our corporate goals for 2018, for Messrs. Primiano and Varadan, the compensation committee determined and, for Drs. Kauffman and Shacham, the compensation committee recommended to the board of directors and the board of directors determined, that their bonuses for 2018 are entirely based on corporate performance relative to the corporate goals. However, actual bonuses approved for 2018 for Drs. Kauffman and Shacham reflect reduced amounts, at the request of Drs. Kauffman and Shacham, of $148,000 and $101,000, respectively, to receive 80% of such named executive officer’s respective annual cash incentive target for 2016, and the compensation committee determined that it was appropriate for Mr. Primiano to receive 85% of his respective annual cash incentive target for 2016.

For 2017, the objective factors contributing to corporate performance were based on (i) the advancementoffset a portion of the clinical developmentcash bonuses paid in August 2018 to certain other employees of our drug candidates, particularly selinexor, (ii) the accrual of patients to our clinical trials, (iii) the achievement of clinical milestones relatingcompany for their contributions to the results from clinical trialscompany’s submission of our drug candidates in hematologic malignancies and solid tumors, (iv) the completion of clinical publications, (v) the generation of cash from our business development activities and(vi) year-end cash position. Based upon these clinical and development achievements and the entry into strategic transactions with Ono Pharmaceutical Co. Ltd. and Anivive Lifesciences as well as the completion of the Company’s capital raising activities, our board of directors, on the recommendation of the compensation committee, determined that it was appropriate for each of Drs. Kauffman and Shacham to receive 79% of such named executive officer’s respective annual cash incentive target for 2017, and the compensation committee determined that it was appropriate for Mr. Primiano to receive 86% of his respective annual cash incentive target for 2017.

Based on the determinations described above, in 2016, we awarded cash incentives to Dr. Kauffman, Dr. Shacham and Mr. Primiano in the amounts of $247,200, $166,000 and $122,000, respectively, and, in 2017, we awarded cash incentives to Dr. Kauffman, Dr. Shacham and Mr. Primiano in the amounts of $251,503, $171,856 and $133,770, respectively.

Special Cash Bonus Awards

From time to time, we may utilize cash bonus awards as compensation tools that provide, among other things, incentives to reward outstanding performance by executives. In November 2017, Mr. Primiano received a bonus in the amount of $1,500 approved by the compensation committee related to his efforts to complete and enter into our license agreement with Ono Pharmaceutical Co., Ltd., which we announced on October 12, 2017. In addition, in January 2018, in connection with our compensation committee’s review and approval of Mr. Primiano’s annual performance-based cash incentive compensation, our compensation committee awarded Mr. Primiano a discretionary bonus of $30,000 for his efforts in 2017 relatedits first NDA to the transaction with Ono Pharmaceutical Co., Ltd.FDA.

Equity Incentive Awards

OurWe use our equity awardawards program to encourage executives to deliver long-term company performance, align executive and stockholder interests and promote retention. The market for qualified and talented executives in the biopharmaceutical industry is the primary vehiclehighly competitive and we compete for offering long-term incentives to our named executive officers. Whiletalent with many companies that have greater resources than we do not currently have any equity ownership guidelines for our named executive officers,do. Accordingly, we believe that equity grants provide our namedcompensation is a crucial component of any competitive executive officers with a strong link to our long-term performance, create an ownership culture and help to align the interests of our named executive officers and our stockholders. We believe stock options and RSUs provide meaningful incentives to our named executive officers to achieve increases in the value of our stock over time. In addition, the vesting feature ofcompensation package we offer.

Historically, our equity grants contributes to executive retention by providing an incentive to our named executive officers to remain employed by us duringawards have generally taken the vesting period.

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In 2017,January 2018, our compensation committee approved annual equity incentive awards for Messrs. Falvey and Primiano and our compensation committee recommended to our board of directors and our board of directors approved annual equity incentive awards for Drs. Kauffman and Shacham. The annual equity incentive awards granted stock options to our named executive officers pursuant toserving at that time are set forth in the 2013 Plan, as follows:table below:

circumstances. We have provided more detailed information about these benefits, along with estimates of their value under various circumstances, under the captions“Executive Compensation—Employment Agreements, Severance and Change in Control Arrangements.” and“Executive Compensation—Potential Payments Upon Termination or Change in Control” below.

We believe providing severance and/or change in control benefits as a component of our compensation structure can help us compete for executive talent and attract and retain highly talented executive officers whose contributions are critical to our long-term success. After consultation with Arnosti, we believe that our severance and change in control benefits are appropriate.

Offer Letter for Anand Varadan

In June 2018, our compensation committee approved, and we entered into, an offer letter with Mr. Varadan that provided for a $405,000 annual base salary, a $25,000 cashsign-on bonus, a target award percentage of 40% under our annual performance-based cash incentive program and a stock option to purchase 150,000 shares of the company’s common stock. Pursuant to his offer letter, the stock option was awarded outside our 2013 Stock Incentive Plan on June 22, 2018 as an inducement material to Mr. Varadan entering into employment with the company in accordance with Nasdaq listing Rule 5635(c)(4). The stock option has an exercise price of $18.68 per share, which was the closing price of the company’s common stock on the Nasdaq Global Select Market on the grant date of June 22, 2018 and has substantially the same terms as stock options granted under our 2013 Stock Incentive Plan. In setting Mr. Varadan’s compensation, our compensation committee considered compensation benchmark data relative to the 2018 peer group, internal pay equity relative to our other executives and Mr. Varadan’s experience.

Separation Arrangements with Michael Falvey

On January 17, 2019, Michael Falvey resigned as Executive Vice President, Chief Financial Officer and Treasurer of the company effective January 18, 2019. Mr. Falvey had previously notified us of his intention to resign. In connection with his resignation, our compensation committee approved, and we entered into a separation agreement and a consulting agreement with Mr. Falvey. Pursuant to the terms of the separation agreement and in consideration of a customary release of any claims by Mr. Falvey against us, Mr. Falvey is entitled to severance benefits consisting of severance pay in the aggregate amount of $202,000 (to be paid in semi-monthly installments for a period of six months) and continuation of healthcare benefit premium payments until no later than July 31, 2019, continued vesting of his unvested equity awards until April 18, 2019 pursuant to the terms of the consulting agreement, and was entitled to payment of an annual performance-based cash incentive for fiscal year 2018 of $173,417, which we paid in February 2019.

Pursuant to the terms of the consulting agreement, Mr. Falvey will provide certain advisory and other consulting services to us from January 18, 2019 until July 18, 2019 (or such earlier date upon which the agreement terminates in accordance with its terms). As full compensation for such services, Mr. Falvey’s outstanding and unvested equity awards shall continue to vest until April 18, 2019, according to their terms, and his vested equity awards as of that date will remain exercisable for three months following the termination of the consulting agreement.

Tax and Accounting Considerations

Section 162(m) of the Internal Revenue Code generally disallows a tax deduction to public companies for compensation in excess of $1 million paid in any taxable year to each of the company’s chief executive officer, chief financial officer and three most highly compensated officers (other than the chief executive officer and chief financial officer). Historically, compensation paid to the Company’s chief financial officer and compensation that qualified under Section 162(m) as performance-based compensation was exempt from the deduction limitation. However, subject to certain transition rules, tax reform legislation signed into law on

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December 22, 2017, expanded the deduction limitation to apply to compensation in excess of $1 million paid in any taxable year to the company’s chief financial officer and eliminated the qualified performance-based compensation exception. As a result, for taxable years beginning after December 31, 2017, all compensation in excess of $1 million paid to each of the executives described above (other than certain grandfathered compensation or compensation paid pursuant to certain equity awards granted during the transition period following our initial public offering) will not be deductible by us. The board of directors reserves the right to use its business judgment to authorize compensation payments that may be subject to the limitations under Section 162(m) when the board of directors believes that compensation is appropriate and in the best interests of the company and our stockholders, after taking into consideration changing business conditions and performance of our employees.

Hedging and Pledging Policy

We have an insider trading policy that is applicable to all of our employees and members of our board of directors. The policy prohibits those individuals and their related persons from engaging in any speculative transactions involving our stock, including the following activities: short sales of our securities, including short sales “against the box”; purchases or sales of puts, calls or other derivative securities based on our securities; standing orders with brokers other than under an approved trading plan, purchases of financial instruments (including prepaid variable forward contracts, equity swaps, collars and exchange funds) that are designed to hedge or offset any decrease in the market value of our securities; the purchase of our securities on margin; borrowing against our securities held in a margin account; or pledging our securities as collateral for a loan. However, an exception may be granted where a person wishes to pledge our securities as collateral for a loan (other than a margin loan) and clearly demonstrates the financial capacity to repay the loan without resort to the pledged securities. Any person who wishes to pledge our securities as collateral for a loan must submit a request for approval to our principal financial officer. In addition, any such request by a director or executive officer must also be reviewed and approved by the Audit Committee.

Compensation Risk Assessment

Our compensation committee has reviewed and evaluated the philosophy and standards on which our compensation programs have been developed and implemented across our company. It is our belief that our compensation programs do not encourage inappropriate actions or risk taking by our executive officers. We do not believe that any risks arising from our employee compensation policies and practices are reasonably likely to have a material adverse effect on our company. In addition, we do not believe that the mix and design of the components of our executive compensation program encourage management to assume excessive risks.

We believe that our current business process and planning cycle fosters the following behaviors and controls that mitigate the potential for adverse risk caused by the action of our executives:

Report of the Compensation Committee on Executive Compensation

The Compensation Committee of the Board of Directors of Karyopharm Therapeutics Inc. has reviewed and discussed the “Compensation Discussion and Analysis” required by Item 402(b) of RegulationS-K with

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management. Based upon such review and discussions, the Compensation Committee recommended to the Board of Directors that the Compensation Discussion and Analysis be included in this proxy statement.

By the Compensation Committee of the Board of Directors of Karyopharm Therapeutics Inc.

Deepika R. Pakianathan Ph.D., Chair

Barry E. Greene

This Compensation Committee Report does not constitute soliciting material and should not be deemed filed or incorporated by reference into any other Karyopharm Therapeutics Inc. filing with the SEC, except to the extent that Karyopharm Therapeutics Inc. specifically incorporates this Report by reference into another Karyopharm Therapeutics Inc. filing.

Summary Compensation Table

The following table sets forth information regarding compensation earned by each of our named executive officers during each of the fiscal years ended December 31, 2016, 2017 and 2018. Our named executive officers for 2018 are Dr. Michael Kauffman, our Chief Executive Officer; Dr. Sharon Shacham, our President and Chief Scientific Officer; Mr. Christopher Primiano, our Executive Vice President, Chief Business Officer, General Counsel and Secretary; Mr. Anand Varadan, our Executive Vice President, Chief Commercial Officer; and Mr. Michael Falvey, our former Executive Vice President, Chief Financial Officer and Treasurer. Mr. Falvey resigned as an officer of the company effective January 18, 2019.

Summary Compensation Table

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2017 2018 Grants of Plan-Based Awards Table

The following table sets forth information regarding each grant of an award made to a NEO during 2018 under any plan, contract, authorization or arrangement pursuant to which cash, securities, similar instruments or other property may be received.

Outstanding Equity Awards at Fiscal2018Year-End

The following table sets forth information concerning outstanding equity awards for each of our named executive officersNEOs at December 31, 2017:2018.

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2018 Option Exercises and Stock Vested Table

The following table sets forth, for each of the NEOs, information with respect to the exercise of stock options during the year ended December 31, 2018.

If we terminate Mr. Varadan’s employment without cause or if Mr. Varadan terminates his employment for good reason, in either case, prior to a change of control, we will be required to pay as severance to Mr. Varadan his base salary for six months. If we terminate Mr. Varadan’s employment without cause, or if Mr. Varadan resigns for good reason, in either case, within one year following a change of control, we will be required to pay as severance to Mr. Varadan his base compensation for 12 months. If Mr. Varadan elects to continue his and his eligible dependents’ participation in the company’s medical and dental benefit plans pursuant to COBRA, the company will pay the monthly premium to continue such coverage during the applicable severance period.

If we terminate Mr. Falvey’s employment without cause or if Mr. Falvey terminates his employment for good reason, in either case, prior to a change of control, we will be required to pay as severance to Mr. Falvey his base salary for six months. If we terminate Mr. Falvey’s employment without cause, or if Mr. Falvey resigns for good reason, in either case, within one year following a change of control, we will be required to pay as severance to Mr. Falvey his base compensation for 12 months. If Mr. Falvey elects to continue his and his eligible dependents’ participation in the company’s medical and dental benefit plans pursuant to COBRA, the company will pay the monthly premium to continue such coverage during the applicable severance period. On January 17, 2019, Michael Falvey resigned as Executive Vice President, Chief Financial Officer and Treasurer of the company effective January 18, 2019. Mr. Falvey had previously notified us of his intention to resign. In connection with his resignation, our compensation committee approved, and we entered into a separation agreement and a consulting agreement with Mr. Falvey. For additional information see “—Separation Arrangements with Michael Falvey.”

Potential Payments Upon Termination or Change in Control

The amount of compensation and benefits payable to each NEO who was employed on December 31, 2018 under our current employment agreements in various termination and change in control situations has been estimated in the tables below. The value of the equity vesting acceleration was calculated for each of the tables below based on the assumption that the change in control and the NEO’s employment termination occurred on December 31, 2018, the last business day of the fiscal year ended December 31, 2018. The per share closing price of our common stock on the Nasdaq Global Select Market as of December 31, 2018, the last trading day of 2018, was $9.37, which was used as the value of our common stock in the change in control. The value of the option vesting acceleration was calculated by multiplying the number of unvested option shares subject to vesting acceleration as of December 31, 2018, by the difference between the per share closing price of our common stock as of December 31, 2018, and the per share exercise price for such unvested option shares. We are not required to make any payments to any of our named executive officers in the event he or she voluntarily resigns without good reason or we terminate his or her employment for cause.

Dr. Michael G. Kauffman

The following table describes the potential payments and benefits upon employment termination for Dr. Kauffman, as if his employment terminated as of December 31, 2018, the last business day of the fiscal year.