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IONS Ionis Pharmaceuticals

Document and Entity Information

Document and Entity Information - shares3 Months Ended
Mar. 31, 2021Apr. 29, 2021
Cover [Abstract]
Entity Registrant NameIonis Pharmaceuticals, Inc.
Entity Central Index Key0000874015
Current Fiscal Year End Date--12-31
Document Type10-Q
Amendment Flagfalse
Document Quarterly Reporttrue
Document Period End DateMar. 31,
2021
Document Fiscal Year Focus2021
Document Fiscal Period FocusQ1
Document Transition Reportfalse
Entity File Number000-19125
Entity Incorporation, State or Country CodeDE
Entity Tax Identification Number33-0336973
Entity Address, Address Line One2855 Gazelle Court
Entity Address, City or TownCarlsbad
Entity Address, State or ProvinceCA
Entity Address, Postal Zip Code92010
City Area Code760
Local Phone Number931-9200
Title of 12(b) SecurityCommon Stock, $.001 Par Value
Trading SymbolIONS
Security Exchange NameNASDAQ
Entity Current Reporting StatusYes
Entity Interactive Data CurrentYes
Entity Filer CategoryLarge Accelerated Filer
Entity Small Businessfalse
Entity Emerging Growth Companyfalse
Entity Shell Companyfalse
Entity Common Stock, Shares Outstanding140,963,028

CONDENSED CONSOLIDATED BALANCE

CONDENSED CONSOLIDATED BALANCE SHEETS - USD ($) $ in ThousandsMar. 31, 2021Dec. 31, 2020
Current assets:
Cash and cash equivalents $ 414,155 $ 397,664
Short-term investments1,405,840 1,494,711
Contracts receivable23,397 76,204
Inventories22,199 21,965
Other current assets123,827 140,163
Total current assets1,989,418 2,130,707
Property, plant and equipment, net180,413 181,077
Patents, net28,795 27,937
Deposits and other assets49,925 50,034
Total assets2,248,551 2,389,755
Current liabilities:
Accounts payable9,506 17,199
Accrued compensation29,263 65,728
Accrued liabilities78,766 90,161
Income taxes payable1,326 1,324
Current portion of 1 percent convertible senior notes, net61,816 308,809
Current portion of long-term obligations7,688 7,301
Current portion of deferred contract revenue106,740 108,376
Total current liabilities295,105 598,898
Long-term deferred contract revenue401,966 424,046
Long-term obligations, less current portion22,943 23,409
Long-term mortgage debt60,002 59,984
Total liabilities1,567,987 1,646,473
Stockholders' equity:
Common stock, $0.001 par value; 300,000,000 shares authorized, 140,924,356 and 140,365,594 shares issued and outstanding at March 31, 2021 (unaudited) and December 31, 2020, respectively141 140
Additional paid-in capital1,925,801 1,895,519
Accumulated other comprehensive loss(24,203)(21,071)
Accumulated deficit(1,221,175)(1,131,306)
Total stockholders' equity680,564 743,282
Total liabilities and stockholders' equity2,248,551 2,389,755
0.125 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net540,679 540,136
1 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net $ 247,292 $ 0

CONDENSED CONSOLIDATED BALANC_2

CONDENSED CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / sharesMar. 31, 2021Dec. 31, 2020
Stockholders' equity:
Common stock, par value (in dollars per share) $ 0.001 $ 0.001
Common stock, shares authorized (in shares)300,000,000 300,000,000
Common stock, shares issued (in shares)140,924,356 140,365,594
Common stock, shares outstanding (in shares)140,924,356 140,365,594
0.125 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes0.125%0.125%
1 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes1.00%1.00%

CONDENSED CONSOLIDATED STATEMEN

CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($) shares in Thousands, $ in Thousands3 Months Ended
Mar. 31, 2021Mar. 31, 2020
Revenue:
Revenue $ 111,607 $ 133,367
Expenses:
Cost of sales2,578 2,548
Research, development and patent139,801 116,952
Selling, general and administrative61,199 74,994
Total operating expenses203,578 194,494
Loss from operations(91,971)(61,127)
Other income (expense):
Investment income4,643 10,479
Interest expense(2,414)(2,207)
Other income (expenses)3 (99)
Loss before income tax (expense) benefit(89,739)(52,954)
Income tax (expense) benefit(130)3,072
Net loss(89,869)(49,882)
Net loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.0 10,254
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (89,869) $ (39,628)
Basic net loss per share (in dollars per share) $ (0.64) $ (0.28)
Diluted net loss per share (in dollars per share) $ (0.64) $ (0.28)
Shares used in computing basic net loss per share (in shares)140,770 139,429
Shares used in computing diluted net loss per share (in shares)140,770 139,429
Commercial Revenue [Member]
Revenue:
Revenue $ 84,448 $ 83,961
SPINRAZA Royalties [Member]
Revenue:
Revenue59,986 66,008
TEGSEDI and WAYLIVRA Revenue, Net [Member]
Revenue:
Revenue19,838 15,159
Licensing and Other Royalty Revenue [Member]
Revenue:
Revenue4,624 2,794
Research and Development Revenue Under Collaborative Agreements [Member]
Revenue:
Revenue $ 27,159 $ 49,406

CONDENSED CONSOLIDATED STATEM_2

CONDENSED CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS - USD ($) $ in Thousands3 Months Ended
Mar. 31, 2021Mar. 31, 2020
CONDENSED CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS [Abstract]
Net loss $ (89,869) $ (49,882)
Unrealized losses on debt securities, net of tax(3,006)(1,954)
Currency translation adjustment(126)9
Comprehensive loss(93,001)(51,827)
Comprehensive loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.0 (10,254)
Comprehensive loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (93,001) $ (41,573)

CONDENSED CONSOLIDATED STATEM_3

CONDENSED CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($) shares in Thousands, $ in ThousandsCommon Stock [Member]Additional Paid In Capital [Member]Accumulated Other Comprehensive Loss [Member]Accumulated Deficit [Member]Total Ionis Stockholders' Equity [Member]Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]Total
Balance at Dec. 31, 2019 $ 140 $ 1,985,650 $ (25,290) $ (596,495) $ 1,364,005 $ 213,453 $ 1,577,458
Balance (in shares) at Dec. 31, 2019140,340
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss $ 0 0 0 (39,628)(39,628)0 (39,628)
Change in unrealized losses, net of tax0 0 (1,954)0 (1,954)0 (1,954)
Foreign currency translation0 0 9 0 9 0 9
Issuance of common stock in connection with employee stock plans $ 0 7,652 0 0 7,652 0 7,652
Issuance of common stock in connection with employee stock plans (in shares)606
Repurchases and retirements of common stock $ (1)0 0 (90,549)(90,550)0 (90,550)
Repurchases and retirements of common stock (in shares)(1,478)
Stock-based compensation expense $ 0 40,790 0 0 40,790 0 40,790
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options $ 0 (11,603)0 0 (11,603)0 (11,603)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)(186)
Noncontrolling interest in Akcea Therapeutics, Inc. $ 0 (6,973)0 0 (6,973)(3,281)(10,254)
Balance at Mar. 31, 2020 $ 139 2,015,516 (27,235)(726,672)1,261,748 210,172 1,471,920
Balance (in shares) at Mar. 31, 2020139,282
Balance at Dec. 31, 2020 $ 140 1,895,519 (21,071)(1,131,306)743,282 0 743,282
Balance (in shares) at Dec. 31, 2020140,366
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss $ 0 0 0 (89,869)(89,869)0 (89,869)
Change in unrealized losses, net of tax0 0 (3,006)0 (3,006)0 (3,006)
Foreign currency translation0 0 (126)0 (126)0 (126)
Issuance of common stock in connection with employee stock plans $ 1 7,758 0 0 7,759 0 7,759
Issuance of common stock in connection with employee stock plans (in shares)809
Stock-based compensation expense $ 0 37,861 0 0 37,861 0 37,861
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options $ 0 (15,337)0 0 (15,337)0 (15,337)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)(251)
Balance at Mar. 31, 2021 $ 141 $ 1,925,801 $ (24,203) $ (1,221,175) $ 680,564 $ 0 $ 680,564
Balance (in shares) at Mar. 31, 2021140,924

CONDENSED CONSOLIDATED STATEM_4

CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($) $ in Thousands3 Months Ended
Mar. 31, 2021Mar. 31, 2020
Operating activities:
Net loss $ (89,869) $ (49,882)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation3,917 3,233
Amortization of right-of-use operating lease assets394 393
Amortization of patents544 486
Amortization of premium (discount) on investments, net4,023 1,062
Amortization of debt issuance costs860 647
Stock-based compensation expense37,861 40,790
Gain on investments(13)(246)
Non-cash losses related to patents221 159
Provision for deferred income taxes0 (2,288)
Changes in operating assets and liabilities:
Contracts receivable52,807 34,429
Inventories(234)(2,181)
Other current and long-term assets16,481 9,532
Income taxes payable2 (532)
Accounts payable(9,569)411
Accrued compensation(36,465)(20,920)
Accrued liabilities and other current liabilities(11,905)(3,006)
Deferred contract revenue(23,717)(19,679)
Net cash used in operating activities(54,662)(7,592)
Investing activities:
Purchases of short-term investments(330,051)(544,375)
Proceeds from sale of short-term investments411,907 459,352
Purchases of property, plant and equipment(1,772)(9,080)
Acquisition of licenses and other assets, net(1,228)(904)
Net cash provided by (used in) investing activities78,856 (95,007)
Financing activities:
Proceeds from equity, net7,760 7,652
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options(15,337)(11,603)
Repurchases and retirements of common stock0 (90,550)
Net cash used in financing activities(7,577)(94,501)
Effects of exchange rates on cash(126)8
Net increase (decrease) in cash and cash equivalents16,491 (197,092)
Cash and cash equivalents at beginning of period397,664 683,287
Cash and cash equivalents at end of period414,155 486,195
Supplemental disclosures of cash flow information:
Interest paid594 601
Income taxes paid2 3
Supplemental disclosures of non-cash investing and financing activities:
Amounts accrued for capital and patent expenditures $ 1,876 $ 4,903

Basis of Presentation

Basis of Presentation3 Months Ended
Mar. 31, 2021
Basis of Presentation [Abstract]
Basis of Presentation1. Basis of Presentation We prepared the unaudited interim condensed consolidated financial statements for the and on the same basis as the audited financial statements for the year ended , with the exception of our retrospective adoption of Accounting Standards Update, or ASU, 2020-06, which simplifies . See Note 2, Significant Accounting Polices , Convertible Debt, for details of our adoption of this guidance. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and notes thereto, should be read in conjunction with the audited financial statements for the year ended included in our Annual Report on Form 10-K filed with the Securities and Exchange Commission, or SEC. In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). We formed Akcea in December 2014. initial public offering, or IPO, which reduced our ownership of Akcea’s common stock below . In October 2020, we acquired the shares of Akcea’s common stock we did not own. We will refer to this transaction as the Akcea Acquisition throughout the remainder of this document.

Significant Accounting Policies

Significant Accounting Policies3 Months Ended
Mar. 31, 2021
Significant Accounting Policies [Abstract]
Significant Accounting Policies2. Significant Accounting Policies Revenue Recognition Our Revenue Sources We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our condensed consolidated balance sheet. Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue sales milestone payments and royalties we earn under our other partnerships. Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net In the United States, or U.S., through the first quarter of 2021, we sold TEGSEDI through an exclusive distribution agreement with a third-party logistics company, or 3PL, that took title to TEGSEDI. The 3PL was our sole customer in the U.S. The 3PL then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In Europe, through 2020, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as distributors. In January 2021, we began commercializing TEGSEDI and WAYLIVRA in Europe through a distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. In April 2021, we expanded our distribution agreement with Sobi to also include commercializing TEGSEDI in North America. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we earn a distribution fee on net sales from Sobi for each medicine. Under our collaboration agreement with PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. Research and development revenue under collaborative agreements We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&D, services, and manufacturing services. See Note 5, Collaborative Arrangements and Licensing Agreements , for collaborations with substantive changes that occurred in 2021. Additionally, see Collaborative Arrangements and Licensing Agreements Steps to Recognize Revenue We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five-step process is as follows:
1. Identify the contract Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:
● We and our partner approved the contract and we are both committed to perform our obligations;
● We have identified our rights, our partner’s rights and the payment terms;
● We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and
● We believe collectability of the consideration is probable.
2 . Identify the performance obligations We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the contract. We typically have only one performance obligation at the inception of a contract, which is to perform R&D services. Often we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item. In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.
3. Determine the transaction price We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price. Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For example, in the fourth quarter of 2020, we earned a $20 million milestone payment from AstraZeneca when AstraZeneca initiated a Phase 2b study for ION449, our medicine in development targeting PCSK9 to lower LDL-cholesterol. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing ION449 was contingent on AstraZeneca initiating a Phase 2b study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to the milestone payment.
4. Allocate the transaction price Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices. We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:
● Estimated future product sales;
● Estimated royalties we may receive from future product sales;
● Estimated contractual milestone payments we may receive;
● Expenses we expect to incur;
● Estimated income taxes; and
● A discount rate. We typically estimate the selling price of R&D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&D services include:
● The number of internal hours we estimate we will spend performing these services;
● The estimated cost of work we will perform;
● The estimated cost of work that we will contract with third parties to perform; and
● The estimated cost of API we will use. For purposes of determining the stand-alone selling price of the R&D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.
5. Recognize revenue We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner. For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods. The following are examples of when we typically recognize revenue based on the types of payments we receive. Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue We recognize royalty revenue, including royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue. Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net Prior to our distribution agreement with Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&A, expenses in our condensed consolidated statements of operations. We classified payments to customers or other parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted these amounts to governmental authorities. Under our distribution agreement with Sobi we concluded that our performance obligation is to supply finished goods inventory to Sobi. This performance obligation is a series of distinct activities that are substantially the same because we transfer title using the same criteria each time we ship inventory to Sobi. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We also recognize distribution fee revenue based on Sobi’s net sales of TEGSEDI and WAYLIVRA. Additionally, Sobi does not generally have a right of return. Reserves for TEGSEDI and WAYLIVRA commercial revenue Prior to our distribution agreement with Sobi, w Organization and Significant Accounting Policies Under our distribution agreement with Sobi, Sobi is financially responsible for any applicable reserves. Research and development revenue under collaboration agreements: Upfront payments When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&D services. For example, under our collaboration agreement with Roche to develop IONIS-FB-L Rx Milestone payments We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-based royalty exception allowed under accounting rules. We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2020, we achieved a $7.5 million milestone payment from Biogen when we advanced a target under our 2018 strategic collaboration. We added this payment to the transaction price and allocated it to our R&D services performance obligation. We are recognizing revenue related to this milestone payment over our estimated period of performance. Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation. For example, in the third quarter of 2020, we recognized $18 million in milestone payments when Biogen initiated a Phase 1/2 trial for ION464, our medicine in development targeting alpha-synuclein to treat patients with multiple system atrophy. We concluded that the milestone payments were not related to our R&D services performance obligation. Therefore, we recognized the milestone payments in full in the third quarter of 2020. License fees We generally recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. For example, in the fourth quarter of 2020, we earned a $30 million license fee from AstraZeneca when AstraZeneca licensed ION455, an investigational medicine in development to treat nonalcoholic steatohepatitis, or NASH. Sublicense fees We recognize sublicense fee revenue in the period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. Amendments to Agreements From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:
1) If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and
2) If the goods and/or services are sold at a stand-alone selling price. If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment. For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI Rx $ million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI Rx in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI Rx and to initiate development of IONIS-FXI-L Rx , which Bayer licensed. As part of the 2017 amendment, Bayer paid us $ million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI Rx and IONIS-FXI-L Rx . Under the 2017 amendment, we concluded we had a new agreement with performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L Rx , to provide R&D services and to deliver API. We allocated the $ million transaction price to these performance obligations. Refer to Note 6, Collaborative Arrangements and Licensing Agreements , for further discussion of the Bayer collaboration. Multiple agreements From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:
● Whether the agreements were negotiated together with a single objective;
● Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or
● Whether the goods and/or services promised under the agreements are a single performance obligation. Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement. For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Contracts Receivable Our contracts receivable balance represents the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider the contracts receivable to be unconditional. We typically receive payment within one quarter of billing our partner or customer As of March 31, 2021, approximately 46.8 percent of our contracts receivables were from three significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two significant customers. Unbilled SPINRAZA Royalties Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our condensed consolidated balance sheet. Deferred Revenue We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our condensed consolidated balance sheet. Cost of Sales Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. Cash, Cash Equivalents and Investments We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as “available-for-sale” and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our condensed consolidated statement of operations. We use the specific identification method to determine the cost of securities sold. We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At March 31, 2021, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in seven privately held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, Seventh Sense Biosystems and Suzhou-Ribo Life Science Co, Ltd. We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our condensed consolidated statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. For example, during the second and fourth quarters of 2020, we revalued our investments in three privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies sold additional equity securities that were similar to the equity we own. These observable price changes resulted in us recognizing a $6.3 million gain on our investment in Dynacure, a $3.0 million gain on our investment in Suzhou-Ribo and a $5.5 million gain on our investment in Aro Biotherapeutics in our condensed consolidated statement of operations during 2020 because the sales were at higher prices compared to our recorded value. Inventory Valuation We reflect our inventory on our condensed consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. We obtained the first regulatory approval for TEGSEDI in July 2018 and for WAYLIVRA in May 2019. At March 31, 2021, our physical inventory for TEGSEDI and WAYLIVRA included API that we produced prior to when we obtained regulatory approval. As such, this API has no cost basis as we had previously expensed the costs as R&D expenses. We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We recorded an insignificant amount of inventory write-offs for the . Our inventory consisted of the following (in thousands):
March 31, 2021 December 31, 2020
Raw materials:
Raw materials- clinical $ 10,695 $ 9,206
Raw materials- commercial 7,502 7,502
Total raw materials 18,197 16,708
Work in process 2,096 2,252
Finished goods 1,906 3,005
Total inventory $ 22,199 $ 21,965 Leases We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-of-use operating lease asset and associated short- and long-term operating lease liability on our condensed consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum lease payments we will pay over the lease term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease term. As our current leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense. Research, Development and Patent Expenses Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our condensed consolidated balance sheet and we expense them as the services are provided. We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. . Income Taxes We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount we expect to realize. We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. We assessed our valuation allowance requirements and recorded a valuation allowance against all of Ionis’ U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize the tax benefits associated with these assets. We based our determination largely on Akcea rejoining the Ionis U.S. consolidated federal tax group in the fourth quarter of 2020. Due to Akcea’s historical and projected financial statement losses, and the negative impact we expect this to have on Ionis’ consolidated taxable income, there is uncertainty of generating sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis’ pre-tax income in future periods may be lower due to increased research and development expenses associated with our pipeline of wholly owned medicines. We continue to maintain a valuation allowance against all our consolidated U.S. federal and state net deferred tax assets. Long-lived Assets We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. Use of Estimates We prepare our condensed consolidated financial statements in conformity with accounting principles generally accepted in the Basic and Diluted Net Loss Per Share Basic net loss per share In the first quarter of 2021, we computed basic net loss per share by dividing our net loss by our weighted-average number of common shares outstanding during the period. For the first quarter of 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the three months ended March 31, 2021 was $0.64. In the first quarter of 2020, prior to the Akcea Acquisition, we calculated our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period to determine our total net loss attributable to our common stockholders. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s net loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than our net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the condensed consolidated statements of operations. Our basic net loss per share for the three months ended March 31, 2020, was calculated as follows (in thousands, except per share amounts):
Three months ended March 31, 2020 Weighted Average Shares Owned in Akcea Akcea’s Net Loss Per Share Basic Net Loss Per Share Calculation (as revised*)
Ionis’ portion of Akcea’s net loss 77,095 $ (0

Investments

Investments3 Months Ended
Mar. 31, 2021
Investments [Abstract]
Investments3. Investments The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2021:
One year or less 67 %
After one year but within two years 20 %
After two years but within three and a half years 13 %
Total 100 % As illustrated above, at March 31, 2021, 87 percent of our available-for-sale securities had a maturity of less than two years. All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date. We invest in available-for-sale securities At March 31, 2021, we had an ownership interest of less than 20 percent in seven private companies and two public companies with which we conduct business. The privately held companies are Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd. The publicly traded companies are Antisense Therapeutics Ltd. and ProQR Therapeutics N.V. The following is a summary of our investments (in thousands):
Gross Unrealized Estimated
March 31, 2021 Cost Gains Losses Fair Value
Available-for-sale securities:
Corporate debt securities (2) $ 446,816 $ 1,838 $ (76 ) $ 448,578
Debt securities issued by U.S. government agencies 80,703 292 (2 ) 80,993
Debt securities issued by the U.S. Treasury (2) 234,164 126 — 234,290
Debt securities issued by states of the U.S. and political subdivisions of the states 121,776 220 (22 ) 121,974
Other municipal debt securities 5,137 — (7 ) 5,130
Total securities with a maturity of one year or less 888,596 2,476 (107 ) 890,965
Corporate debt securities 325,335 3,108 (245 ) 328,198
Debt securities issued by U.S. government agencies 96,698 36 (164 ) 96,570
Debt securities issued by the U.S. Treasury 59,030 326 (35 ) 59,321
Debt securities issued by states of the U.S. and political subdivisions of the states 34,515 81 (25 ) 34,571
Other municipal debt 6,233 — (20 ) 6,213
Total securities with a maturity of more than one year 521,811 3,551 (489 ) 524,873
Total available-for-sale securities $ 1,410,407 $ 6,027 $ (596 ) $ 1,415,838
Equity securities:
Total equity securities included in other current assets (3) $ 4,712 $ — $ (1,514 ) $ 3,198
Total equity securities included in deposits and other assets (4) 15,062 15,938 — 31,000
Total equity securities 19,774 15,938 (1,514 ) 34,198
Total available-for-sale and equity securities $ 1,430,181 $ 21,965 $ (2,110 ) $ 1,450,036
Gross Unrealized Estimated
December 31, 2020 Cost Gains Losses Fair Value
Available-for-sale securities:
Corporate debt securities (2) $ 514,182 $ 2,194 $ (41 ) $ 516,335
Debt securities issued by U.S. government agencies 94,234 354 (2 ) 94,586
Debt securities issued by the U.S. Treasury (2) 307,576 233 (9 ) 307,800
Debt securities issued by states of the U.S. and political subdivisions of the states 104,271 196 (12 ) 104,455
Other municipal debt securities 5,191 — (7 ) 5,184
Total securities with a maturity of one year or less 1,025,454 2,977 (71 ) 1,028,360
Corporate debt securities 325,079 4,941 (40 ) 329,980
Debt securities issued by U.S. government agencies 80,099 185 (9 ) 80,275
Debt securities issued by the U.S. Treasury 50,318 383 (4 ) 50,697
Debt securities issued by states of the U.S. and political subdivisions of the states 31,779 91 (16 ) 31,854
Other municipal debt securities 1,041 — — 1,041
Total securities with a maturity of more than one year 488,316 5,600 (69 ) 493,847
Total available-for-sale securities $ 1,513,770 $ 8,577 $ (140 ) $ 1,522,207
Equity securities:
Total equity securities included in other current assets (3) $ 4,712 $ — $ (2,681 ) $ 2,031
Total equity securities included in deposits and other assets (4) 15,062 15,938 — 31,000
Total equity securities 19,774 15,938 (2,681 ) 33,031
Total available-for-sale and equity securities $ 1,533,544 $ 24,515 $ (2,821 ) $ 1,555,238
(1) We hold our available-for-sale securities at amortized cost.
(2) Includes investments classified as cash equivalents on our condensed consolidated balance sheet.
(3) Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.
(4) Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at . The following is a summary of our investments we consider to be temporarily impaired at (in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities’ amortized cost basis at maturity.
Number of Investments Estimated Fair Value Unrealized Losses
Corporate debt securities 101 $ 233,665 $ (321 )
Debt securities issued by U.S. government agencies 7 60,681 (166 )
Debt securities issued by the U.S. Treasury 6 52,838 (35 )
Debt securities issued by states of the U.S. and political subdivisions of the states 297 76,712 (47 )
Other municipal debt securities 3 11,343 (27 )
Total temporarily impaired securities 414 $ 435,239 $ (596 )

Fair Value Measurements

Fair Value Measurements3 Months Ended
Mar. 31, 2021
Fair Value Measurements [Abstract]
Fair Value Measurements4. Fair Value Measurements We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices. The following tables present the major security types we held at and that we regularly measure and carry at fair value. As of and , . The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities’ fair value (in thousands):
At March 31, 2021 Quoted Prices in Active Markets (Level 1) Significant Other Observable Inputs (Level 2)
Cash equivalents (1) $ 372,050 $ 372,050 $ —
Corporate debt securities (2) 776,776 — 776,776
Debt securities issued by U.S. government agencies (3) 177,563 — 177,563
Debt securities issued by the U.S. Treasury (3) 293,611 293,611 —
Debt securities issued by states of the U.S. and political subdivisions of the states (3) 156,545 — 156,545
Other municipal debt securities (3) 11,343 — 11,343
Investment in ProQR Therapeutics N.V. (4) 3,198 3,198 —
Total $ 1,791,086 $ 668,859 $ 1,122,227
At December 31, 2020 Quoted Prices in Active Markets (Level 1) Significant Other Observable Inputs (Level 2)
Cash equivalents (1) $ 221,125 $ 221,125 $ —
Corporate debt securities (2) 846,315 — 846,315
Debt securities issued by U.S. government agencies (3) 174,861 — 174,861
Debt securities issued by the U.S. Treasury (5) 358,497 358,497 —
Debt securities issued by states of the U.S. and political subdivisions of the states (3) 136,309 — 136,309
Other municipal debt securities (3) 6,225 — 6,225
Investment in ProQR Therapeutics N.V. (4) 2,031 2,031 —
Total $ 1,745,363 $ 581,653 $ 1,163,710 The following footnotes reference lines on our condensed consolidated balance sheet:
(1) Included in cash and cash equivalents on our condensed consolidated balance sheet.
(2) $10.0 million was included in cash and cash equivalents, with the difference included in short-term investments.
(3) Included in short-term investments.
(4) Included in other current assets on our condensed consolidated balance sheet.
(5) $17.5 million included in cash and cash equivalents on our condensed consolidated balance sheet, with the difference included in short-term investments on our condensed consolidated balance sheet. Convertible Notes Our 1% Notes and 0.125% Notes had a fair value of $314.6 million and $527.3 million at March 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2 measurements because the notes do not trade regularly.

Collaborative Arrangements and

Collaborative Arrangements and Licensing Agreements3 Months Ended
Mar. 31, 2021
Collaborative Arrangements and Licensing Agreements [Abstract]
Collaborative Arrangements and Licensing Agreements5. Collaborative Arrangements and Licensing Agreements Below, we have included our Biogen collaboration, which is our only collaboration with substantive changes during 2021 from those included in Note 6 of our audited financial statements included in our Annual Report on Form 10-K for the year ended December 31, 2020 . Strategic Partnership Biogen We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen’s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. We and Biogen are currently developing eight investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, Alzheimer’s disease During the three months ended March 31, 2021 and 2020, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):
Three Months Ended March 31,
2021 2020
SPINRAZA royalties (commercial revenue) $ 60.0 $ 66.0
R&D revenue 18.1 21.4
Total revenue from our relationship with Biogen $ 78.1 $ 87.4
Percentage of total revenue 70 % 66 % Our condensed consolidated balance sheet at March 31, 2021 and December 31, 2020 During the first three months of 2021, we did not have any changes to our performance obligations, transaction price or the timing in which we expect to recognize revenue under our Biogen collaborations. In April 2021, we achieved a $10 million milestone payment from Biogen when Biogen advanced ION541, an investigational medicine targeting ataxin 2 to treat patients with ALS. We will achieve the next payment of $8 million if Biogen advances one of the medicines under our 2013 strategic neurology collaboration.

Convertible Debt

Convertible Debt3 Months Ended
Mar. 31, 2021
Convertible Debt [Abstract]
Convertible Debt6. Convertible Debt 0 Percent Convertible Senior Notes and Call Spread In April 2021, we completed a $632.5 million offering of convertible senior notes. We used a portion of the net proceeds from the issuance of the 0 percent convertible senior notes, or 0% Notes, to repurchase $247.9 million in principal of our 1% Notes for $257.0 million. Following the closing of the debt transaction in April 2021, we had the following 0%
0%
Outstanding principal balance $ 632.5
Maturity date April 2026
Interest rate 0 percent
Conversion price per share $ 57.84
Effective conversion price per share with call spread $ 76.39
Total shares of common stock subject to conversion 10.9 In conjunction with the April 2021 offering, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0% Notes by increasing the effective conversion price on our 0% Notes. We increased our effective conversion price to $76.39 with the same number of underlying shares as our 0% Notes. The call spread cost us $46.9 million, of which $136.7 million was for the note hedge purchase, offset by $89.8 million we received for selling the warrants. Similar to our 0% Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0% Notes. The note hedges will expire upon maturity of the 0% Notes, or April 2026. The note hedges and warrants are separate transactions and are not part of the terms of our 0% Notes. The holders of the 0% Notes do not have any rights with respect to the note hedges and warrants. 0.125 Percent Convertible Senior Notes and Call Spread At March 31, 2021, we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):
0.125% Notes
Outstanding principal balance $ 548.8
Maturity date December 2024
Interest rate 0.125 percent
Conversion price per share $ 83.28
Effective conversion price per share with call spread $ 123.38
Total shares of common stock subject to conversion 6.6
Unamortized debt issuance costs $ 8.1 In conjunction with the issuance of our Notes in December 2019, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our . We increased our effective conversion price to $ with the same number of underlying shares as our Notes. The call spread cost us $ million, of which $ million was for the note hedge purchase, offset by $ million we received for selling the warrants. Similar to our , our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the . The note hedges will expire upon maturity of the , or December 2024. The note hedges and warrants are separate transactions and are not part of the terms of our . The holders of the do not have any rights with respect to the note hedges and warrants. We recorded the amount paid for the note hedges and the amount received for the warrants in additional paid-in capital in our condensed consolidated balance sheet. See our Call Spread accounting policy in Note 2, Significant Accounting Policies 1 Percent Convertible Senior Notes At March 31, 2021, we had the following 1% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):
1% Notes
Outstanding principal balance $ 309.9
Maturity date November 2021
Interest rate 1 percent
Conversion price per share $ 66.81
Total shares of common stock subject to conversion 4.6
Unamortized debt issuance costs $ 0.8 In April 2021, we repurchased $247.9 million in aggregate principal amount of our 1% Notes in privately negotiated transactions. As a result, in April 2021, the remaining principal outstanding for our 1% Notes was $62.0 million, resulting in 0.9 million shares of common stock subject to conversion. As a result of the repurchase, we reclassified the repurchased portion of our 1% Notes from current to non-current liabilities on our condensed consolidated balance sheet as of March 31, 2021 because we replaced this portion of our outstanding debt with long-term debt. Other Terms of Convertible Senior Notes The 0%, 0.125% and 1% Notes are convertible under certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus any accrued and unpaid interest.

Severance and Retention Costs

Severance and Retention Costs3 Months Ended
Mar. 31, 2021
Severance and Retention Costs [Abstract]
Severance and Retention Costs7. Severance and Retention Costs Akcea Acquisition As a result of the Akcea Acquisition in October 2020, we began recognizing severance and retention expenses in the fourth quarter of 2020. The following table summarizes our total estimated severance and retention expenses related to the Akcea Acquisition (in millions):
Severance and Retention Expenses
Total estimated expenses $ 28.5
Expenses incurred in the three months ended December 31, 2020 15.3
Expenses incurred in the three months ended March 31, 2021 5.4
Remaining estimated expenses to be recognized through October 2021 $ 7.8 The following table summarizes our severance and retention expenses related to the Akcea Acquisition that we recognized during the three months ended March 31, 2021 (in millions):
Three Months Ended March 31, 2021
Research, development and patent expenses $ 2.5
Selling, general and administrative expenses 2.9
Total $ 5.4 The following table summarizes the severance and retention reserve amounts related to the Akcea Acquisition that we included in accrued compensation for the period indicated (in millions):
Three Months Ended March 31, 2021
Beginning balance $ 14.7
Amounts expensed during the period 6.1
Reserve adjustments during the period (0.7 )
Net amount expensed during the period 5.4
Amounts paid during the period (9.0 )
Ending balance $ 11.1 The reserve adjustments during the period primarily related to forfeitures of severance and retention payments as a result of employee terminations before they earned the amounts. Restructured European Operations As a result of restructuring our European operations, or Restructured European Operations, in December 2020, we began recognizing severance and retention expenses in the fourth quarter of 2020. The following table summarizes our total severance and retention expenses related to our Restructured European Operations (in millions):
Severance and Retention Expenses
Total estimated expenses $ 13.6
Expenses incurred in the three months ended December 31, 2020 12.5
Expenses incurred in the three months ended March 31, 2021 0.7
Remaining estimated expenses through October 2021 $ 0.4 The following table summarizes the severance and retention expenses related to our Restructured European Operations that we recognized during the three months ended March 31, 2021 (in millions):
Three Months Ended March 31, 2021
Research, development and patent expenses $ 0.1
Selling, general and administrative expenses 0.6
Total $ 0.7 The following table summarizes the severance and retention reserve amounts related to our Restructured European operations that we included in accrued compensation for the periods indicated (in millions):
Three Months Ended March 31, 2021
Beginning balance $ 12.4
Amounts expensed during the period 2.2
Reserve adjustments during the period (1.5 )
Net amount expensed during the period 0.7
Amounts paid during the period (11.9 )
Ending balance $ 1.2 The reserve adjustments during the period primarily related to tax expense adjustments. Restructured North American TEGSEDI Operations In April 2021, we entered into a distribution agreement with Sobi for TEGSEDI in North America. Under the terms of the distribution agreement, we will retain the marketing authorizations for TEGSEDI in the U.S. and Canada. We will continue to supply commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion leaders. We will also continue to lead the TEGSEDI global commercial strategy. Sobi will otherwise have responsibility for commercializing TEGSEDI in the U.S. and Canada and will assume these activities by August 2021. In connection with restructuring our North American TEGSEDI operations, or Restructured North American TEGSEDI Operations, we enacted a plan to reorganize our Akcea workforce in North America to better align with the needs of our business, or the Reorganization Plan, and to focus on our wholly owned pipeline. Under the Reorganization Plan, we expect to incur restructuring charges in the range of $11 million to $14 million principally in the second quarter of 2021.

Basis of Presentation (Policies

Basis of Presentation (Policies)3 Months Ended
Mar. 31, 2021
Basis of Presentation [Abstract]
Basis of PresentationWe prepared the unaudited interim condensed consolidated financial statements for the and on the same basis as the audited financial statements for the year ended , with the exception of our retrospective adoption of Accounting Standards Update, or ASU, 2020-06, which simplifies . See Note 2, Significant Accounting Polices , Convertible Debt, for details of our adoption of this guidance. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and notes thereto, should be read in conjunction with the audited financial statements for the year ended included in our Annual Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.
ConsolidationIn our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). We formed Akcea in December 2014. initial public offering, or IPO, which reduced our ownership of Akcea’s common stock below . In October 2020, we acquired the shares of Akcea’s common stock we did not own. We will refer to this transaction as the Akcea Acquisition throughout the remainder of this document.

Significant Accounting Polici_2

Significant Accounting Policies (Policies)3 Months Ended
Mar. 31, 2021
Significant Accounting Policies [Abstract]
Revenue RecognitionRevenue Recognition Our Revenue Sources We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our condensed consolidated balance sheet. Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue sales milestone payments and royalties we earn under our other partnerships. Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net In the United States, or U.S., through the first quarter of 2021, we sold TEGSEDI through an exclusive distribution agreement with a third-party logistics company, or 3PL, that took title to TEGSEDI. The 3PL was our sole customer in the U.S. The 3PL then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In Europe, through 2020, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as distributors. In January 2021, we began commercializing TEGSEDI and WAYLIVRA in Europe through a distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. In April 2021, we expanded our distribution agreement with Sobi to also include commercializing TEGSEDI in North America. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we earn a distribution fee on net sales from Sobi for each medicine. Under our collaboration agreement with PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. Research and development revenue under collaborative agreements We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&D, services, and manufacturing services. See Note 5, Collaborative Arrangements and Licensing Agreements , for collaborations with substantive changes that occurred in 2021. Additionally, see Collaborative Arrangements and Licensing Agreements Steps to Recognize Revenue We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five-step process is as follows:
1. Identify the contract Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:
● We and our partner approved the contract and we are both committed to perform our obligations;
● We have identified our rights, our partner’s rights and the payment terms;
● We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and
● We believe collectability of the consideration is probable.
2 . Identify the performance obligations We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the contract. We typically have only one performance obligation at the inception of a contract, which is to perform R&D services. Often we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item. In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.
3. Determine the transaction price We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price. Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For example, in the fourth quarter of 2020, we earned a $20 million milestone payment from AstraZeneca when AstraZeneca initiated a Phase 2b study for ION449, our medicine in development targeting PCSK9 to lower LDL-cholesterol. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing ION449 was contingent on AstraZeneca initiating a Phase 2b study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to the milestone payment.
4. Allocate the transaction price Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices. We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:
● Estimated future product sales;
● Estimated royalties we may receive from future product sales;
● Estimated contractual milestone payments we may receive;
● Expenses we expect to incur;
● Estimated income taxes; and
● A discount rate. We typically estimate the selling price of R&D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&D services include:
● The number of internal hours we estimate we will spend performing these services;
● The estimated cost of work we will perform;
● The estimated cost of work that we will contract with third parties to perform; and
● The estimated cost of API we will use. For purposes of determining the stand-alone selling price of the R&D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.
5. Recognize revenue We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner. For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods. The following are examples of when we typically recognize revenue based on the types of payments we receive. Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue We recognize royalty revenue, including royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue. Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net Prior to our distribution agreement with Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&A, expenses in our condensed consolidated statements of operations. We classified payments to customers or other parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted these amounts to governmental authorities. Under our distribution agreement with Sobi we concluded that our performance obligation is to supply finished goods inventory to Sobi. This performance obligation is a series of distinct activities that are substantially the same because we transfer title using the same criteria each time we ship inventory to Sobi. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We also recognize distribution fee revenue based on Sobi’s net sales of TEGSEDI and WAYLIVRA. Additionally, Sobi does not generally have a right of return. Reserves for TEGSEDI and WAYLIVRA commercial revenue Prior to our distribution agreement with Sobi, w Organization and Significant Accounting Policies Under our distribution agreement with Sobi, Sobi is financially responsible for any applicable reserves. Research and development revenue under collaboration agreements: Upfront payments When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&D services. For example, under our collaboration agreement with Roche to develop IONIS-FB-L Rx Milestone payments We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-based royalty exception allowed under accounting rules. We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2020, we achieved a $7.5 million milestone payment from Biogen when we advanced a target under our 2018 strategic collaboration. We added this payment to the transaction price and allocated it to our R&D services performance obligation. We are recognizing revenue related to this milestone payment over our estimated period of performance. Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation. For example, in the third quarter of 2020, we recognized $18 million in milestone payments when Biogen initiated a Phase 1/2 trial for ION464, our medicine in development targeting alpha-synuclein to treat patients with multiple system atrophy. We concluded that the milestone payments were not related to our R&D services performance obligation. Therefore, we recognized the milestone payments in full in the third quarter of 2020. License fees We generally recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. For example, in the fourth quarter of 2020, we earned a $30 million license fee from AstraZeneca when AstraZeneca licensed ION455, an investigational medicine in development to treat nonalcoholic steatohepatitis, or NASH. Sublicense fees We recognize sublicense fee revenue in the period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. Amendments to Agreements From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:
1) If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and
2) If the goods and/or services are sold at a stand-alone selling price. If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment. For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI Rx $ million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI Rx in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI Rx and to initiate development of IONIS-FXI-L Rx , which Bayer licensed. As part of the 2017 amendment, Bayer paid us $ million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI Rx and IONIS-FXI-L Rx . Under the 2017 amendment, we concluded we had a new agreement with performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L Rx , to provide R&D services and to deliver API. We allocated the $ million transaction price to these performance obligations. Refer to Note 6, Collaborative Arrangements and Licensing Agreements , for further discussion of the Bayer collaboration. Multiple agreements From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:
● Whether the agreements were negotiated together with a single objective;
● Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or
● Whether the goods and/or services promised under the agreements are a single performance obligation. Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement. For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.
Contracts ReceivableContracts Receivable Our contracts receivable balance represents the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider the contracts receivable to be unconditional. We typically receive payment within one quarter of billing our partner or customer As of March 31, 2021, approximately 46.8 percent of our contracts receivables were from three significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two significant customers.
Unbilled SPINRAZA RoyaltiesUnbilled SPINRAZA Royalties Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our condensed consolidated balance sheet.
Deferred RevenueDeferred Revenue We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our condensed consolidated balance sheet.
Cost of SalesCost of Sales Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales.
Cash, Cash Equivalents and InvestmentsCash, Cash Equivalents and Investments We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as “available-for-sale” and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our condensed consolidated statement of operations. We use the specific identification method to determine the cost of securities sold. We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At March 31, 2021, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in seven privately held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, Seventh Sense Biosystems and Suzhou-Ribo Life Science Co, Ltd. We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our condensed consolidated statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. For example, during the second and fourth quarters of 2020, we revalued our investments in three privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies sold additional equity securities that were similar to the equity we own. These observable price changes resulted in us recognizing a $6.3 million gain on our investment in Dynacure, a $3.0 million gain on our investment in Suzhou-Ribo and a $5.5 million gain on our investment in Aro Biotherapeutics in our condensed consolidated statement of operations during 2020 because the sales were at higher prices compared to our recorded value.
Inventory ValuationInventory Valuation We reflect our inventory on our condensed consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. We obtained the first regulatory approval for TEGSEDI in July 2018 and for WAYLIVRA in May 2019. At March 31, 2021, our physical inventory for TEGSEDI and WAYLIVRA included API that we produced prior to when we obtained regulatory approval. As such, this API has no cost basis as we had previously expensed the costs as R&D expenses. We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We recorded an insignificant amount of inventory write-offs for the . Our inventory consisted of the following (in thousands):
March 31, 2021 December 31, 2020
Raw materials:
Raw materials- clinical $ 10,695 $ 9,206
Raw materials- commercial 7,502 7,502
Total raw materials 18,197 16,708
Work in process 2,096 2,252
Finished goods 1,906 3,005
Total inventory $ 22,199 $ 21,965
LeasesLeases We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-of-use operating lease asset and associated short- and long-term operating lease liability on our condensed consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum lease payments we will pay over the lease term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease term. As our current leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.
Research and Development ExpensesOur research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our condensed consolidated balance sheet and we expense them as the services are provided.
Patent ExpensesWe capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. .
Income TaxesIncome Taxes We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount we expect to realize. We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. We assessed our valuation allowance requirements and recorded a valuation allowance against all of Ionis’ U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize the tax benefits associated with these assets. We based our determination largely on Akcea rejoining the Ionis U.S. consolidated federal tax group in the fourth quarter of 2020. Due to Akcea’s historical and projected financial statement losses, and the negative impact we expect this to have on Ionis’ consolidated taxable income, there is uncertainty of generating sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis’ pre-tax income in future periods may be lower due to increased research and development expenses associated with our pipeline of wholly owned medicines. We continue to maintain a valuation allowance against all our consolidated U.S. federal and state net deferred tax assets.
Long-Lived AssetsLong-lived Assets We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets.
Use of EstimatesUse of Estimates We prepare our condensed consolidated financial statements in conformity with accounting principles generally accepted in the
Basic and Diluted Net Loss per ShareBasic and Diluted Net Loss Per Share Basic net loss per share In the first quarter of 2021, we computed basic net loss per share by dividing our net loss by our weighted-average number of common shares outstanding during the period. For the first quarter of 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the three months ended March 31, 2021 was $0.64. In the first quarter of 2020, prior to the Akcea Acquisition, we calculated our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period to determine our total net loss attributable to our common stockholders. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s net loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than our net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the condensed consolidated statements of operations. Our basic net loss per share for the three months ended March 31, 2020, was calculated as follows (in thousands, except per share amounts):
Three months ended March 31, 2020 Weighted Average Shares Owned in Akcea Akcea’s Net Loss Per Share Basic Net Loss Per Share Calculation (as revised*)
Ionis’ portion of Akcea’s net loss 77,095 $ (0.42 ) $ (32,674 )
Akcea’s net loss attributable to our ownership $ (32,674 )
Ionis’ stand-alone net loss (7,032 )
Net loss available to Ionis common stockholders $ (39,706 )
Weighted average shares outstanding 139,429
Basic net loss per share $ (0.28 )
* We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 2, Significant Accounting Policies Diluted net loss per share For the three months ended March 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock from the following would have had an anti-dilutive effect on net loss per share:
● 0.125 percent convertible senior notes;
● Note hedges related to the 0.125 percent convertible senior notes;
● 1 percent convertible senior notes;
● Dilutive stock options;
● Unvested restricted stock units, or RSUs;
● Unvested performance restricted stock units, or PRSUs; and
● Employee Stock Purchase Plan, or ESPP. Additionally as of March 31, 2021, we had warrants related to our 0.125 percent convertible senior notes outstanding. We will include the shares issuable under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.
Convertible DebtConvertible Debt Adoption of ASU 2020-06 In August 2020, the FASB issued ASU 2020-06, which simplifies , amends the guidance on derivative scope exceptions for contracts in an entity’s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. As of March 31, 2021, we had outstanding convertible notes, our senior convertible notes, or Notes, which mature in December 2024, and our senior convertible notes, or Notes, which mature in November 2021. The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component. Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and our convertible debt instruments were not issued at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the periods presented. We have labeled our prior period financial statements “as revised” to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of operations from our first quarter 2020 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted: The following table summarizes the adjustments we made to the condensed consolidated balance sheet we originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):
December 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
1 percent convertible senior notes $ 293,161 $ 15,648 $ 308,809
0.125 percent convertible senior notes $ 455,719 $ 84,417 $ 540,136
Additional paid-in-capital $ 2,113,646 $ (218,127 ) $ 1,895,519
Accumulated deficit $ (1,249,368 ) $ 118,062 $ (1,131,306 ) Under ASU 2020-06, our revised ending balances for our 1% Notes and 0.125% Notes as of December 31, 2020 represent the principal balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However, because we have a full valuation allowance on our deferred tax assets, there was no impact to our condensed consolidated balance sheet related to our deferred tax assets. The following table summarizes the adjustments we made to the condensed consolidated statement of operations we originally reported at March 31, 2020 to adopt ASU 2020-06 (in thousands):
Three Months Ended March 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
Interest expense $ (10,990 ) $ 8,783 $ (2,207 )
Loss before income tax benefit $ (61,737 ) $ 8,783 $ (52,954 )
Income tax benefit $ 3,257 $ (185 ) $ 3,072
Net loss $ (58,480 ) $ 8,598 $ (49,882 )
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (48,226 ) $ 8,598 $ (39,628 )
Basic and diluted net loss per share $ (0.35 ) $ 0.07 $ (0.28 ) Under ASU 2020-06, our revised interest expense is lower as we are no longer recording non-cash interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders’ equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our condensed consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated effective interest rates for our 1% Notes and 0.125% Notes were 1.4 percent and 0.5 percent, respectively. The following tables summarize the adjustments we made to our condensed consolidated statements of stockholders’ equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):
December 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
Additional paid-in-capital $ 2,113,646 $ (218,127 ) $ 1,895,519
Accumulated deficit $ (1,249,368 ) $ 118,062 $ (1,131,306 )
Total stockholders' equity $ 843,347 $ (100,065 ) $ 743,282
December 31, 2019
As Previously Reported ASU 2020-06 Adjustment As Revised
Additional paid-in-capital $ 2,203,778 $ (218,128 ) $ 1,985,650
Accumulated deficit $ (707,534 ) $ 111,039 $ (596,495 )
Total stockholders' equity $ 1,684,547 $ (107,089 ) $ 1,577,458
Call SpreadCall Spread In conjunction with the issuance of our 0.125% Notes in December 2019, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting. We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480, therefore we account for the note hedges and warrants using the Derivatives and Hedging – Contracts in Entity’s Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders’ equity. We recorded the aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our condensed consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.
Segment InformationSegment Information In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating results on an aggregate basis and manages our operations as a single operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. In October 2020, we acquired the remaining common stock of Akcea that we did not own and fully integrated Akcea’s operations into ours as of January 1, 2021.
Stock-Based Compensation ExpenseStock-based Compensation Expense We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service period in our condensed consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions. During the three months ended March 31, 2021 and 2020, we did not grant any stock options or RSUs to our Board of Directors. For the three months ended March 31, 2021 and 2020, we used the following weighted-average assumptions in our Black-Scholes calculations: Employee Stock Options:
Three Months Ended March 31,
2021 2020
Risk-free interest rate 0.5 % 1.6 %
Dividend yield 0.0 % 0.0 %
Volatility 55.1 % 58.9 %
Expected life 4.9 years 4.7 years ESPP:
Three Months Ended March 31,
2021 2020
Risk-free interest rate 0.1 % 1.1 %
Dividend yield 0.0 % 0.0 %
Volatility 39.1 % 47.2 %
Expected life 6 months 6 months RSU’s: The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted after June 2020 to our board of directors fully vest after one year. The weighted-average grant date fair value of RSUs granted to employees for the three months ended March 31, 2021 was $62.02 per share. PRSU’s: Beginning in 2020, we added performance-based restricted stock units, or PRSU, awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the terms of the grants, one third We determined the fair value of Dr. Monia’s PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date fair value of PRSUs granted to Dr. Monia for the three months ended March 31, 2021 was $77.17 per share. The following table summarizes stock-based compensation expense for the three months ended March 31, 2021 and 2020 (in thousands).
Three Months Ended March 31,
2021 2020
Cost of sales $ 182 $ 237
Research, development and patent expense 25,899 25,556
Selling, general and administrative expense 11,780 14,997
Total $ 37,861 $ 40,790 As of March 31, 2021, total unrecognized estimated non-cash stock-based compensation expense related to non-vested stock options, RSUs and PRSUs was $101.8 million, $109.6 million and $3.8 million, respectively. Our actual expenses may differ from these estimates because we will adjust our unrecognized non-cash stock-based compensation expense for future forfeitures. We expect to recognize the cost of non-cash stock-based compensation expense related to our non-vested stock options, RSUs and PRSUs over a weighted average amortization period of 1.4 years, 1.8 years and 1.7 years, respectively.
Impact of Recently Issued Accounting StandardsImpact of Recently Issued Accounting Standards As disclosed in the “Convertible Debt” policy above within this footnote, we adopted the simplified accounting for convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.

Significant Accounting Polici_3

Significant Accounting Policies (Tables)3 Months Ended
Mar. 31, 2021
Significant Accounting Policies [Abstract]
InventoryOur inventory consisted of the following (in thousands):
March 31, 2021 December 31, 2020
Raw materials:
Raw materials- clinical $ 10,695 $ 9,206
Raw materials- commercial 7,502 7,502
Total raw materials 18,197 16,708
Work in process 2,096 2,252
Finished goods 1,906 3,005
Total inventory $ 22,199 $ 21,965
Basic Net Loss per ShareOur basic net loss per share for the three months ended March 31, 2020, was calculated as follows (in thousands, except per share amounts):
Three months ended March 31, 2020 Weighted Average Shares Owned in Akcea Akcea’s Net Loss Per Share Basic Net Loss Per Share Calculation (as revised*)
Ionis’ portion of Akcea’s net loss 77,095 $ (0.42 ) $ (32,674 )
Akcea’s net loss attributable to our ownership $ (32,674 )
Ionis’ stand-alone net loss (7,032 )
Net loss available to Ionis common stockholders $ (39,706 )
Weighted average shares outstanding 139,429
Basic net loss per share $ (0.28 )
* We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 2, Significant Accounting Policies
Adoption of ASU 2020-06The following table summarizes the adjustments we made to the condensed consolidated balance sheet we originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):
December 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
1 percent convertible senior notes $ 293,161 $ 15,648 $ 308,809
0.125 percent convertible senior notes $ 455,719 $ 84,417 $ 540,136
Additional paid-in-capital $ 2,113,646 $ (218,127 ) $ 1,895,519
Accumulated deficit $ (1,249,368 ) $ 118,062 $ (1,131,306 ) The following table summarizes the adjustments we made to the condensed consolidated statement of operations we originally reported at March 31, 2020 to adopt ASU 2020-06 (in thousands):
Three Months Ended March 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
Interest expense $ (10,990 ) $ 8,783 $ (2,207 )
Loss before income tax benefit $ (61,737 ) $ 8,783 $ (52,954 )
Income tax benefit $ 3,257 $ (185 ) $ 3,072
Net loss $ (58,480 ) $ 8,598 $ (49,882 )
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (48,226 ) $ 8,598 $ (39,628 )
Basic and diluted net loss per share $ (0.35 ) $ 0.07 $ (0.28 ) The following tables summarize the adjustments we made to our condensed consolidated statements of stockholders’ equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):
December 31, 2020
As Previously Reported ASU 2020-06 Adjustment As Revised
Additional paid-in-capital $ 2,113,646 $ (218,127 ) $ 1,895,519
Accumulated deficit $ (1,249,368 ) $ 118,062 $ (1,131,306 )
Total stockholders' equity $ 843,347 $ (100,065 ) $ 743,282
December 31, 2019
As Previously Reported ASU 2020-06 Adjustment As Revised
Additional paid-in-capital $ 2,203,778 $ (218,128 ) $ 1,985,650
Accumulated deficit $ (707,534 ) $ 111,039 $ (596,495 )
Total stockholders' equity $ 1,684,547 $ (107,089 ) $ 1,577,458
Weighted-Average Assumptions for Stock OptionsEmployee Stock Options:
Three Months Ended March 31,
2021 2020
Risk-free interest rate 0.5 % 1.6 %
Dividend yield 0.0 % 0.0 %
Volatility 55.1 % 58.9 %
Expected life 4.9 years 4.7 years
Weighted-Average Assumptions for ESPPESPP:
Three Months Ended March 31,
2021 2020
Risk-free interest rate 0.1 % 1.1 %
Dividend yield 0.0 % 0.0 %
Volatility 39.1 % 47.2 %
Expected life 6 months 6 months
Stock-Based Compensation ExpenseThe following table summarizes stock-based compensation expense for the three months ended March 31, 2021 and 2020 (in thousands).
Three Months Ended March 31,
2021 2020
Cost of sales $ 182 $ 237
Research, development and patent expense 25,899 25,556
Selling, general and administrative expense 11,780 14,997
Total $ 37,861 $ 40,790

Investments (Tables)

Investments (Tables)3 Months Ended
Mar. 31, 2021
Investments [Abstract]
Contract Maturity of Available-for-Sale SecuritiesThe following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2021:
One year or less 67 %
After one year but within two years 20 %
After two years but within three and a half years 13 %
Total 100 %
Summary of InvestmentsThe following is a summary of our investments (in thousands):
Gross Unrealized Estimated
March 31, 2021 Cost Gains Losses Fair Value
Available-for-sale securities:
Corporate debt securities (2) $ 446,816 $ 1,838 $ (76 ) $ 448,578
Debt securities issued by U.S. government agencies 80,703 292 (2 ) 80,993
Debt securities issued by the U.S. Treasury (2) 234,164 126 — 234,290
Debt securities issued by states of the U.S. and political subdivisions of the states 121,776 220 (22 ) 121,974
Other municipal debt securities 5,137 — (7 ) 5,130
Total securities with a maturity of one year or less 888,596 2,476 (107 ) 890,965
Corporate debt securities 325,335 3,108 (245 ) 328,198
Debt securities issued by U.S. government agencies 96,698 36 (164 ) 96,570
Debt securities issued by the U.S. Treasury 59,030 326 (35 ) 59,321
Debt securities issued by states of the U.S. and political subdivisions of the states 34,515 81 (25 ) 34,571
Other municipal debt 6,233 — (20 ) 6,213
Total securities with a maturity of more than one year 521,811 3,551 (489 ) 524,873
Total available-for-sale securities $ 1,410,407 $ 6,027 $ (596 ) $ 1,415,838
Equity securities:
Total equity securities included in other current assets (3) $ 4,712 $ — $ (1,514 ) $ 3,198
Total equity securities included in deposits and other assets (4) 15,062 15,938 — 31,000
Total equity securities 19,774 15,938 (1,514 ) 34,198
Total available-for-sale and equity securities $ 1,430,181 $ 21,965 $ (2,110 ) $ 1,450,036
Gross Unrealized Estimated
December 31, 2020 Cost Gains Losses Fair Value
Available-for-sale securities:
Corporate debt securities (2) $ 514,182 $ 2,194 $ (41 ) $ 516,335
Debt securities issued by U.S. government agencies 94,234 354 (2 ) 94,586
Debt securities issued by the U.S. Treasury (2) 307,576 233 (9 ) 307,800
Debt securities issued by states of the U.S. and political subdivisions of the states 104,271 196 (12 ) 104,455
Other municipal debt securities 5,191 — (7 ) 5,184
Total securities with a maturity of one year or less 1,025,454 2,977 (71 ) 1,028,360
Corporate debt securities 325,079 4,941 (40 ) 329,980
Debt securities issued by U.S. government agencies 80,099 185 (9 ) 80,275
Debt securities issued by the U.S. Treasury 50,318 383 (4 ) 50,697
Debt securities issued by states of the U.S. and political subdivisions of the states 31,779 91 (16 ) 31,854
Other municipal debt securities 1,041 — — 1,041
Total securities with a maturity of more than one year 488,316 5,600 (69 ) 493,847
Total available-for-sale securities $ 1,513,770 $ 8,577 $ (140 ) $ 1,522,207
Equity securities:
Total equity securities included in other current assets (3) $ 4,712 $ — $ (2,681 ) $ 2,031
Total equity securities included in deposits and other assets (4) 15,062 15,938 — 31,000
Total equity securities 19,774 15,938 (2,681 ) 33,031
Total available-for-sale and equity securities $ 1,533,544 $ 24,515 $ (2,821 ) $ 1,555,238
(1) We hold our available-for-sale securities at amortized cost.
(2) Includes investments classified as cash equivalents on our condensed consolidated balance sheet.
(3) Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.
(4) Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at .
Temporarily Impaired InvestmentsThe following is a summary of our investments we consider to be temporarily impaired at (in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities’ amortized cost basis at maturity.
Number of Investments Estimated Fair Value Unrealized Losses
Corporate debt securities 101 $ 233,665 $ (321 )
Debt securities issued by U.S. government agencies 7 60,681 (166 )
Debt securities issued by the U.S. Treasury 6 52,838 (35 )
Debt securities issued by states of the U.S. and political subdivisions of the states 297 76,712 (47 )
Other municipal debt securities 3 11,343 (27 )
Total temporarily impaired securities 414 $ 435,239 $ (596 )

Fair Value Measurements (Tables

Fair Value Measurements (Tables)3 Months Ended
Mar. 31, 2021
Fair Value Measurements [Abstract]
Assets Measured at Fair Value on a Recurring BasisThe following tables present the major security types we held at and that we regularly measure and carry at fair value. As of and , . The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities’ fair value (in thousands):
At March 31, 2021 Quoted Prices in Active Markets (Level 1) Significant Other Observable Inputs (Level 2)
Cash equivalents (1) $ 372,050 $ 372,050 $ —
Corporate debt securities (2) 776,776 — 776,776
Debt securities issued by U.S. government agencies (3) 177,563 — 177,563
Debt securities issued by the U.S. Treasury (3) 293,611 293,611 —
Debt securities issued by states of the U.S. and political subdivisions of the states (3) 156,545 — 156,545
Other municipal debt securities (3) 11,343 — 11,343
Investment in ProQR Therapeutics N.V. (4) 3,198 3,198 —
Total $ 1,791,086 $ 668,859 $ 1,122,227
At December 31, 2020 Quoted Prices in Active Markets (Level 1) Significant Other Observable Inputs (Level 2)
Cash equivalents (1) $ 221,125 $ 221,125 $ —
Corporate debt securities (2) 846,315 — 846,315
Debt securities issued by U.S. government agencies (3) 174,861 — 174,861
Debt securities issued by the U.S. Treasury (5) 358,497 358,497 —
Debt securities issued by states of the U.S. and political subdivisions of the states (3) 136,309 — 136,309
Other municipal debt securities (3) 6,225 — 6,225
Investment in ProQR Therapeutics N.V. (4) 2,031 2,031 —
Total $ 1,745,363 $ 581,653 $ 1,163,710 The following footnotes reference lines on our condensed consolidated balance sheet:
(1) Included in cash and cash equivalents on our condensed consolidated balance sheet.
(2) $10.0 million was included in cash and cash equivalents, with the difference included in short-term investments.
(3) Included in short-term investments.
(4) Included in other current assets on our condensed consolidated balance sheet.
(5) $17.5 million included in cash and cash equivalents on our condensed consolidated balance sheet, with the difference included in short-term investments on our condensed consolidated balance sheet.

Collaborative Arrangements an_2

Collaborative Arrangements and Licensing Agreements (Tables)3 Months Ended
Mar. 31, 2021
Biogen [Member]
Collaborative Arrangements and Licensing Agreements [Abstract]
Revenue from Collaborative RelationshipDuring the three months ended March 31, 2021 and 2020, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):
Three Months Ended March 31,
2021 2020
SPINRAZA royalties (commercial revenue) $ 60.0 $ 66.0
R&D revenue 18.1 21.4
Total revenue from our relationship with Biogen $ 78.1 $ 87.4
Percentage of total revenue 70 % 66 %

Convertible Debt (Tables)

Convertible Debt (Tables)3 Months Ended
Mar. 31, 2021
0% Convertible Senior Notes [Member]
Convertible Notes [Abstract]
Convertible NotesFollowing the closing of the debt transaction in April 2021, we had the following 0%
0%
Outstanding principal balance $ 632.5
Maturity date April 2026
Interest rate 0 percent
Conversion price per share $ 57.84
Effective conversion price per share with call spread $ 76.39
Total shares of common stock subject to conversion 10.9
0.125% Convertible Senior Notes [Member]
Convertible Notes [Abstract]
Convertible NotesAt March 31, 2021, we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):
0.125% Notes
Outstanding principal balance $ 548.8
Maturity date December 2024
Interest rate 0.125 percent
Conversion price per share $ 83.28
Effective conversion price per share with call spread $ 123.38
Total shares of common stock subject to conversion 6.6
Unamortized debt issuance costs $ 8.1
1% Convertible Senior Notes [Member]
Convertible Notes [Abstract]
Convertible NotesAt March 31, 2021, we had the following 1% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):
1% Notes
Outstanding principal balance $ 309.9
Maturity date November 2021
Interest rate 1 percent
Conversion price per share $ 66.81
Total shares of common stock subject to conversion 4.6
Unamortized debt issuance costs $ 0.8

Severance and Retention Costs (

Severance and Retention Costs (Tables)3 Months Ended
Mar. 31, 2021
Akcea Acquisition [Member]
Severance and Retention Costs [Abstract]
Severance and Retention CostsAs a result of the Akcea Acquisition in October 2020, we began recognizing severance and retention expenses in the fourth quarter of 2020. The following table summarizes our total estimated severance and retention expenses related to the Akcea Acquisition (in millions):
Severance and Retention Expenses
Total estimated expenses $ 28.5
Expenses incurred in the three months ended December 31, 2020 15.3
Expenses incurred in the three months ended March 31, 2021 5.4
Remaining estimated expenses to be recognized through October 2021 $ 7.8 The following table summarizes our severance and retention expenses related to the Akcea Acquisition that we recognized during the three months ended March 31, 2021 (in millions):
Three Months Ended March 31, 2021
Research, development and patent expenses $ 2.5
Selling, general and administrative expenses 2.9
Total $ 5.4 The following table summarizes the severance and retention reserve amounts related to the Akcea Acquisition that we included in accrued compensation for the period indicated (in millions):
Three Months Ended March 31, 2021
Beginning balance $ 14.7
Amounts expensed during the period 6.1
Reserve adjustments during the period (0.7 )
Net amount expensed during the period 5.4
Amounts paid during the period (9.0 )
Ending balance $ 11.1
Restructured European Operations [Member]
Severance and Retention Costs [Abstract]
Severance and Retention CostsAs a result of restructuring our European operations, or Restructured European Operations, in December 2020, we began recognizing severance and retention expenses in the fourth quarter of 2020. The following table summarizes our total severance and retention expenses related to our Restructured European Operations (in millions):
Severance and Retention Expenses
Total estimated expenses $ 13.6
Expenses incurred in the three months ended December 31, 2020 12.5
Expenses incurred in the three months ended March 31, 2021 0.7
Remaining estimated expenses through October 2021 $ 0.4 The following table summarizes the severance and retention expenses related to our Restructured European Operations that we recognized during the three months ended March 31, 2021 (in millions):
Three Months Ended March 31, 2021
Research, development and patent expenses $ 0.1
Selling, general and administrative expenses 0.6
Total $ 0.7 The following table summarizes the severance and retention reserve amounts related to our Restructured European operations that we included in accrued compensation for the periods indicated (in millions):
Three Months Ended March 31, 2021
Beginning balance $ 12.4
Amounts expensed during the period 2.2
Reserve adjustments during the period (1.5 )
Net amount expensed during the period 0.7
Amounts paid during the period (11.9 )
Ending balance $ 1.2

Basis of Presentation (Details)

Basis of Presentation (Details) - Akcea [Member]Mar. 31, 2021Jul. 31, 2017
Basis of Presentation [Abstract]
Percentage ownership100.00%
Maximum [Member]
Basis of Presentation [Abstract]
Percentage ownership100.00%

Significant Accounting Polici_4

Significant Accounting Policies, Revenue Recognition (Details) $ in Thousands1 Months Ended3 Months Ended
Feb. 28, 2017USD ($)PerformanceObligationMay 31, 2015USD ($)Mar. 31, 2021USD ($)PerformanceObligationDec. 31, 2020USD ($)Sep. 30, 2020USD ($)Mar. 31, 2020USD ($)Dec. 31, 2018USD ($)Jun. 30, 2018Agreement
Revenue Recognition [Abstract]
Number of performance obligations at inception of contract | PerformanceObligation1
Revenue $ 111,607 $ 133,367
Biogen [Member]
Revenue Recognition [Abstract]
Number of agreements | Agreement2
AstraZeneca [Member] | ION449 [Member]
Revenue Recognition [Abstract]
Revenue $ 20,000
AstraZeneca [Member] | ION455 [Member]
Revenue Recognition [Abstract]
Revenue30,000
IONIS-FB-L for Complement-Mediated Diseases [Member]
Revenue Recognition [Abstract]
Upfront payment received $ 75,000
Biogen 2018 Strategic Neurology [Member]
Revenue Recognition [Abstract]
Milestone payment received and added to transaction price $ 7,500
Biogen 2013 Strategic Neurology [Member] | ION464 [Member]
Revenue Recognition [Abstract]
Revenue $ 18,000
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received $ 100,000
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received $ 75,000
Number of separate performance obligations | PerformanceObligation3
Transaction price $ 75,000

Significant Accounting Polici_5

Significant Accounting Policies, Contracts Receivable (Details) - Partner3 Months Ended12 Months Ended
Mar. 31, 2021Dec. 31, 2020
Contracts Receivable [Abstract]
Period of time after billing when payment is received3 months
Significant Partners [Abstract]
Number of significant customers3 2
Contracts Receivables [Member] | Credit Concentration [Member] | Three Significant Customers [Member]
Significant Partners [Abstract]
Concentration percentage46.80%
Contracts Receivables [Member] | Credit Concentration [Member] | Two Significant Customers [Member]
Significant Partners [Abstract]
Concentration percentage99.50%

Significant Accounting Polici_6

Significant Accounting Policies, Deferred Revenue (Details) - USD ($) $ in Millions3 Months Ended
Mar. 31, 2021Mar. 31, 2020
Deferred Revenue [Abstract]
Revenue recognized from amounts in beginning deferred revenue balance $ 26 $ 28

Significant Accounting Polici_7

Significant Accounting Policies, Cash, Cash Equivalents and Investments (Details) $ in Thousands3 Months Ended9 Months Ended
Mar. 31, 2021USD ($)CompanyJun. 30, 2020USD ($)Mar. 31, 2020USD ($)Dec. 31, 2020Investment
Cash, Cash Equivalents and Investments [Abstract]
Number of publicly held companies in which there is an equity ownership interest of less than 20% | Company2
Number of privately held companies in which there is an equity ownership interest of less than 20% | Company7
Number of investments in privately held companies that were revalued | Investment3
Gain on investment $ 13 $ 246
Dynacure [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment $ 6,300
Suzhou-Ribo [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment3,000
Aro Biotherapeutics [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment $ 5,500

Significant Accounting Polici_8

Significant Accounting Policies, Inventory Valuation (Details) - USD ($) $ in ThousandsMar. 31, 2021Dec. 31, 2020
Inventory Valuation [Abstract]
Raw materials $ 18,197 $ 16,708
Work in process2,096 2,252
Finished goods1,906 3,005
Total inventory22,199 21,965
Clinical [Member]
Inventory Valuation [Abstract]
Raw materials10,695 9,206
Commercial [Member]
Inventory Valuation [Abstract]
Raw materials $ 7,502 $ 7,502

Significant Accounting Polici_9

Significant Accounting Policies, Basic and Diluted Net Loss per Share (Details) - USD ($) $ / shares in Units, shares in Thousands, $ in Thousands3 Months Ended
Mar. 31, 2021Mar. 31, 2020Dec. 31, 2020
Basic Net Loss per Share [Abstract]
Basic net loss per share (in dollars per share) $ (0.64) $ (0.28)
Net loss $ (89,869) $ (39,628)
Net income (loss) available to Ionis common shareholders $ (39,706)
Weighted average shares outstanding (in shares)140,770 139,429
0.125 Percent Convertible Senior Notes [Member]
Basic Net Loss per Share [Abstract]
Interest rate on convertible senior notes0.125%0.125%
1 Percent Convertible Senior Notes [Member]
Basic Net Loss per Share [Abstract]
Interest rate on convertible senior notes1.00%1.00%
Ionis [Member]
Basic Net Loss per Share [Abstract]
Net loss $ (7,032)
Akcea [Member]
Basic Net Loss per Share [Abstract]
Percentage ownership100.00%
Net loss $ (32,674)
Akcea [Member] | Common Stock [Member]
Basic Net Loss per Share [Abstract]
Weighted average shares owned in Akcea (in shares)77,095
Basic net loss per share (in dollars per share) $ (0.42)
Net loss $ (32,674)

Significant Accounting Polic_10

Significant Accounting Policies, Convertible Debt (Details) $ / shares in Units, $ in Thousands3 Months Ended
Mar. 31, 2021USD ($)Note$ / sharesMar. 31, 2020USD ($)$ / sharesDec. 31, 2020USD ($)Dec. 31, 2019USD ($)
Convertible Debt [Abstract]
Number of outstanding convertible notes | Note2
Condensed Consolidated Balance Sheet [Abstract]
1 percent convertible senior notes, net $ 61,816 $ 308,809
Additional paid-in capital1,925,801 1,895,519
Accumulated deficit(1,221,175)(1,131,306)
Condensed Consolidated Statement of Operations [Abstract]
Interest expense(2,414) $ (2,207)
Loss before income tax (expense) benefit(89,739)(52,954)
Income tax (expense) benefit(130)3,072
Net loss(89,869)(49,882)
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (89,869) $ (39,628)
Basic net loss per share (in dollars per share) | $ / shares $ (0.64) $ (0.28)
Diluted net loss per share (in dollars per share) | $ / shares $ (0.64) $ (0.28)
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance $ 680,564 $ 1,471,920 743,282 $ 1,577,458
Additional Paid In Capital [Member]
Condensed Consolidated Statement of Operations [Abstract]
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders0 0
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance1,925,801 2,015,516 1,895,519 1,985,650
Accumulated Deficit [Member]
Condensed Consolidated Statement of Operations [Abstract]
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders(89,869)(39,628)
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance(1,221,175)(726,672)(1,131,306)(596,495)
Total Ionis Stockholders' Equity [Member]
Condensed Consolidated Statement of Operations [Abstract]
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders(89,869)(39,628)
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance $ 680,564 1,261,748 $ 743,282 1,364,005
0.125 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes0.125%0.125%
Condensed Consolidated Balance Sheet [Abstract]
Convertible senior notes $ 540,679 $ 540,136
Condensed Consolidated Statement of Operations [Abstract]
Effective interest rate0.50%
1 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes1.00%1.00%
Condensed Consolidated Balance Sheet [Abstract]
Convertible senior notes $ 247,292 $ 0
Condensed Consolidated Statement of Operations [Abstract]
Effective interest rate1.40%
As Previously Reported [Member]
Condensed Consolidated Balance Sheet [Abstract]
1 percent convertible senior notes, net293,161
Additional paid-in capital2,113,646
Accumulated deficit(1,249,368)
Condensed Consolidated Statement of Operations [Abstract]
Interest expense(10,990)
Loss before income tax (expense) benefit(61,737)
Income tax (expense) benefit3,257
Net loss(58,480)
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ (48,226)
Basic net loss per share (in dollars per share) | $ / shares $ (0.35)
Diluted net loss per share (in dollars per share) | $ / shares $ (0.35)
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance843,347 1,684,547
As Previously Reported [Member] | Additional Paid In Capital [Member]
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance2,113,646 2,203,778
As Previously Reported [Member] | Accumulated Deficit [Member]
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance(1,249,368)(707,534)
As Previously Reported [Member] | 0.125 Percent Convertible Senior Notes [Member]
Condensed Consolidated Balance Sheet [Abstract]
Convertible senior notes455,719
Adjustment [Member] | ASU 2020-06 [Member]
Condensed Consolidated Balance Sheet [Abstract]
1 percent convertible senior notes, net15,648
Additional paid-in capital(218,127)
Accumulated deficit118,062
Net deferred tax assets0
Condensed Consolidated Statement of Operations [Abstract]
Interest expense $ 8,783
Loss before income tax (expense) benefit8,783
Income tax (expense) benefit(185)
Net loss8,598
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders $ 8,598
Basic net loss per share (in dollars per share) | $ / shares $ 0.07
Diluted net loss per share (in dollars per share) | $ / shares $ 0.07
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance(100,065)(107,089)
Adjustment [Member] | ASU 2020-06 [Member] | Additional Paid In Capital [Member]
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance(218,127)(218,128)
Adjustment [Member] | ASU 2020-06 [Member] | Accumulated Deficit [Member]
Condensed Consolidated Statements of Stockholders' Equity [Abstract]
Balance118,062 $ 111,039
Adjustment [Member] | ASU 2020-06 [Member] | 0.125 Percent Convertible Senior Notes [Member]
Condensed Consolidated Balance Sheet [Abstract]
Convertible senior notes $ 84,417

Significant Accounting Polic_11

Significant Accounting Policies, Segment Information (Details)3 Months Ended
Mar. 31, 2021Segment
Segment Information [Abstract]
Number of operating segments2

Significant Accounting Polic_12

Significant Accounting Policies, Stock-Based Compensation Expense (Details) $ / shares in Units, $ in Thousands3 Months Ended
Mar. 31, 2021USD ($)Period$ / sharessharesMar. 31, 2020USD ($)shares
Stock-based Compensation Expense [Abstract]
Stock-based compensation expense $ 37,861 $ 40,790
Cost of Sales [Member]
Stock-based Compensation Expense [Abstract]
Stock-based compensation expense182 237
Research, Development and Patent Expense [Member]
Stock-based Compensation Expense [Abstract]
Stock-based compensation expense25,899 25,556
Selling, General and Administrative Expense [Member]
Stock-based Compensation Expense [Abstract]
Stock-based compensation expense11,780 $ 14,997
Stock Options [Member]
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation expense related to non-vested stock options $ 101,800
Weighted average period for recognition1 year 4 months 24 days
Stock Options [Member] | Board of Directors [Member]
Stock-based Compensation Expense [Abstract]
Stock options granted (in shares) | shares0 0
Stock Options [Member] | Employees [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate0.50%1.60%
Dividend yield0.00%0.00%
Volatility55.10%58.90%
Expected life4 years 10 months 24 days4 years 8 months 12 days
ESPP [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate0.10%1.10%
Dividend yield0.00%0.00%
Volatility39.10%47.20%
Expected life6 months6 months
RSUs [Member]
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested units $ 109,600
Weighted average period for recognition1 year 9 months 18 days
RSUs [Member] | Board of Directors [Member]
Stock-based Compensation Expense [Abstract]
Units granted (in shares) | shares0 0
RSUs [Member] | Board of Directors [Member] | Maximum [Member]
RSUs and PRSUs [Abstract]
Vesting period4 years
RSUs [Member] | Board of Directors [Member] | Minimum [Member]
RSUs and PRSUs [Abstract]
Vesting period1 year
RSUs [Member] | Employees [Member]
RSUs and PRSUs [Abstract]
Vesting period4 years
Weighted-average grant date fair value (in dollars per share) | $ / shares $ 62.02
PRSUs [Member]
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested units $ 3,800
Weighted average period for recognition1 year 8 months 12 days
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member]
RSUs and PRSUs [Abstract]
Number of performance periods | Period3
Vesting period3 years
Number of units guaranteed to vest | shares0
Weighted-average grant date fair value (in dollars per share) | $ / shares $ 77.17
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Maximum [Member]
RSUs and PRSUs [Abstract]
Percentage of units guaranteed to vest150.00%
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Minimum [Member]
RSUs and PRSUs [Abstract]
Percentage of units guaranteed to vest0.00%
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | One-Year Period [Member]
RSUs and PRSUs [Abstract]
Vesting percentage33.30%
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Two-Year Period [Member]
RSUs and PRSUs [Abstract]
Vesting percentage33.30%
PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Three-Year Period [Member]
RSUs and PRSUs [Abstract]
Vesting percentage33.30%

Investments, Contract Maturity

Investments, Contract Maturity of Available-for-Sale Securities (Details)3 Months Ended
Mar. 31, 2021Company
Contract Maturity of Available-for-Sale Securities [Abstract]
One year or less67.00%
After one year but within two years20.00%
After two years but within three and a half years13.00%
Total100.00%
Percentage of available-for-sale securities with a maturity of less than two years87.00%
Maximum contract maturity period, range 11 year
Maximum contract maturity period, range 22 years
Maximum contract maturity period, range 33 years 6 months
Ownership Interests in Private and Public Companies [Abstract]
Number of privately held companies in which there is an equity ownership interest of less than 20%7
Number of publicly held companies in which there is an equity ownership interest of less than 20%2

Investments, Summary of Investm

Investments, Summary of Investments (Details) - USD ($) $ in Thousands3 Months Ended12 Months Ended
Mar. 31, 2021Dec. 31, 2020
Summary of Investments [Abstract]
Cost $ 1,430,181 $ 1,533,544
Gross unrealized gains21,965 24,515
Gross unrealized losses(2,110)(2,821)
Estimated fair value1,450,036 1,555,238
Available-for-sale Securities [Member]
Summary of Investments [Abstract]
Cost[1]1,410,407 1,513,770
Gross unrealized gains6,027 8,577
Gross unrealized losses(596)(140)
Estimated fair value1,415,838 1,522,207
Available-for-sale Securities [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1]888,596 1,025,454
Gross unrealized gains2,476 2,977
Gross unrealized losses(107)(71)
Estimated fair value890,965 1,028,360
Available-for-sale Securities [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]521,811 488,316
Gross unrealized gains3,551 5,600
Gross unrealized losses(489)(69)
Estimated fair value524,873 493,847
Corporate Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1],[2]446,816 514,182
Gross unrealized gains1,838 2,194
Gross unrealized losses(76)(41)
Estimated fair value448,578 516,335
Corporate Debt Securities [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]325,335 325,079
Gross unrealized gains3,108 4,941
Gross unrealized losses(245)(40)
Estimated fair value328,198 329,980
Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1]80,703 94,234
Gross unrealized gains292 354
Gross unrealized losses(2)(2)
Estimated fair value80,993 94,586
Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]96,698 80,099
Gross unrealized gains36 185
Gross unrealized losses(164)(9)
Estimated fair value96,570 80,275
Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1],[2]234,164 307,576
Gross unrealized gains126 233
Gross unrealized losses0 (9)
Estimated fair value234,290 307,800
Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]59,030 50,318
Gross unrealized gains326 383
Gross unrealized losses(35)(4)
Estimated fair value59,321 50,697
Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1]121,776 104,271
Gross unrealized gains220 196
Gross unrealized losses(22)(12)
Estimated fair value121,974 104,455
Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]34,515 31,779
Gross unrealized gains81 91
Gross unrealized losses(25)(16)
Estimated fair value34,571 31,854
Other Municipal Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]
Summary of Investments [Abstract]
Cost[1]5,137 5,191
Gross unrealized gains0 0
Gross unrealized losses(7)(7)
Estimated fair value5,130 5,184
Other Municipal Debt Securities [Member] | Securities with Maturity of More than One Year [Member]
Summary of Investments [Abstract]
Cost[1]6,233 1,041
Gross unrealized gains0 0
Gross unrealized losses(20)0
Estimated fair value6,213 1,041
Equity Securities [Member]
Summary of Investments [Abstract]
Cost19,774 19,774
Gross unrealized gains15,938 15,938
Gross unrealized losses(1,514)(2,681)
Estimated fair value34,198 33,031
Equity Securities in Publicly Traded Company [Member]
Summary of Investments [Abstract]
Cost[3]4,712 4,712
Gross unrealized gains0 0
Gross unrealized losses(1,514)(2,681)
Estimated fair value3,198 2,031
Equity Securities in Private Companies [Member]
Summary of Investments [Abstract]
Cost[4]15,062 15,062
Gross unrealized gains15,938 15,938
Gross unrealized losses0 0
Estimated fair value $ 31,000 $ 31,000
[1]We hold our available-for-sale securities at amortized cost.
[2]Includes investments classified as cash equivalents on our condensed consolidated balance sheet.
[3]Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.
[4]Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer.

Investments, Investments Tempor

Investments, Investments Temporarily Impaired (Details) $ in ThousandsMar. 31, 2021USD ($)Investment
Temporarily Impaired Investments [Abstract]
Number of investments | Investment414
Estimated fair value, less than 12 months of temporary impairment $ 435,239
Unrealized losses, less than 12 months of temporary impairment $ (596)
Corporate Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments | Investment101
Estimated fair value, less than 12 months of temporary impairment $ 233,665
Unrealized losses, less than 12 months of temporary impairment $ (321)
Debt Securities Issued by U.S. Government Agencies [Member]
Temporarily Impaired Investments [Abstract]
Number of investments | Investment7
Estimated fair value, less than 12 months of temporary impairment $ 60,681
Unrealized losses, less than 12 months of temporary impairment $ (166)
Debt Securities Issued by the U.S. Treasury [Member]
Temporarily Impaired Investments [Abstract]
Number of investments | Investment6
Estimated fair value, less than 12 months of temporary impairment $ 52,838
Unrealized losses, less than 12 months of temporary impairment $ (35)
Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Temporarily Impaired Investments [Abstract]
Number of investments | Investment297
Estimated fair value, less than 12 months of temporary impairment $ 76,712
Unrealized losses, less than 12 months of temporary impairment $ (47)
Other Municipal Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments | Investment3
Estimated fair value, less than 12 months of temporary impairment $ 11,343
Unrealized losses, less than 12 months of temporary impairment $ (27)

Fair Value Measurements (Detail

Fair Value Measurements (Details) - USD ($) $ in ThousandsMar. 31, 2021Dec. 31, 2020
1 Percent Convertible Senior Notes [Member]
Fair Value Measurements [Abstract]
Interest rate on convertible senior notes1.00%1.00%
0.125 Percent Convertible Senior Notes [Member]
Fair Value Measurements [Abstract]
Interest rate on convertible senior notes0.125%0.125%
Significant Other Observable Inputs (Level 2) [Member] | 1 Percent Convertible Senior Notes [Member]
Fair Value Measurements [Abstract]
Fair value of convertible notes $ 314,600
Significant Other Observable Inputs (Level 2) [Member] | 0.125 Percent Convertible Senior Notes [Member]
Fair Value Measurements [Abstract]
Fair value of convertible notes527,300
Recurring Basis [Member]
Fair Value Measurements [Abstract]
Cash equivalents[1]372,050 $ 221,125
Investment in ProQR Therapeutics N.V.[2]3,198 2,031
Total1,791,086 1,745,363
Recurring Basis [Member] | Corporate Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities[3]776,776 846,315
Recurring Basis [Member] | Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities10,000 10,000
Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities[4]177,563 174,861
Recurring Basis [Member] | Debt Securities Issued by the U.S. Treasury [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities293,611 [4]358,497 [5]
Recurring Basis [Member] | Debt Securities Issued by the U.S. Treasury [Member] | Cash and Cash Equivalents [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities17,500
Recurring Basis [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities[4]156,545 136,309
Recurring Basis [Member] | Other Municipal Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities[4]11,343 6,225
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member]
Fair Value Measurements [Abstract]
Cash equivalents372,050 221,125
Investment in ProQR Therapeutics N.V.3,198 2,031
Total668,859 581,653
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities0 0
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities0 0
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by the U.S. Treasury [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities293,611 358,497
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities0 0
Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Other Municipal Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities0 0
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member]
Fair Value Measurements [Abstract]
Cash equivalents0 0
Investment in ProQR Therapeutics N.V.0 0
Total1,122,227 1,163,710
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities776,776 846,315
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities177,563 174,861
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by the U.S. Treasury [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities0 0
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities156,545 136,309
Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Other Municipal Debt Securities [Member]
Fair Value Measurements [Abstract]
Available-for-sale securities11,343 6,225
Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member]
Fair Value Measurements [Abstract]
Total $ 0 $ 0
[1]Included in cash and cash equivalents on our condensed consolidated balance sheet.
[2]Included in other current assets on our condensed consolidated balance sheet.
[3]$10.0 million was included in cash and cash equivalents, with the difference included in short-term investments.
[4]Included in short-term investments.
[5]$17.5 million included in cash and cash equivalents on our condensed consolidated balance sheet, with the difference included in short-term investments on our condensed consolidated balance sheet.

Collaborative Arrangements an_3

Collaborative Arrangements and Licensing Agreements (Details) $ in Thousands1 Months Ended3 Months Ended
Apr. 30, 2021USD ($)Mar. 31, 2021USD ($)MedicineMar. 31, 2020USD ($)Dec. 31, 2020USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue $ 111,607 $ 133,367
SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue59,986 66,008
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue $ 27,159 49,406
Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being developed | Medicine8
Cumulative payments received $ 2,900,000
Revenue78,100 $ 87,400
Deferred revenue $ 447,700 $ 465,800
Biogen [Member] | Revenue [Member] | Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage70.00%66.00%
Biogen [Member] | SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue $ 60,000 $ 66,000
Biogen [Member] | R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue $ 18,100 $ 21,400
2013 Strategic Neurology [Member] | Plan [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Next prospective payment $ 8,000
2013 Strategic Neurology [Member] | ION541 [Member] | Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Milestone payment achieved $ 10,000

Convertible Debt (Details)

Convertible Debt (Details) - USD ($) $ / shares in Units, shares in Millions, $ in Millions1 Months Ended3 Months Ended
Apr. 30, 2021Dec. 31, 2019Mar. 31, 2021Dec. 31, 2020
Convertible Debt [Abstract]
Cost of call spread $ 52.6
Purchase of note hedges108.7
Proceeds from issuance of warrants $ 56.1
Subsequent Event [Member]
Convertible Debt [Abstract]
Cost of call spread $ 46.9
Purchase of note hedges136.7
Proceeds from issuance of warrants89.8
0% Convertible Senior Notes [Member] | Subsequent Event [Member]
Convertible Debt [Abstract]
Face amount of offering632.5
Outstanding principal balance $ 632.5
Maturity dateApr. 30,
2026
Interest rate0.00%
Conversion price per share (in dollars per share) $ 57.84
Effective conversion price per share with call spread (in dollars per share) $ 76.39
Total shares of common stock subject to conversion (in shares)10.9
Percentage of principal amount used as purchase price upon occurrence of fundamental change100.00%
0.125% Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Outstanding principal balance $ 548.8
Maturity dateDec. 31,
2024
Interest rate0.125%0.125%
Conversion price per share (in dollars per share) $ 83.28
Effective conversion price per share with call spread (in dollars per share) $ 123.38
Total shares of common stock subject to conversion (in shares)6.6
Unamortized debt issuance costs $ 8.1
Percentage of principal amount used as purchase price upon occurrence of fundamental change100.00%
1% Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Outstanding principal balance $ 309.9
Maturity dateNov. 30,
2021
Interest rate1.00%1.00%
Conversion price per share (in dollars per share) $ 66.81
Total shares of common stock subject to conversion (in shares)4.6
Unamortized debt issuance costs $ 0.8
Percentage of principal amount used as purchase price upon occurrence of fundamental change100.00%
1% Convertible Senior Notes [Member] | Subsequent Event [Member]
Convertible Debt [Abstract]
Principal amount repurchased $ 247.9
Repurchase of convertible notes257
Outstanding principal balance $ 62
Total shares of common stock subject to conversion (in shares)0.9

Severance and Retention Costs,

Severance and Retention Costs, Akcea Acquisition (Details) - Akcea Acquisition [Member] - USD ($) $ in Millions3 Months Ended
Mar. 31, 2021Dec. 31, 2020
Severance and Retention Costs [Abstract]
Total estimated expenses $ 28.5
Remaining estimated expenses to be recognized through October 20217.8
Beginning balance14.7
Amounts expensed during the period6.1
Reserve adjustments during the period(0.7)
Net amount expensed during the period5.4 $ 15.3
Amounts paid during the period(9)
Ending balance11.1 $ 14.7
R&D Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the period2.5
SG&A Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the period $ 2.9

Severance and Retention Costs_2

Severance and Retention Costs, Restructured European Operations (Details) - Restructured European Operations [Member] - USD ($) $ in Millions3 Months Ended
Mar. 31, 2021Dec. 31, 2020
Severance and Retention Costs [Abstract]
Total estimated expenses $ 13.6
Remaining estimated expenses to be recognized through October 20210.4
Beginning balance12.4
Amounts expensed during the period2.2
Reserve adjustments during the period(1.5)
Net amount expensed during the period0.7 $ 12.5
Amounts paid during the period(11.9)
Ending balance1.2 $ 12.4
R&D Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the period0.1
SG&A Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the period $ 0.6

Severance and Retention Costs_3

Severance and Retention Costs, Restructured North American TEGSEDI Operations (Details) - Restructured North American TEGSEDI Operations [Member] $ in MillionsMar. 31, 2021USD ($)
Minimum [Member]
Severance and Retention Costs [Abstract]
Total estimated expenses $ 11
Maximum [Member]
Severance and Retention Costs [Abstract]
Total estimated expenses $ 14