0000874015-23-000105 | 10-K | XBRL Viewer | Ionis Pharmaceuticals INC

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Employment Benefits	12 Months Ended
Employment Benefits	Dec. 31, 2022
Employment Benefits [Abstract]
Employment Benefits	8. Employment Benefits We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a percentage of their salary up to the IRS annual limits of $20,500 and $27,000 in 2022 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $5.6 million, $5.5 million and $5.7 million in matching contributions for the years ended December 31, 2022, 2021 and 2020, respectively.

- Definition

The entire disclosure for retirement benefits.

+ References

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+ Details

Income Taxes (Tables)

12 Months Ended

Dec. 31, 2022

Income Taxes [Abstract]

Income (Loss) Before Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2022			2021			2020
United States	$	(258,493	)	$	(29,966	)	$	(137,222	)
Foreign		508			818			2,670
Income (loss) before income taxes	$	(257,985	)	$	(29,148	)	$	(134,552	)

Income Tax Expense (Benefit)

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2022		2021			2020
Current:
Federal	$	10,522	$	(200	)	$	(837	)
State		1,129		(690	)		3,782
Foreign		86		339			518
Total current income tax expense (benefit)		11,737		(551	)		3,463

Deferred:
Federal		—		—			341,728
State		—		—			—
Total deferred income tax benefit		—		—			341,728
Total income tax expense (benefit)	$	11,737	$	(551	)	$	345,191

Reconciliation of Statutory to Effective Tax Rate

Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):

	Year Ended December 31,
	2022					2021					2020
Pre-tax income (loss)	$	(257,985	)			$	(29,148	)			$	(134,552	)

Statutory rate		(54,177	)	21.0	%		(6,121	)	21.0	%		(28,256	)	21.0	%
State income tax net of federal benefit		(13,622	)	5.3	%		4,278		(14.7	)%		(37,705	)	28.0	%
Foreign		(49	)	0.0	%		143		(0.5	)%		49		0.0	%
Net change in valuation allowance		104,951		(40.7	)%		2,885		(9.9	)%		460,898		(342.5	)%
Loss on debt transactions		—		—			262		(0.9	)%		—		—
Tax credits		(39,729	)	15.4	%		(23,198	)	79.6	%		(18,774	)	14.0	%
Deferred tax true-up		(20	)	0.0	%		(24	)	0.1	%		(206	)	0.2	%
Tax rate change		(3,091	)	1.2	%		12,838		(44.0	)%		(32,951	)	24.5	%
Non-deductible compensation		3,023		(1.2	)%		5,085		(17.4	)%		7,931		(5.9	)%
Other non-deductible items		57		0.0	%		84		(0.3	)%		193		(0.1	)%
Stock-based compensation		14,030		(5.4	)%		4,720		(16.2	)%		17,435		(13.0	)%
Impacts from Akcea Merger		—		—			—		—			(22,032	)	16.4	%
Other		364		(0.1	)%		(1,503	)	5.1	%		(1,391	)	0.9	%
Effective rate	$	11,737		(4.5	)%	$	(551	)	1.9	%	$	345,191		(256.5	)%

Deferred Tax Assets and Liabilities

Significant components of our deferred tax assets and liabilities as of December 31, 2022 and 2021 are as follows (in thousands):

	Year Ended December 31,
	2022			2021
Deferred Tax Assets:
Net operating loss carryovers	$	87,802		$	85,600
Tax credits		277,436			269,538
Deferred revenue		85,700			104,330
Stock-based compensation		86,983			86,611
Intangible and capital assets		104,649			92,542
Convertible debt		34,384			45,681
Interest expense limitation		—			6,996
Capitalized research and development expenses		119,635			—
Long-term lease liabilities		45,612			5,119
Other		15,813			9,929
Total deferred tax assets	$	858,014		$	706,346

Deferred Tax Liabilities:
Fixed assets		(4,475	)		(3,303	)
Right-of-use assets		(44,504	)		(4,159	)
Other		(313	)		(1,111	)
Net deferred tax asset	$	808,722		$	697,773
Valuation allowance		(808,722	)		(697,773	)
Total net deferred tax assets and liabilities	$	—		$	—

Gross Unrecognized Tax Benefits

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2022			2021			2020
Beginning balance of unrecognized tax benefits	$	55,085		$	54,163		$	69,784
Decrease for prior period tax positions		(267	)		(695	)		(24,154	)
Increase for prior period tax positions		259			263			7,023
Increase for current period tax positions		1,490			1,354			1,510
Ending balance of unrecognized tax benefits	$	56,567		$	55,085		$	54,163

Collaborative Arrangements and Licensing Agreements

12 Months Ended

Dec. 31, 2022

Collaborative Arrangements and Licensing Agreements [Abstract]

Collaborative Arrangements and Licensing Agreements

7. Collaborative Arrangements and Licensing Agreements

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 numerous investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, ADand Parkinson’s disease. In addition to these medicines, our collaborations with Biogen include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 31, 2022, we have received more than $3.4 billion from our Biogen collaborations.

Spinal Muscular Atrophy Collaborations

SPINRAZA

In January 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA. From inception through December 31, 2022, we earned more than $1.8 billion in total revenue under our SPINRAZA collaboration, including more than $1.4 billion in revenue from SPINRAZA royalties and more than $425 million in R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance obligations under our collaboration in 2016.

In January 2023, we entered into a royalty purchase agreement with Royalty Pharma in which Royalty Pharma will receive 25 percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion in annual sales. Royalty Pharma’s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $475 million or $550 million, depending on the timing and occurrence of FDA approval of pelacarsen, which Novartis is developing. Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments, for further discussion of this agreement.

New antisense medicines for the treatment of SMA

In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization activities and costs for such therapies. Under the collaboration agreement, we received a $25 million upfront payment in the fourth quarter of 2017. In December 2021, we earned a $60 million license fee payment when Biogen exercised its option to license ION306. We will receive development and regulatory milestone payments from Biogen if new medicines, including ION306, advance towards marketing approval.

Over the term of the collaboration, we are eligible to receive up to $1.2 billion, which is comprised of a $25 million upfront payment, up to $110 million in license fees, up to $80 million in development milestone payments, up to $180 million in regulatory milestone payments, up to $800 million in sales milestone payments and other payments, including up to $555 million if Biogen advances ION306, which includes up to $45 million in development milestone payments, up to $110 million in regulatory milestone payments and up to $400 million in sales milestone payments. In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales. From inception through December 31, 2022, we received $85 million in payments under this collaboration. We will achieve the next payment of up to $45 millionfor the initiation of a Phase 3 trial under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we completed our R&D services performance obligation under this collaboration.

In the fourth quarter of 2021, we identified another performance obligation upon Biogen’s license of ION306 because the license we granted to Biogen is distinct from our other performance obligations. We recognized the $60 million license fee for ION306 as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration.

Neurology Collaborations

2018 Strategic Neurology

In April 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a Stock Purchase Agreement, or SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected medicines. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will have the option to license the selected medicine after it completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

In the second quarter of 2018, we received $1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment.

Over the term of our collaboration, we are eligible to receive up to $270 million, which is comprised of a $15 million license fee, up to $105 million in development milestone payments and up to $150 million in regulatory milestone payments for each medicine that achieves marketing approval. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales. We are currently advancing multiple programs under this collaboration and from inception through December 31, 2022, we have received nearly $1.1 billion in payments under this collaboration. We will achieve the next payment of $7.5 million if Biogen designates or advances another programunder this collaboration.

At the commencement of this collaboration, we considered that the collaboration agreement and SPA 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. We identified one performance obligation, which was to perform R&D services for Biogen. We determined our transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock. We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.

From inception through December 31, 2022, we have included $616 million in payments in the transaction price for our R&D services performance obligation under this collaboration, including $23 million of milestone payments we achieved in 2021 and $11 million of milestone payments we achieved in 2020. These milestone payments did not create new performance obligations because they are part of our original R&D services performance obligation. Therefore, we included these amounts in our transaction price for our R&D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.

2013 Strategic Neurology

In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing five investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease (ION859), two medicines for ALS (tofersen and ION541), a medicine for multiple system atrophy (ION464) and a medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in registration for SOD1 ALS. As a result, Biogen is responsible for global development, regulatory and commercialization activities and costs for tofersen.

Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. Under this collaboration, we received a $35 million license fee payment when Biogen licensed tofersen from us in 2018.

Over the term of the collaboration for tofersen, we are eligible to receive nearly $110 million, which is comprised of the $35 million license fee received in 2018, up to $18 million in development milestone payments and up to $55 million in regulatory milestone payments. For each of the other antisense molecules that are chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million, which is comprised of a $70 million license fee, up to $60 million in development milestone payments, including amounts related to the cost of clinical trials, and up to $130 million in regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 31, 2022, we have received more than $300 million in payments under this collaboration. We will achieve the next payment of $16 million if the FDA approves Biogen’s NDA filing of tofersen.

At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&D services, we include these amounts in our transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During 2020, we completed our remaining research and development services and recognized the remaining revenue related to this performance obligation. From inception through the completion of our R&D services performance obligation in 2020, we included $145 million in total payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance obligations for the respective payment. For example, in the third quarter of 2022, we earned a $9 million milestone payment when the FDA accepted Biogen’s NDA filing of tofersen, which we recognized in full because we did not have any performance obligations related to this milestone payment.

2012 Neurology

In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through the completion of the first Phase 2 study for each program. Under this collaboration, Biogen is conducting the IONIS-MAPT_Rx study for AD and we are currently advancing ION582 for AS. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million, which is comprised of a $70 million license fee, up to $10 million in development milestone payments per program and up to $130 million in regulatory milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the two programs. From inception through December 31, 2022, we have received nearly $170 million in payments under this collaboration, including nearly $20 million in milestone payments we received from Biogen for advancing ION582 and a $10 million milestone payment we received from Biogen when Biogen advanced IONIS-MAPT_Rxduring 2022. We will achieve the next payment of up to $25 million if Biogen advances a medicine under this collaboration.

Under our collaboration, we determined we had a performance obligation to perform R&D services. We allocated $40 million in total payments to the transaction price for our R&D services performance obligation. In the third quarter of 2019, we completed our R&D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation.

When we commenced development for IONIS-MAPT_Rx we identified our development work as a separate performance obligation. In the fourth quarter of 2022, we completed our R&D services performance obligation for IONIS-MAPT_Rx. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. From inception through December 31, 2022, we have included $57 million in the transaction price for our IONIS-MAPT_Rx development performance obligation, including $19.5 million of milestone payments we earned from Biogen in 2020 when we advanced IONIS-MAPT_Rx.

In the fourth quarter of 2019, we identified another performance obligation upon Biogen’s license of IONIS-MAPT_Rx because the license we granted to Biogen is distinct from our other performance obligations. We recognized the $45 million license fee for IONIS-MAPT_Rx as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is responsible for global development, regulatory and commercialization activities and costs for IONIS-MAPT_Rx.

In the fourth quarter of 2022, we achieved $14.5 million in milestone payments when Biogen advanced ION582. We will recognize revenue as we perform services based on our effort to satisfy our R&D services performance obligation relative to the total effort expected to satisfy our performance obligation for ION582.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
SPINRAZA royalties (commercial revenue)	$	242.3		$	267.8		$	286.6
R&D revenue		124.4			161.0			122.0
Total revenue from our relationship with Biogen	$	366.7		$	428.8		$	408.6
Percentage of total revenue		62	%		53	%		56	%

Our consolidated balance sheets at December 31, 2022 and 2021 included deferred revenue of $351.2 million and $407.5 million, respectively, related to our relationship with Biogen.

Joint Development and Commercialization Arrangement

AstraZeneca

Eplontersen Collaboration

In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain countries in Latin America.

Over the term of the collaboration, we are eligible to receive up to $3.6 billion, which is comprised of a $200 million upfront payment, up to $485 million in development and approval milestone payments and up to $2.9 billion in sales milestone payments. The agreement also includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.

We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.

We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to AstraZeneca and as a result we had one performance obligation. For our sole performance obligation, we determined the transaction price was the $200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.

We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 development program, we recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of our commercial and medical affairs expenses.

We will achieve the next payment of up to $50 million upon the first regulatory approval under this collaboration. From inception through December 31, 2022, we have received nearly $260 million in payments under this collaboration.

Research and Development Partners

AstraZeneca

In addition to our collaboration for eplontersen, we have a collaboration with AstraZeneca focused on the treatment of cardiovascular, renal and metabolic diseases. In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed multiple medicines from us, including medicines in development to treat people with ATTR amyloidosis, a genetically associated form of kidney disease and NASH. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us.

Over the term of the collaboration, we are eligible to receive up to $5.8 billion, which is comprised of a $65 million upfront payment, up to $290 million in license fees, up to $1.1 billion in development milestone payments, up to $2.9 billion in regulatory milestone payments and up to $1.5 billion in sales milestone payments. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. We will achieve the next payment of $10 million under this collaboration if AstraZeneca advances a medicine under this collaboration. From inception through December 31, 2022, we have received more than $280 million in payments under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our performance obligation in the fourth quarter of 2021. As we achieved milestone payments for our R&D services, we included these amounts in our transaction price for our R&D services performance obligation. From inception through the completion of our performance obligation, we have included $90 million in payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example, in the fourth quarter of 2021, we earned a $30 million license fee when AstraZeneca licensed a target for a metabolic disease. We recognized the license fee as revenue at that time because AstraZeneca had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to AstraZeneca.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
R&D revenue	$	79.2		$	254.6		$	88.0
Percentage of total revenue		13	%		31	%		12	%

We did not have any deferred revenue from our relationship with AstraZeneca at December 31, 2022 and 2021.

GSK

In March 2010, we entered into a collaboration with GSK using our antisense drug discovery platform to discover and develop new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Our collaboration with GSK currently includes two medicines targeting hepatitis B virus, or HBV: bepirovirsen and IONIS-HBV-L_Rx. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.

Over the term of the collaboration, we are eligible to receive nearly $260 million, which is comprised of a $25 million license fee, up to $42.5 million in development milestone payments, up to $120 million in regulatory milestone payments and up to $70 million in sales milestone payments if GSK successfully develops bepirovirsen. In addition, we are eligible to receive tiered royalties up to the low-teens on net sales of bepirovirsen. From inception through December 31, 2022, we have received more than $50 million in payments under the HBV program collaboration.

We completed our R&D services performance obligations under our collaboration in the first quarter of 2015. We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019 because the license was distinct from our other performance obligations. We recognized the $25 million license fee for the HBV program as revenue at that time because GSK had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to GSK.

We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and royalties as GSK advances the HBV program. In January 2023, we earned a $15 million milestone when GSK initiated a Phase 3 study of bepirovirsen. We will achieve the next payment of $15 million if the FDA accepts an NDA filing of bepirovirsen for review.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2022		2021		2020
R&D revenue	$	—	$	—	$	0.2
Percentage of total revenue		—		—		—

We did not have any deferred revenue from our relationship with GSK at December 31, 2022 and 2021.

Novartis

In January 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen and olezarsen. Novartis is responsible for conducting and funding development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019. In connection with Novartis’ license of pelacarsen, we and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen. When Novartis decided to not exercise its option for olezarsen, we retained rights to develop and commercialize olezarsen.

Over the term of the collaboration, we are eligible to receive up to $900 million, which is comprised of a $75 million upfront payment, a $150 million license fee, a $25 million development milestone payment, up to $290 million in regulatory milestone payments and up to $360 million in sales milestone payments. From inception through December 31, 2022, we have received nearly $275 million in payments under this collaboration. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. In August 2021, we earned a $25 million milestone payment from Novartis when Novartis achieved 50 percent enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of pelacarsen. We recognized the milestone payment in full in the third quarter of 2021 because we did not have any remaining performance obligations related to the milestone payment. We will achieve the next payment of up to $75 million if Novartis advances regulatory activities for pelacarsen.

In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100 million in the first quarter of 2017.

At the commencement of this collaboration, we identified four separate performance obligations:

●

R&D services for pelacarsen;

●

R&D services for olezarsen;

●

API for pelacarsen; and

●

API for olezarsen.

We determined that the R&D services for each medicine and the API for each medicine were distinct performance obligations.

We determined our transaction price to be $108.4 million, comprised of the following:

●

$75 million from the upfront payment;

●

$28.4 million for the premium paid by Novartis for its purchase of our common stock at a premium in the first quarter of 2017; and

●

$5.0 million for the potential premium Novartis would have paid if they purchased our common stock in the future.

We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

●

$64.0 million for the R&D services for pelacarsen;

●

$40.1 million for the R&D services for olezarsen;

●

$1.5 million for the delivery of pelacarsen API; and

●

$2.8 million for the delivery of olezarsen API.

We completed our R&D services performance obligations for olezarsen and pelacarsenin 2019. As such, we recognized all revenue we allocated to the olezarsen and pelacarsenR&D services as of the end of 2019.

We recognized revenue related to the R&D services for pelacarsen and olezarsen performance obligations as we performed services based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2022		2021			2020
R&D revenue	$	0.2	$	25.5		$	1.0
Percentage of total revenue		—		3	%		—

We did not have any deferred revenue from our relationship with Novartis at December 31, 2022 and 2021.

As described in the Biogen SPINRAZA section above, in January 2023, we entered into a royalty purchase agreement with Royalty Pharma. Under the agreement, in addition to a minority interest in SPINRAZA royalties, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen. Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments, for further discussion of this agreement.

Roche

Huntington’s Disease

In April 2013, we formed an alliance with Hoffmann-La Roche Inc and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in people with early-stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and costs for tominersen.

Over the term of the collaboration, we are eligible to receive up to $395 million, which is comprised of a $30 million upfront payment, a $45 million license fee, up to $70 million in development milestone payments, up to $170 million in regulatory milestone payments and up to $80 million in sales milestone payments as tominersen advances. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net sales of any product resulting from this alliance. From inception through December 31, 2022, we have received more than $150 million in payments under this collaboration. We will achieve the next payment of $17.5 million if Roche advances a medicine under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&D services, we included these amounts in our transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation over our period of performance, which ended in the third quarter of 2017.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In 2019, we earned $35 million in milestone payments when Roche advanced tominersen under this collaboration. In March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded iDMC.

In January 2023, Roche initiated the Phase 2, GENERATION HD2, study of tominersen in patients with prodromal or early manifest HD. Roche is focusing on early-stage and younger patients based on the post-hoc analyses from the GENERATION HD1 study that suggested tominersen may benefit these patient groups. We do not have any remaining performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.

IONIS-FB-L_Rx for Complement-Mediated Diseases

In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-L_Rx, one for the treatment of patients with GA, the advanced stage of dry AMD, and a second for the treatment of patients with IgA nephropathy.

After positive data from a Phase 2 clinical study, Roche licensed IONIS-FB-L_Rx in July 2022 for $35 million. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L_Rx, except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding. In July 2022, we amended our IONIS-FB-L_Rx collaboration agreement with Roche. The amendment changed future potential milestone payments we could receive under the collaboration. We determined there were no changes that would require adjustments to revenue we previously recognized.

Over the term of the collaboration, we are eligible to receive more than $810 million, which is comprised of a $75 million upfront payment, a $35 million license fee, up to $145 million in development milestones, up to $279 million in regulatory milestones and up to $280 million in sales milestone payments. In addition, we are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. From inception through December 31, 2022, we have received more than $130 million in payments under this collaboration. We will achieve the next payment of up to $90 million if Roche advances IONIS-FB-L_Rx under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation in the third quarter of 2024.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
R&D revenue	$	67.2		$	17.2		$	5.9
Percentage of total revenue		11	%		2	%		1	%

Our consolidated balance sheets at December 31, 2022 and 2021 included deferred revenue of $22.4 million and $31.6 million related to our relationship with Roche, respectively.

Commercialization Partnerships

Swedish Orphan Biovitrum AB (Sobi)

We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution agreements with Sobi. 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. In exchange, we earn a distribution fee on net sales from Sobi for each medicine.

PTC Therapeutics

In August 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In December 2021, we started receiving royalties from PTC for TEGSEDI sales.

Technology Enhancement Collaborations

Bicycle License Agreement

In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license Bicycle’s technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricted our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7.2 million equity investment for the shares we received in Bicycle. We recognized the remaining $34.8 million as R&D expense in 2021. From inception through December 31, 2022, we have paid Bicycle $46.6 million under this collaboration agreement.

Metagenomi License Agreement

In November 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize investigational medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four additional genetic targets using gene editing technologies. As a result, we paid $80 million to license Metagenomi’s technologies. We recorded the $80 million payment as R&D expense in 2022 upon receiving a license from Metagenomi for intellectual property that is in research with no current alternate use. We will also pay Metagenomi certain fees for the selection of genetic targets, and contingent on the achievement of certain development, regulatory and sales events, milestone payments and royalties. In addition, we will reimburse Metagenomi for certain of its costs in conducting its research and drug discovery activities under the collaboration.

Other Agreements

Alnylam Pharmaceuticals, Inc.

Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alnylam gave us a technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained exclusive license rights to 4 therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.

In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41.2 million for payments owed to us by Alnylam related to Alnylam’s agreement with Sanofi Genzyme. We recognized the $41.2 million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021		2020
R&D revenue	$	21.4		$	—	$	47.9
Percentage of total revenue		4	%		—		7	%

We did not have any deferred revenue from our relationship with Alnylam at December 31, 2022 and 2021.

Fair Value Measurements

12 Months Ended

Dec. 31, 2022

Fair Value Measurements [Abstract]

Fair Value Measurements

3. 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 traded 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 December 31, 2022 and 2021 that we regularly measure and carry at fair value. As of December 31, 2022, we did not have any investments that we valued using Level 3 inputs. 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 December 31, 2022		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	211,655	$	211,655	$	—
Corporate debt securities (3)		726,950		—		726,950
Debt securities issued by U.S. government agencies (2)		165,055		—		165,055
Debt securities issued by the U.S. Treasury (2)		748,475		748,475		—
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		74,917		—		74,917
Other municipal debt securities (2)		5,994		—		5,994
Publicly traded equity securities included in other current assets (4)		10,539		10,539		—
Total	$	1,943,585	$	970,669	$	972,916

	At December 31, 2021		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	541,199	$	541,199	$	—	$	—
Corporate debt securities (2)		764,059		—		764,059		—
Debt securities issued by U.S. government agencies (2)		120,868		—		120,868		—
Debt securities issued by the U.S. Treasury (2)		182,634		182,634		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (5)		174,464		—		174,464		—
Other municipal debt securities (2)		6,099		—		6,099		—
Publicly traded equity securities included in other current assets (4)		18,205		3,875		—		14,330
Total	$	1,807,528	$	727,708	$	1,065,490	$	14,330

________________

(1)	Included in cash and cash equivalents in our consolidated balance sheets.

(2)	Included in short-term investments.

(3)	$11.0 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.

(4)	Included in other current assets in our consolidated balance sheets.

(5)	$2.3 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.

Convertible Notes

Our 0.125% Notes and 0% Notes had a fair value of $498.9 million and $587.3 million at December 31, 2022, 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.

- Definition

The entire disclosure for the fair value of financial instruments (as defined), including financial assets and financial liabilities (collectively, as defined), and the measurements of those instruments as well as disclosures related to the fair value of non-financial assets and liabilities. Such disclosures about the financial instruments, assets, and liabilities would include: (1) the fair value of the required items together with their carrying amounts (as appropriate); (2) for items for which it is not practicable to estimate fair value, disclosure would include: (a) information pertinent to estimating fair value (including, carrying amount, effective interest rate, and maturity, and (b) the reasons why it is not practicable to estimate fair value; (3) significant concentrations of credit risk including: (a) information about the activity, region, or economic characteristics identifying a concentration, (b) the maximum amount of loss the entity is exposed to based on the gross fair value of the related item, (c) policy for requiring collateral or other security and information as to accessing such collateral or security, and (d) the nature and brief description of such collateral or security; (4) quantitative information about market risks and how such risks are managed; (5) for items measured on both a recurring and nonrecurring basis information regarding the inputs used to develop the fair value measurement; and (6) for items presented in the financial statement for which fair value measurement is elected: (a) information necessary to understand the reasons for the election, (b) discussion of the effect of fair value changes on earnings, (c) a description of [similar groups] items for which the election is made and the relation thereof to the balance sheet, the aggregate carrying value of items included in the balance sheet that are not eligible for the election; (7) all other required (as defined) and desired information.

+ References + Details

Income Taxes, Income Tax Expense (Benefit) (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Current [Abstract]
Federal	$ 10,522	$ (200)	$ (837)
State	1,129	(690)	3,782
Foreign	86	339	518
Total current income tax expense (benefit)	11,737	(551)	3,463
Deferred [Abstract]
Federal	0	0	341,728
State	0	0	0
Total deferred income tax benefit	0	0	341,728
Total income tax expense (benefit)	$ 11,737	$ (551)	$ 345,191

Stockholders' Equity

12 Months Ended

Dec. 31, 2022

Stockholders' Equity [Abstract]

Stockholders' Equity

5. Stockholders’ Equity

Preferred Stock

We are authorized to issue up to 15 million shares of “blank check” Preferred Stock. As of December 31, 2022, there were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2022.

Common Stock

At December 31, 2022 and 2021, we had 300 million shares of common stock authorized, of which 142.1 million and 141.2 million were issued and outstanding, respectively. As of December 31, 2022, total common shares reserved for future issuance were 43.2 million.

During the years ended December 31, 2022, 2021 and 2020, we issued 1.2 million, 1.1 million and 1.7 million shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $6.4 million, $11.6 million and $52.0 million in 2022, 2021 and 2020, respectively.

Share Repurchase Program

In September 2019, our board of directors approved a share repurchase program of up to $125 million of our common stock. In 2019, we repurchased 535,000 shares for $34.4 million. In the first quarter of 2020, we repurchased an additional 1.5 million shares for $90.5 million.

Stock Plans

1989 Stock Option Plan

In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2022, a total of 12 thousand options were outstanding, of which options to purchase 12 thousand shares were exercisable, and 65 thousand shares were available for future grant under the 1989 Plan.

2011 Equity Incentive Plan

In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan, or 2011 Plan, to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In the second quarter of 2021, after receiving approval from our stockholders, we amended our 2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from 23.0 million to 29.7 million and added a fungible share counting ratio whereby the share reserve will be reduced by 1.7 shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by 1.7 shares for each share of common stock returning from a full value award. The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options, RSU and PRSU awards to our employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2022, a total of 13.7 million options were outstanding, of which 9.4 million were exercisable, 2.7 million restricted stock unit awards were outstanding, and 5.8 million shares were available for future grant under the 2011 Plan.

Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer, and vice presidents. If one of our executive officers or vice presidents is terminated or resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted employee’s stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.

2020 Equity Incentive Plan

In connection with the Akcea Merger in October 2020, we assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. 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. The 2020 Plan provided for the issuance of up to 2.6 million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from approximately 2.6 million to 1.6 million. We assumed the 2020 Plan in connection with Ionis’ reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.

The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2022, a total of 0.3 million options were outstanding, of which 61 thousand were exercisable, 0.1 million restricted stock unit awards were outstanding, and 1.2 million shares were available for future grant under the 2020 Plan.

Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur.

Corporate Transactions and Change in Control under 2011 and 2020 Plans

In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:

●

arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);

●

arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the surviving or acquiring corporation (or its parent company);

●

accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;

●

arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;

●

cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and

●

arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.

2002 Non-Employee Directors’ Stock Option Plan

In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 1992 Non-Employee Directors’ Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors’ Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2 million to 2.0 million. In June 2020, after receiving approval from our stockholders, we further amended our 2002 Plan. The amendments included:

●

An increase to the total number of shares reserved for issuance under the plan from 2.0 million to 2.8 million shares;

●

A reduction to the amount of the automatic awards under the plan;

●

A revision to the vesting schedule of new awards granted; and

●

An extension of the term of the plan.

Options under this plan expire 10 years from the date of grant. At December 31, 2022, a total of 0.9 million options were outstanding, of which 0.8 million were exercisable, 0.1 million restricted stock unit awards were outstanding, and 0.6 million shares were available for future grant under the 2002 Plan.

Employee Stock Purchase Plan

In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2022. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10percent of each employee’s compensation) at the lower of 85percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2022, employees purchased and we issued to employees 0.1 million shares under the ESPP at a weighted average price of $28.57 per share. At December 31, 2022, there were 0.5 million shares available for purchase under the ESPP.

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2022 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2021		14,089		$	54.04
Granted		2,864		$	34.78
Exercised		(123	)	$	29.35
Cancelled/forfeited/expired		(1,860	)	$	53.96
Outstanding at December 31, 2022		14,970		$	50.57		4.01	$	12,243
Exercisable at December 31, 2022		10,285		$	53.74		2.56	$	1,651

The weighted-average estimated fair values of options granted were $18.66, $24.35 and $29.43 for the years ended December 31, 2022, 2021 and 2020, respectively. The total intrinsic value of options exercised during the years ended December 31, 2022, 2021 and 2020 were $1.4 million, $2.5 million and $15.5 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $3.6 million, $8.5 million and $43.7 million for the years ended December 31, 2022, 2021 and 2020, respectively. For the year ended December 31, 2022, the weighted-average fair value of options exercised was $40.71. As of December 31, 2022, total unrecognized compensation cost related to non-vested stock options was $41.1 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Restricted Stock Unit Activity

The following table summarizes the RSU activity for the year ended December 31, 2022 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2021		2,618		$	58.05
Granted		1,401		$	36.14
Vested		(958	)	$	57.05
Cancelled/forfeited		(295	)	$	48.61
Non-vested at December 31, 2022		2,766		$	48.30

For the years ended December 31, 2022, 2021 and 2020, the weighted-average grant date fair value of RSUs granted was $36.14, $57.02 and $60.57 per RSU, respectively. As of December 31, 2022, total unrecognized compensation cost related to RSUs was $45.8 million. We expect to recognize this cost over a weighted average period of 1.2 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Performance Restricted Stock Unit Activity

The following table summarizes the PRSU activity for the year ended December 31, 2022 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2021		59		$	79.20
Granted		105		$	42.28
Vested		(16	)	$	75.03
Cancelled/forfeited		(5	)	$	79.11
Non-vested at December 31, 2022		143		$	52.59

For the years ended December 31, 2022, 2021 and 2020, the weighted-average grant date fair value of PRSUs granted was $42.28, $77.17 and $93.09 per PRSU, respectively. As of December 31, 2022, total unrecognized compensation cost related to PRSUs was $2.4 million. We expect to recognize this cost over a weighted average period of 0.9 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Stock-based Compensation Expense and Valuation Information

The following table summarizes stock-based compensation expense for the years ended December 31, 2022, 2021 and 2020 (in thousands):

	Year Ended December 31,
	2022		2021		2020
Cost of sales	$	533	$	456	$	1,991
Research, development and patent		73,704		87,522		115,584
Selling, general and administrative		26,027		32,700		112,542
Total	$	100,264	$	120,678	$	230,117

In October 2020, as part of the Akcea Merger, Akcea’s outstanding equity awards vested under Akcea’s Plan. As a result, in 2020, we recognized all unrecognized stock-based compensation, which totaled $59.3 million, under Akcea’s Plan.

Refer to Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, for further details on how we determine the fair value of stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP.

For the years ended December 31, 2022, 2021 and 2020, we used the following weighted-average assumptions in our Black-Scholes calculations:

Ionis Employee Stock Options:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		2.1	%		0.6	%		1.5	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		54.5	%		54.0	%		58.6	%
Expected life	6.3 years			4.9 years			4.7 years

Ionis Board of Director Stock Options:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		2.9	%		1.2	%		0.5	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		56.2	%		55.9	%		57.6	%
Expected life	7.4 years			7.3 years			6.7 years

Ionis ESPP:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		1.2	%		0.1	%		0.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		50.1	%		42.4	%		47.9	%
Expected life	6 months			6 months			6 months

Risk-Free Interest Rate. We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.

Dividend Yield. We base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.

Volatility. We use an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.

Expected Life. The expected term of stock options we have granted represents the period of time that we expect them to be outstanding. Historically, we estimated the expected term of options we have granted based on actual and projected exercise patterns. In 2021, our Compensation Committee approved an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the 2020 Equity Incentive Plan, or 2020 Plan, that increased the contractual term of stock options granted under these plans from seven to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the expected life of stock options granted to employees in the year ended December 31, 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional historical information, we will transition to calculating our expected term based on our historical exercise patterns.

Forfeitures. We reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience.

- Definition

The entire disclosure for shareholders' equity comprised of portions attributable to the parent entity and noncontrolling interest, including other comprehensive income. Includes, but is not limited to, balances of common stock, preferred stock, additional paid-in capital, other capital and retained earnings, accumulated balance for each classification of other comprehensive income and amount of comprehensive income.

+ References

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+ Details

Stockholders' Equity, Stock Plans (Details)	1 Months Ended	12 Months Ended
Stockholders' Equity, Stock Plans (Details)	Jun. 30, 2009 shares	Dec. 31, 2022 Officer $ / shares shares	Dec. 31, 2021 shares	Jun. 30, 2021 shares	Dec. 31, 2020 shares	Jun. 30, 2020 shares	Jun. 30, 2019 shares	May 31, 2017 shares	Jun. 30, 2015 shares	May 31, 2015 shares
Stock Options [Member]
Stock Plans [Abstract]
Number of options outstanding (in shares)		14,970,000	14,089,000
Number of options exercisable (in shares)		10,285,000
1989 Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)		20,000,000
Number of options outstanding (in shares)		12,000
Number of options exercisable (in shares)		12,000
Number of shares available for grant (in shares)		65,000
1989 Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
1989 Stock Option Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2011 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)				29,700,000			23,000,000	16,000,000	11,000,000	5,500,000
Reduction in fungible share reserve for each share issued pursuant to full value award (n shares)				(1.7)
Increase in fungible share reserve for each share returning from a full value award (in shares)				1.7
Number of options outstanding (in shares)		13,700,000
Number of options exercisable (in shares)		9,400,000
Number of shares available for grant (in shares)		5,800,000
Number of executive officers terminated before change in control when vesting will accelerate for executive officers \| Officer		1
Period before change in control when vesting will accelerate for executive officers		3 months
Period after change in control when vesting will accelerate for executive officers		12 months
2011 Equity Incentive Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
2011 Equity Incentive Plan [Member] \| Stock Options [Member] \| Issued after December 31, 2021 [Member]
Stock Plans [Abstract]
Award term		10 years
2011 Equity Incentive Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2011 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
Number of awards outstanding (in shares)		2,700,000
2020 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)				1,600,000	2,600,000
Number of options outstanding (in shares)		300,000
Number of options exercisable (in shares)		61,000
Number of shares available for grant (in shares)		1,200,000
2020 Equity Incentive Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
2020 Equity Incentive Plan [Member] \| Stock Options [Member] \| Issued after December 31, 2021 [Member]
Stock Plans [Abstract]
Award term		10 years
2020 Equity Incentive Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2020 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
Number of awards outstanding (in shares)		100,000
2002 Non-Employee Directors' Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)						2,800,000			2,000,000	1,200,000
Number of options outstanding (in shares)		900,000
Number of options exercisable (in shares)		800,000
Number of shares available for grant (in shares)		600,000
2002 Non-Employee Directors' Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Award term		10 years
2002 Non-Employee Directors' Stock Option Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Number of awards outstanding (in shares)		100,000
Employee Stock Purchase Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)		3,200,000
Number of additional shares reserved for issuance (in shares)	150,000	150,000
Maximum percentage of employee compensation used to purchase shares		10.00%
Percentage of fair market value used to determine purchase price of stock		85.00%
Holding period for purchased stock		6 months
Shares purchased and issued under ESPP (in shares)		100,000
Weighted average purchase price (in dollars per share) \| $ / shares		$ 28.57
Shares available for purchase under ESPP (in shares)		500,000

Collaborative Arrangements and Licensing Agreements (Tables)

12 Months Ended

Dec. 31, 2022

Biogen [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
SPINRAZA royalties (commercial revenue)	$	242.3		$	267.8		$	286.6
R&D revenue		124.4			161.0			122.0
Total revenue from our relationship with Biogen	$	366.7		$	428.8		$	408.6
Percentage of total revenue		62	%		53	%		56	%

AstraZeneca [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
R&D revenue	$	79.2		$	254.6		$	88.0
Percentage of total revenue		13	%		31	%		12	%

GSK [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2022		2021		2020
R&D revenue	$	—	$	—	$	0.2
Percentage of total revenue		—		—		—

Novartis [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2022		2021			2020
R&D revenue	$	0.2	$	25.5		$	1.0
Percentage of total revenue		—		3	%		—

Roche [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021			2020
R&D revenue	$	67.2		$	17.2		$	5.9
Percentage of total revenue		11	%		2	%		1	%

Alnylam [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2022, 2021 and 2020, we earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):

	Year Ended December 31,
	2022			2021		2020
R&D revenue	$	21.4		$	—	$	47.9
Percentage of total revenue		4	%		—		7	%

Fair Value Measurements (Details) - USD ($)
$ in Thousands

Dec. 31, 2022

Dec. 31, 2021

Apr. 30, 2021

Dec. 31, 2020

Dec. 31, 2019

Fair Value Measurements [Abstract]

Available-for-sale securities

$ 1,721,391

$ 1,248,124

Equity securities

$ 50,911

$ 50,527

0.125% Notes [Member]

Fair Value Measurements [Abstract]

Interest rate on convertible senior notes

0.125%

0% Notes [Member]

Fair Value Measurements [Abstract]

Interest rate on convertible senior notes

0.00%

Recurring Basis [Member]

Fair Value Measurements [Abstract]

Cash equivalents

^[1]

$ 211,655

$ 541,199

Total

1,943,585

1,807,528

Recurring Basis [Member] | Other Current Assets [Member]

Fair Value Measurements [Abstract]

Equity securities

^[2]

10,539

18,205

Recurring Basis [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

726,950

^[3]

764,059

^[4]

Recurring Basis [Member] | Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

11,000

2,300

Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[4]

165,055

120,868

Recurring Basis [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[4]

748,475

182,634

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

74,917

^[4]

174,464

^[5]

Recurring Basis [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[4]

5,994

6,099

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

211,655

541,199

Total

970,669

727,708

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Other Current Assets [Member]

Fair Value Measurements [Abstract]

Equity securities

10,539

3,875

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

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 securities

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 securities

748,475

182,634

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 securities

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Total

972,916

1,065,490

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0.125% Notes [Member]

Fair Value Measurements [Abstract]

Fair value of convertible notes

498,900

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0% Notes [Member]

Fair Value Measurements [Abstract]

Fair value of convertible notes

587,300

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Other Current Assets [Member]

Fair Value Measurements [Abstract]

Equity securities

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

726,950

764,059

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 securities

165,055

120,868

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 securities

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 securities

74,917

174,464

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

5,994

6,099

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Total

$ 0

14,330

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Other Current Assets [Member]

Fair Value Measurements [Abstract]

Equity securities

14,330

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [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

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

$ 0

[1]	Included in cash and cash equivalents in our consolidated balance sheets.
[2]	Included in other current assets in our consolidated balance sheets.
[3]	$11.0 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.
[4]	Included in short-term investments.
[5]	$2.3 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.

Investments (Tables)

12 Months Ended

Dec. 31, 2022

Investments [Abstract]

Contract Maturity of Available-for-Sale Securities

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2022:

One year or less	70	%
After one year but within two years	28	%
After two years but within three and a half years	2	%
Total	100	%

Summary of Investments

The following is a summary of our investments (in thousands):

	Amortized		Gross Unrealized					Estimated
December 31, 2022	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	513,790	$	23	$	(4,365	)	$	509,448
Debt securities issued by U.S. government agencies		133,585		—		(1,829	)		131,756
Debt securities issued by the U.S. Treasury (1)		512,655		23		(5,124	)		507,554
Debt securities issued by states of the U.S. and political subdivisions of the states		57,484		18		(686	)		56,816
Other municipal debt securities		6,008		—		(14	)		5,994
Total securities with a maturity of one year or less		1,223,522		64		(12,018	)		1,211,568
Corporate debt securities		227,631		14		(10,143	)		217,502
Debt securities issued by U.S. government agencies		34,339		—		(1,040	)		33,299
Debt securities issued by the U.S. Treasury		245,030		—		(4,109	)		240,921
Debt securities issued by states of the U.S. and political subdivisions of the states		18,314		116		(329	)		18,101
Total securities with a maturity of more than one year		525,314		130		(15,621	)		509,823
Total available-for-sale securities	$	1,748,836	$	194	$	(27,639	)	$	1,721,391
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	—	$	(1,358	)	$	10,539
Total equity securities included in deposits and other assets (3)		23,115		17,257		—			40,372
Total equity securities	$	35,012	$	17,257	$	(1,358	)	$	50,911
Total available-for-sale and equity securities	$	1,783,848	$	17,451	$	(28,997	)	$	1,772,302

	Amortized		Gross Unrealized					Estimated
December 31, 2021	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	383,870	$	728	$	(226	)	$	384,372
Debt securities issued by U.S. government agencies		48,493		19		(18	)		48,494
Debt securities issued by the U.S. Treasury (1)		45,424		—		(64	)		45,360
Debt securities issued by states of the U.S. and political subdivisions of the states		134,770		45		(37	)		134,778
Total securities with a maturity of one year or less		612,557		792		(345	)		613,004
Corporate debt securities		382,000		331		(2,644	)		379,687
Debt securities issued by U.S. government agencies		72,935		—		(561	)		72,374
Debt securities issued by the U.S. Treasury		137,635		139		(500	)		137,274
Debt securities issued by states of the U.S. and political subdivisions of the states		39,909		1		(224	)		39,686
Other municipal debt securities		6,136		—		(37	)		6,099
Total securities with a maturity of more than one year		638,615		471		(3,966	)		635,120
Total available-for-sale securities	$	1,251,172	$	1,263	$	(4,311	)	$	1,248,124
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	7,145	$	(837	)	$	18,205
Total equity securities included in deposits and other assets (3)		15,615		16,707		—			32,322
Total equity securities	$	27,512	$	23,852	$	(837	)	$	50,527
Total available-for-sale and equity securities	$	1,278,684	$	25,115	$	(5,148	)	$	1,298,651

________________

(1)	Includes investments classified as cash equivalents in our consolidated balance sheets.

(2)

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. In the year ended December 31, 2022, we recognized a $7.7 million unrealized non-cash loss in our consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.

(3)

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 in our consolidated balance sheets.

Temporarily Impaired Investments

The following is a summary of our investments we considered to be temporarily impaired at December 31, 2022 (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.

			Less than 12 Months of Temporary Impairment					More than 12 Months of Temporary Impairment					Total Temporary Impairment
	Number of Investments		Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses
Corporate debt securities		384	$	384,136	$	(2,629	)	$	305,367	$	(11,879	)	$	689,503	$	(14,508	)
Debt securities issued by U.S. government agencies		48		93,862		(538	)		70,233		(2,331	)		164,095		(2,869	)
Debt securities issued by the U.S. Treasury		75		616,826		(6,082	)		86,325		(3,151	)		703,151		(9,233	)
Debt securities issued by states of the U.S. and political subdivisions of the states		110		18,117		(225	)		31,465		(790	)		49,582		(1,015	)
Other municipal debt securities		2		—		—			5,993		(14	)		5,993		(14	)
Total temporarily impaired securities		619	$	1,112,941	$	(9,474	)	$	499,383	$	(18,165	)	$	1,612,324	$	(27,639	)

CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($) shares in Thousands, $ in Thousands	Common 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	$ 213,454	$ 1,577,459
Balance (in shares) at Dec. 31, 2019	140,340
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	(444,263)	(444,263)	0	(444,263)
Change in unrealized gains (losses), net of tax	0	0	3,729	0	3,729	0	3,729
Foreign currency translation	0	0	617	0	617	0	617
Issuance of common stock in connection with employee stock plans	$ 1	52,033	0	0	52,034	0	52,034
Issuance of common stock in connection with employee stock plans (in shares)	1,721
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards	$ 0	(324,022)	301	0	(323,721)	(220,965)	(544,686)
Repurchases and retirements of common stock	$ (1)	0	0	(90,548)	(90,549)	0	(90,549)
Repurchases and retirements of common stock (in shares)	(1,478)
Stock-based compensation expense	$ 0	230,117	0	0	230,117	0	230,117
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(13,410)	0	0	(13,410)	0	(13,410)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(217)
Deferred tax liability adjustment due to purchase of noncontrolling interest of Akcea Therapeutics, Inc.	$ 0	7,714	0	0	7,714	0	7,714
Noncontrolling interest in Akcea Therapeutics, Inc.	0	(42,563)	(428)	0	(42,991)	7,511	(35,480)
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, 2020	140,366
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	(28,597)	(28,597)	0	(28,597)
Change in unrealized gains (losses), net of tax	0	0	(11,486)	0	(11,486)	0	(11,486)
Foreign currency translation	0	0	(111)	0	(111)	0	(111)
Issuance of common stock in connection with employee stock plans	$ 1	11,563	0	0	11,564	0	11,564
Issuance of common stock in connection with employee stock plans (in shares)	1,132
Issuance of warrants	$ 0	89,752	0	0	89,752	0	89,752
Purchase of note hedges	0	(136,620)	0	0	(136,620)	0	(136,620)
Stock-based compensation expense	0	120,678	0	0	120,678	0	120,678
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(16,725)	0	0	(16,725)	0	(16,725)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(288)
Balance at Dec. 31, 2021	$ 141	1,964,167	(32,668)	(1,159,903)	771,737	0	771,737
Balance (in shares) at Dec. 31, 2021	141,210
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	(269,722)	(269,722)	0	(269,722)
Change in unrealized gains (losses), net of tax	0	0	(24,395)	0	(24,395)	0	(24,395)
Foreign currency translation	0	0	(417)	0	(417)	0	(417)
Issuance of common stock in connection with employee stock plans	$ 1	6,372	0	0	6,373	0	6,373
Issuance of common stock in connection with employee stock plans (in shares)	1,194
Stock-based compensation expense	$ 0	100,264	0	0	100,264	0	100,264
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(10,953)	0	0	(10,953)	0	(10,953)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(346)
Balance at Dec. 31, 2022	$ 142	$ 2,059,850	$ (57,480)	$ (1,429,625)	$ 572,887	$ 0	$ 572,887
Balance (in shares) at Dec. 31, 2022	142,058

Collaborative Arrangements and Licensing Agreements, Metagenomi License Agreement (Details) - Metagenomi License Agreement [Member] $ in Millions	3 Months Ended
	Dec. 31, 2022 USD ($)	Nov. 30, 2022 Target
Collaborative Arrangement and Licensing Agreement [Abstract]
Payment to license intellectual property \| $	$ 80
Research and development expense \| $	$ 80
Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of targets to be researched, developed and commercialized \| Target		4
Number of additional targets to be researched, developed and commercialized \| Target		4

Collaborative Arrangements and Licensing Agreements, Bicycle License Agreement (Details) - Bicycle License Agreement [Member] - USD ($) $ in Millions	1 Months Ended	12 Months Ended
	Jul. 31, 2021	Dec. 31, 2022	Dec. 31, 2021
Collaborative Arrangement and Licensing Agreement [Abstract]
Payment of license fee	$ 42.0
Trading restriction period under lock up agreement		1 year
Equity investment			$ 7.2
R&D expense			$ 34.8
Cumulative payments made		$ 46.6

Long-Term Obligations and Commitments (Tables)

12 Months Ended

Dec. 31, 2022

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2022			2021

0 percent convertible senior notes	$	622,242		$	619,119
0.125 percent convertible senior notes		544,504			542,314
Lease liabilities		186,156			22,058
Mortgage debt		8,998			60,054
Other obligations		7,295			7,505
Total	$	1,369,195		$	1,251,050
Less: current portion		(7,535	)		(3,526	)
Total Long-Term Obligations	$	1,361,660		$	1,247,524

Convertible Notes [Abstract]

Debt Maturity Schedules

Annual convertible and mortgage debt maturities, including fixed and determinable interest, at December 31, 2022 are as follows (in thousands):

2023	$	1,281
2024		550,107
2025		595
2026		633,095
2027		447
Thereafter		8,708
Total debt and mortgage maturities	$	1,194,233
Less: Current portion included in other current liabilities		(151	)
Less: Fixed and determinable interest		(3,526	)
Less: Debt issuance costs		(14,831	)
Total long-term debt	$	1,175,725

Amounts Related to Operating Leases

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2022
Right-of-use operating lease assets	$	181.5
Operating lease liabilities	$	186.2
Weighted average remaining lease term	13.8 years
Weighted average discount rate		6.9	%

Future Payments for Operating Lease Liabilities

As of December 31, 2022, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,
2023	$	20,071
2024		20,391
2025		20,640
2026		20,781
2027		20,800
Thereafter		196,911
Total minimum lease payments		299,594
Less: Imputed interest		(113,438	)
Less: Current portion (included in other current liabilities)		(7,215	)
Total long-term lease liabilities	$	178,941

0% Notes [Member]

Convertible Notes [Abstract]

Convertible Senior Notes

At December 31, 2022, we had the following 0% Notes outstanding (in millions except interest rate and price per share data):

	0% Notes
Outstanding principal balance	$	632.5
Unamortized debt issuance costs	$	10.3
Maturity date	April 2026
Interest rate	0 percent
Effective interest rate	0.5 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% Notes [Member]

Convertible Notes [Abstract]

Convertible Senior Notes

At December 31, 2022, we had the following 0.125% Notes outstanding with interest payable semi-annually (in millions except interest rate and price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Unamortized debt issuance costs	$	4.3
Maturity date	December 2024
Interest rate	0.125 percent
Effective interest rate	0.5 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

- Definition

Tabular disclosure of long-debt instruments or arrangements, including identification, terms, features, collateral requirements and other information necessary to a fair presentation. These are debt arrangements that originally required repayment more than twelve months after issuance or greater than the normal operating cycle of the entity, if longer.

+ References

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-Subparagraph (SX 210.12-04(a))
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Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef
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+ Details

Investments, Investments Temporarily Impaired (Details) $ in Thousands	Dec. 31, 2022 USD ($) Investment
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	619
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 1,112,941
More than 12 months of temporary impairment	499,383
Total temporary impairment	1,612,324
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	(9,474)
More than 12 months of temporary impairment	(18,165)
Total temporary impairment	$ (27,639)
Corporate Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	384
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 384,136
More than 12 months of temporary impairment	305,367
Total temporary impairment	689,503
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	(2,629)
More than 12 months of temporary impairment	(11,879)
Total temporary impairment	$ (14,508)
Debt Securities Issued by U.S. Government Agencies [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	48
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 93,862
More than 12 months of temporary impairment	70,233
Total temporary impairment	164,095
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	(538)
More than 12 months of temporary impairment	(2,331)
Total temporary impairment	$ (2,869)
Debt Securities Issued by the U.S. Treasury [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	75
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 616,826
More than 12 months of temporary impairment	86,325
Total temporary impairment	703,151
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	(6,082)
More than 12 months of temporary impairment	(3,151)
Total temporary impairment	$ (9,233)
Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	110
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 18,117
More than 12 months of temporary impairment	31,465
Total temporary impairment	49,582
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	(225)
More than 12 months of temporary impairment	(790)
Total temporary impairment	$ (1,015)
Other Municipal Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	2
Estimated Fair Value [Abstract]
Less than 12 months of temporary impairment	$ 0
More than 12 months of temporary impairment	5,993
Total temporary impairment	5,993
Unrealized Losses [Abstract]
Less than 12 months of temporary impairment	0
More than 12 months of temporary impairment	(14)
Total temporary impairment	$ (14)

Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Gross Unrecognized Tax Benefits [Roll Forward]
Beginning balance of unrecognized tax benefits	$ 55,085	$ 54,163	$ 69,784
Decrease for prior period tax positions	(267)	(695)	(24,154)
Increase for prior period tax positions	259	263	7,023
Increase for current period tax positions	1,490	1,354	1,510
Ending balance of unrecognized tax benefits	56,567	55,085	54,163
Unrecognized tax benefits that could impact effective tax rate, if recognized	6,200	6,200	6,400
Decrease in unrecognized tax benefits that is reasonably possible	15,000
Interest and penalties on gross unrecognized tax benefits	$ 800	$ 500	$ 300

Organization and Significant Accounting Policies, Basic and Diluted Net Loss per Share (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

2 Months Ended

3 Months Ended

10 Months Ended

12 Months Ended

Dec. 31, 2020

Dec. 31, 2022

Dec. 31, 2021

Oct. 31, 2020

Dec. 31, 2022

Dec. 31, 2021

Dec. 31, 2020

Apr. 30, 2021

Dec. 31, 2019

Basic Net Income (Loss) per Share [Abstract]

Basic net loss per share (in dollars per share)

$ (0.37)

^[1],[2]

$ 1.59

^[1],[2]

$ (1.9)

$ (0.2)

$ (3.18)

Net loss

$ (269,722)

$ (28,597)

$ (444,263)

Income (loss) available to Ionis common stockholders

$ 224,612

$ (444,464)

Weighted average shares outstanding (in shares)

141,205

141,848

141,021

139,612

0.125% Notes [Member]

Basic Net Income (Loss) per Share [Abstract]

Interest rate on convertible senior notes

0.125%

1% Notes [Member]

Basic Net Income (Loss) per Share [Abstract]

Interest rate on convertible senior notes

1.00%

0% Notes [Member]

Basic Net Income (Loss) per Share [Abstract]

Interest rate on convertible senior notes

0.00%

Ionis [Member]

Basic Net Income (Loss) per Share [Abstract]

Net loss

$ (246,702)

Akcea [Member]

Basic Net Income (Loss) per Share [Abstract]

Percentage ownership

100.00%

Akcea [Member]

Basic Net Income (Loss) per Share [Abstract]

Weighted average shares owned in Akcea (in shares)

77,095

Basic net loss per share (in dollars per share)

$ (1.45)

Net loss

$ (85,987)

$ (111,775)

$ (197,762)

[1]	We compute net income (loss) per share independently for each quarter during the year.
[2]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) by our weighted-average number of common shares outstanding during the period.

Organization and Significant Accounting Policies, Cash, Cash Equivalents and Investments (Details)	Dec. 31, 2022 Company
Cash, Cash Equivalents and Investments [Abstract]
Number of publicly held companies in which there is an equity ownership interest of less than 20%	3
Number of privately held companies in which there is an equity ownership interest of less than 20%	8

Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($) $ in Thousands	1 Months Ended	3 Months Ended	12 Months Ended
	Oct. 31, 2022	Dec. 31, 2022	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Property, Plant and Equipment [Abstract]
Less accumulated depreciation		$ (87,716)	$ (87,716)	$ (102,653)
Property, plant and equipment, net		74,294	74,294	178,069
Net proceeds from sale of real estate assets	$ 202,600
Gain on sale of real estate assets		150,100	150,135	0	$ 0
Property, Plant and Equipment, Excluding Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		153,441	153,441	257,660
Property, plant and equipment, net		65,725	65,725	155,007
Computer Software, Laboratory, Manufacturing and Other Equipment [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		74,351	$ 74,351	72,802
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			3 years
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			10 years
Building, Building Improvements and Building Systems [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		41,158	$ 41,158	144,046
Building, Building Improvements and Building Systems [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			15 years
Building, Building Improvements and Building Systems [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			40 years
Land Improvements [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			20 years
Property, plant and equipment		0	$ 0	10,077
Leasehold Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		28,357	$ 28,357	20,144
Leasehold Improvements [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			5 years
Leasehold Improvements [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			15 years
Furniture and Fixtures [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		9,575	$ 9,575	10,591
Furniture and Fixtures [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			5 years
Furniture and Fixtures [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful life			10 years
Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment		$ 8,569	$ 8,569	$ 23,062

Fourth Quarter Financial Data (Unaudited)

12 Months Ended

Dec. 31, 2022

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

10. Fourth Quarter Financial Data (Unaudited)

The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2022 and 2021 are as follows (in thousands, except per share data).

Three Months Ended December 31,	2022			2021
Revenue (1)	$	151,890		$	440,006
Operating expenses (2)	$	359,909		$	219,403
Income (loss) from operations	$	(208,019	)	$	220,603
Net income (loss) (3)	$	(52,430	)	$	224,613
Basic net income (loss) per share (4) (5)	$	(0.37	)	$	1.59
Diluted net income (loss) per share (4) (6)	$	(0.37	)	$	1.41

________________

(1)	Revenue was lower in the three months ended December 31, 2022 compared to the same period in 2021 due to the $200 million we earned in the fourth quarter of 2021 from AstraZeneca to jointly develop and commercialize eplontersen.

(2)	Operating expenses were higher in the three months ended December 31, 2022 compared to the same period in 2021 primarily due to the $80 million upfront payment we made for our collaboration with Metagenomi in the fourth quarter of 2022.

(3)	Our net loss for the three months ended December 31, 2022 includes the $150.1 million gain we recognized from the sale and leaseback transaction for our headquarters in Carlsbad, California.

(4)	We compute net income (loss) per share independently for each quarter during the year.

(5)	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) by our weighted-average number of common shares outstanding during the period.

(6)	We had net income for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):

Three Months Ended December 31, 2021	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	224,612		141,205	$	1.59
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		46
Shares issuable upon restricted stock award issuance		—		1,065
Shares issuable related to our ESPP		—		34
Shares issuable related to our 0 percent convertible notes		777		10,936
Shares issuable related to our 0.125 percent convertible notes		716		6,590
Shares issuable related to our 1 percent convertible notes		105		464
Income available to Ionis common stockholders, plus assumed conversions	$	226,210		160,340	$	1.41

Investments

12 Months Ended

Dec. 31, 2022

Investments [Abstract]

Investments

2. Investments

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2022:

One year or less	70	%
After one year but within two years	28	%
After two years but within three and a half years	2	%
Total	100	%

As illustrated above, at December 31, 2022, 98 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.

At December 31, 2022, we had an ownership interest of less than 20 percent in eight privately held companies and three publicly held companies with which we conduct business.

The following is a summary of our investments (in thousands):

	Amortized		Gross Unrealized					Estimated
December 31, 2022	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	513,790	$	23	$	(4,365	)	$	509,448
Debt securities issued by U.S. government agencies		133,585		—		(1,829	)		131,756
Debt securities issued by the U.S. Treasury (1)		512,655		23		(5,124	)		507,554
Debt securities issued by states of the U.S. and political subdivisions of the states		57,484		18		(686	)		56,816
Other municipal debt securities		6,008		—		(14	)		5,994
Total securities with a maturity of one year or less		1,223,522		64		(12,018	)		1,211,568
Corporate debt securities		227,631		14		(10,143	)		217,502
Debt securities issued by U.S. government agencies		34,339		—		(1,040	)		33,299
Debt securities issued by the U.S. Treasury		245,030		—		(4,109	)		240,921
Debt securities issued by states of the U.S. and political subdivisions of the states		18,314		116		(329	)		18,101
Total securities with a maturity of more than one year		525,314		130		(15,621	)		509,823
Total available-for-sale securities	$	1,748,836	$	194	$	(27,639	)	$	1,721,391
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	—	$	(1,358	)	$	10,539
Total equity securities included in deposits and other assets (3)		23,115		17,257		—			40,372
Total equity securities	$	35,012	$	17,257	$	(1,358	)	$	50,911
Total available-for-sale and equity securities	$	1,783,848	$	17,451	$	(28,997	)	$	1,772,302

	Amortized		Gross Unrealized					Estimated
December 31, 2021	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	383,870	$	728	$	(226	)	$	384,372
Debt securities issued by U.S. government agencies		48,493		19		(18	)		48,494
Debt securities issued by the U.S. Treasury (1)		45,424		—		(64	)		45,360
Debt securities issued by states of the U.S. and political subdivisions of the states		134,770		45		(37	)		134,778
Total securities with a maturity of one year or less		612,557		792		(345	)		613,004
Corporate debt securities		382,000		331		(2,644	)		379,687
Debt securities issued by U.S. government agencies		72,935		—		(561	)		72,374
Debt securities issued by the U.S. Treasury		137,635		139		(500	)		137,274
Debt securities issued by states of the U.S. and political subdivisions of the states		39,909		1		(224	)		39,686
Other municipal debt securities		6,136		—		(37	)		6,099
Total securities with a maturity of more than one year		638,615		471		(3,966	)		635,120
Total available-for-sale securities	$	1,251,172	$	1,263	$	(4,311	)	$	1,248,124
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	7,145	$	(837	)	$	18,205
Total equity securities included in deposits and other assets (3)		15,615		16,707		—			32,322
Total equity securities	$	27,512	$	23,852	$	(837	)	$	50,527
Total available-for-sale and equity securities	$	1,278,684	$	25,115	$	(5,148	)	$	1,298,651

________________

(1)	Includes investments classified as cash equivalents in our consolidated balance sheets.

(2)

(3)

			Less than 12 Months of Temporary Impairment					More than 12 Months of Temporary Impairment					Total Temporary Impairment
	Number of Investments		Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses
Corporate debt securities		384	$	384,136	$	(2,629	)	$	305,367	$	(11,879	)	$	689,503	$	(14,508	)
Debt securities issued by U.S. government agencies		48		93,862		(538	)		70,233		(2,331	)		164,095		(2,869	)
Debt securities issued by the U.S. Treasury		75		616,826		(6,082	)		86,325		(3,151	)		703,151		(9,233	)
Debt securities issued by states of the U.S. and political subdivisions of the states		110		18,117		(225	)		31,465		(790	)		49,582		(1,015	)
Other municipal debt securities		2		—		—			5,993		(14	)		5,993		(14	)
Total temporarily impaired securities		619	$	1,112,941	$	(9,474	)	$	499,383	$	(18,165	)	$	1,612,324	$	(27,639	)

Legal Proceedings	12 Months Ended
Legal Proceedings	Dec. 31, 2022
Legal Proceedings [Abstract]
Legal Proceedings	9. Legal Proceedings From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the status of each legal matter and assess our potential financial exposure. If we consider the potential loss from any legal proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of any proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the amount of accruals we recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding and may revise our estimates. On August 5, 2021, four purported former stockholders of Akcea filed an action in the Delaware Court of Chancery captioned John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the Delaware Action. The plaintiffs in the Delaware Action asserted claims against (i) former members of Akcea’s board of directors; and (ii) Ionis, or collectively, the Defendants. The plaintiffs asserted putatively direct claims on behalf of a purported class of former Akcea stockholders. The plaintiffs in the Delaware Action asserted that the Defendants breached their fiduciary duties in connection with the October 2020 take-private transaction that Ionis and Akcea entered into, in which Akcea became a wholly-owned subsidiary of Ionis. We believe this lawsuit is without merit. However, the outcome of this lawsuit or any other lawsuit that may be filed challenging the October 2020 take-private transaction is uncertain. Accordingly, on June 3, 2022, the parties reached an agreement in principle to settle the Delaware Action for $12.5 million. A Stipulation and Agreement of Compromise, Settlement and Release, or the Stipulation and Settlement Agreement reflecting the terms of the proposed settlement was executed and filed with the Delaware Court of Chancery on July 5, 2022. On October 11, 2022, the Delaware Court of Chancery entered an Order and Final Judgment, or the Order, approving the Stipulation and Settlement Agreement in full after determining that the Stipulation and Settlement Agreement was fair, reasonable, and adequate. The Order provides for the full settlement, satisfaction, compromise and release of all claims that were asserted in the Delaware Action. The Order contains no admission of wrongdoing on the part of any of the Defendants. We recorded a net settlement expense of $7.7 million within other expense in the accompanying consolidated statements of operations in 2022. On January 19, 2022, a purported stockholder of Ionis filed a stockholder derivative complaint in the Delaware Court of Chancery captioned Leo Shumacher, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0059, or the Shumacher Action. The complaint names Ionis’ board of directors, or the Board, as defendants and names Ionis as a nominal defendant. The Shumacher Action Plaintiff asserts a breach of fiduciary duty claim against the Board for awarding and receiving allegedly excessive compensation. The Shumacher Action Plaintiff also asserts an unjust enrichment claim against the non-executive directors as a result of the compensation they received. The complaint seeks, among other things, damages, restitution, attorneys’ fees and costs, and such other relief as deemed just and proper by the court. On March 18, 2022, Ionis and the Board moved to dismiss the complaint. On May 24, 2022, the parties entered into a Stipulation and Agreement of Compromise, Settlement and Release. On May 25, 2022, another purported stockholder of Ionis filed a stockholder derivative complaint also in the Delaware Court of Chancery captioned Robert S. Cohen, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0453, or the Cohen Action. The complaint names the Board as defendants and names Ionis as a nominal defendant. The Cohen Action Plaintiff asserts claims for breach of fiduciary duty, unjust enrichment, aiding and abetting breaches of fiduciary duty, and waste against the Board for awarding and receiving allegedly excessive non-executive director compensation for the years 2018, 2019, and 2020. On June 2, 2022, the Cohen Action Plaintiff filed a motion to consolidate the related Cohen Action and Shumacher Action. On July 5, 2022, the Court denied the motion to consolidate in favor of the settlement pending in the Shumacher Action. On July 18, 2022, Ionis filed a Form 8-K disclosing the pending settlement and attaching the Notice of Pendency of Settlement of Action. On September 21, 2022, the Court held a hearing to consider whether the terms of the settlement should be approved, at which hearing the Cohen Action plaintiff objected to the settlement. At the conclusion of the hearing, the Court declined to approve the settlement and directed the parties to meet and confer on the issue of the scope of the release. On February 7, 2023, the parties entered into an Amended Stipulation and Agreement of Compromise, Settlement and Release. We and our Board have denied, and continue to deny, any and all allegations of wrongdoing or liability asserted in the Shumacher and Cohen Actions.

Stockholders' Equity, Performance Restricted Stock Unit Activity (Details) - Performance Restricted Stock Units [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Millions	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Number of Shares [Abstract]
Non-vested at beginning of period (in shares)	59
Granted (in shares)	105
Vested (in shares)	(16)
Cancelled/forfeited (in shares)	(5)
Non-vested at end of period (in shares)	143	59
Weighted Average Grant Date Fair Value per Share [Abstract]
Non-vested at beginning of period (in dollars per share)	$ 79.2
Granted (in dollars per share)	42.28	$ 77.17	$ 93.09
Vested (in dollars per share)	75.03
Cancelled/forfeited (in dollars per share)	79.11
Non-vested at end of period (in dollars per share)	$ 52.59	$ 79.2
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested units	$ 2.4
Weighted average period for recognition	10 months 24 days

Organization and Significant Accounting Policies, Stock-Based Compensation Expense (Details)	12 Months Ended
	Dec. 31, 2022 Period shares
Stock Options Granted Prior to January 1, 2022 [Member]
Stock-Based Compensation Expense [Abstract]
Award term	7 years
Stock Options Granted on January 1, 2022 and Thereafter [Member]
Stock-Based Compensation Expense [Abstract]
Award term	10 years
RSUs [Member] \| Employees [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	4 years
RSUs [Member] \| Board of Directors [Member] \| Granted Prior to June 2020 [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	4 years
RSUs [Member] \| Board of Directors [Member] \| Granted After June 2020 [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	1 year
PRSUs [Member] \| Executive Officers [Member]
Stock-Based Compensation Expense [Abstract]
Number of performance periods \| Period	3
Vesting period	3 years
Number of units guaranteed to vest (in shares) \| shares	0
PRSUs [Member] \| Executive Officers [Member] \| Minimum [Member]
Stock-Based Compensation Expense [Abstract]
Percentage of units guaranteed to vest	0.00%
PRSUs [Member] \| Executive Officers [Member] \| Maximum [Member]
Stock-Based Compensation Expense [Abstract]
Percentage of units guaranteed to vest	150.00%
PRSUs [Member] \| Executive Officers [Member] \| One-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	1 year
PRSUs [Member] \| Executive Officers [Member] \| Two-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	2 years
PRSUs [Member] \| Executive Officers [Member] \| Three-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	3 years

Organization and Significant Accounting Policies, Accumulated Other Comprehensive Loss (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2022

Dec. 31, 2021

Dec. 31, 2020

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

$ 771,737

$ 743,282

$ 1,577,459

Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.

(127)

Net other comprehensive income (losses) for the year

(24,812)

(11,597)

4,219

Balance

572,887

771,737

743,282

Income tax expense included in other comprehensive loss

Accumulated Other Comprehensive Loss [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

(32,668)

(21,071)

(25,290)

Balance

(57,480)

(32,668)

(21,071)

Unrealized Gains (Losses) on Securities [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

^[1]

(24,395)

(11,486)

3,729

Currency Translation Adjustment [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

$ (417)

$ (111)

$ 617

[1]	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2022, 2021 and 2020.

- Definition

Amount after tax and reclassification adjustments of other comprehensive income (loss).

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section 45
-Paragraph 1A
-Subparagraph (b)
-URI https://asc.fasb.org/extlink&oid=126968391&loc=SL7669619-108580

Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section 50
-Paragraph 4
-URI https://asc.fasb.org/extlink&oid=124431353&loc=SL124442407-227067

Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 505
-SubTopic 10
-Section 50
-Paragraph 2
-URI https://asc.fasb.org/extlink&oid=126973232&loc=d3e21463-112644

Reference 4: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 830
-SubTopic 30
-Section 45
-Paragraph 17
-URI https://asc.fasb.org/extlink&oid=118261656&loc=d3e32136-110900

Reference 5: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section S99
-Paragraph 2
-Subparagraph (SX 210.5-03(21))
-URI https://asc.fasb.org/extlink&oid=126953954&loc=SL114868664-224227

Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section 55
-Paragraph 15
-URI https://asc.fasb.org/extlink&oid=124507222&loc=d3e1436-108581

Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 830
-SubTopic 30
-Section 45
-Paragraph 20
-URI https://asc.fasb.org/extlink&oid=118261656&loc=d3e32211-110900

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 830
-SubTopic 30
-Section 50
-Paragraph 1
-URI https://asc.fasb.org/extlink&oid=6450520&loc=d3e32583-110901

Reference 9: http://www.xbrl.org/2009/role/commonPracticeRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section 50
-Paragraph 5
-URI https://asc.fasb.org/extlink&oid=124431353&loc=SL124442411-227067

Reference 10: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section 45
-Paragraph 1B
-Subparagraph (b)
-URI https://asc.fasb.org/extlink&oid=126968391&loc=SL7669625-108580

Reference 11: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 942
-SubTopic 220
-Section S99
-Paragraph 1
-Subparagraph (SX 210.9-04(23))
-URI https://asc.fasb.org/extlink&oid=120399700&loc=SL114874048-224260

Reference 12: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 944
-SubTopic 220
-Section S99
-Paragraph 1
-Subparagraph (SX 210.7-04(19))
-URI https://asc.fasb.org/extlink&oid=120400993&loc=SL114874131-224263

+ Details

- Definition

Amount of tax expense (benefit) allocated to other comprehensive income (loss).

+ References

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- Definition

Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.

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+ Details

Collaborative Arrangements and Licensing Agreements, Novartis (Details) $ in Thousands, shares in Millions	1 Months Ended	3 Months Ended	12 Months Ended
	Aug. 31, 2021 USD ($)	Mar. 31, 2017 USD ($) PerformanceObligation shares	Dec. 31, 2022 USD ($)	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Jan. 31, 2023
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 587,367	$ 810,456	$ 729,264
Pelacarsen API [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Percentage of royalty payments paid to Royalty Pharma on annual sales of medicine						25.00%
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			284,009	468,061	$ 364,565
Novartis [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration			900,000
Upfront payment received		$ 75,000
Maximum amount of license fees over term of collaboration			150,000
Maximum amount of development milestone payments over term of collaboration			25,000
Maximum amount of regulatory milestone payments over term of collaboration			290,000
Maximum amount of sales milestone payments over term of collaboration			360,000
Cumulative payments received			275,000
Next payment to be achieved			75,000
Shares issued (in shares) \| shares		1.6
Proceeds from sale of common stock		$ 100,000
Number of separate performance obligations \| PerformanceObligation		4
Transaction price		$ 108,400
Premium received on shares issued		28,400
Potential premium received if common stock is purchased in the future		5,000
Deferred revenue			$ 0	$ 0
Novartis [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage			0.00%	3.00%	0.00%
Novartis [Member] \| R&D Services for Pelacarsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price		64,000
Novartis [Member] \| R&D Services for Olezarsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price		40,100
Novartis [Member] \| Pelacarsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on sales of medicine			20.00%
Percentage enrollment in Lp(a) HORIZON Phase 3 cardiovascular outcome study	50.00%
Transaction price		1,500
Revenue	$ 25,000
Novartis [Member] \| Olezarsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price		$ 2,800
Novartis [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 200	$ 25,500	$ 1,000

Collaborative Arrangements and Licensing Agreements, Roche (Details) $ in Thousands	1 Months Ended	12 Months Ended
	Jul. 31, 2022 USD ($)	Dec. 31, 2022 USD ($) Indication	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Oct. 31, 2018 USD ($) PerformanceObligation	Apr. 30, 2013 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 587,367	$ 810,456	$ 729,264
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		284,009	468,061	$ 364,565
Roche [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue		$ 22,400	$ 31,600
Roche [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage		11.00%	2.00%	1.00%
Roche [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 67,200	$ 17,200	$ 5,900
Collaboration to Develop Treatments for Huntington's Disease with Roche [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration		395,000
Maximum amount of upfront payments over term of collaboration		30,000
Maximum amount of license fees over term of collaboration		45,000
Maximum amount of development milestone payments over term of collaboration		70,000
Maximum amount of regulatory milestone payments over term of collaboration		170,000
Maximum amount of sales milestone payments over term of collaboration		80,000
Maximum amount of milestone payments for each additional medicine successfully developed over term of collaboration		136,500
Cumulative payments received		150,000
Next payment to be achieved		17,500
Number of separate performance obligations \| PerformanceObligation							1
Transaction price							$ 30,000
Revenue					$ 35,000
IONIS-FB-L for Complement-Mediated Diseases [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration		810,000
Maximum amount of upfront payments over term of collaboration		75,000
Maximum amount of license fees over term of collaboration		35,000
Maximum amount of development milestone payments over term of collaboration		145,000
Maximum amount of regulatory milestone payments over term of collaboration		279,000
Maximum amount of sales milestone payments over term of collaboration		280,000
Cumulative payments received		130,000
Next payment to be achieved		$ 90,000
Number of separate performance obligations \| PerformanceObligation						1
Transaction price						$ 75,000
Number of disease indications \| Indication		2
Royalty percentage received on net sales of medicine		20.00%
Revenue	$ 35,000
IONIS-FB-L for Complement-Mediated Diseases [Member] \| GA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication		1
IONIS-FB-L for Complement-Mediated Diseases [Member] \| IgAN [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication		1

Organization and Significant Accounting Policies, Contracts Receivable (Details) - Partner	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021
Contracts Receivable [Abstract]
Period of time after billing when payment is received	3 months
Contracts Receivable [Abstract]
Number of significant customers	1	2
Contracts Receivables [Member] \| Credit Concentration [Member] \| One Significant Customer [Member]
Contracts Receivable [Abstract]
Concentration percentage	82.50%
Contracts Receivables [Member] \| Credit Concentration [Member] \| Two Significant Customers [Member]
Contracts Receivable [Abstract]
Concentration percentage		93.80%

Employment Benefits (Details) - USD ($)	12 Months Ended
Employment Benefits (Details) - USD ($)	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Employee Benefits [Abstract]
Matching contributions	$ 5,600,000	$ 5,500,000	$ 5,700,000
Minimum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	20,500
Maximum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	$ 27,000

Long-Term Obligations and Commitments, Royalty Revenue Monetization (Details) - Subsequent Event [Member] $ in Millions	1 Months Ended
	Jan. 31, 2023 USD ($)
Royalty Revenue Monetization [Abstract]
Upfront payment received	$ 500
Maximum amount of payments receivable for additional milestones	625
SPINRAZA [Member]
Royalty Revenue Monetization [Abstract]
Maximum amount of annual sales on which royalty payments are paid	$ 1,500
SPINRAZA [Member] \| Minimum [Member]
Royalty Revenue Monetization [Abstract]
Percentage of royalty payments paid on annual sales of medicine	25.00%
Maximum royalty payments made before royalty interest reverts back	$ 475
SPINRAZA [Member] \| Maximum [Member]
Royalty Revenue Monetization [Abstract]
Percentage of royalty payments paid on annual sales of medicine	45.00%
Maximum royalty payments made before royalty interest reverts back	$ 550
Pelacarsen [Member]
Royalty Revenue Monetization [Abstract]
Percentage of royalty payments paid on annual sales of medicine	25.00%

Long-Term Obligations and Commitments

12 Months Ended

Dec. 31, 2022

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations and Commitments

4. Long-Term Obligations and Commitments

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2022			2021

0 percent convertible senior notes	$	622,242		$	619,119
0.125 percent convertible senior notes		544,504			542,314
Lease liabilities		186,156			22,058
Mortgage debt		8,998			60,054
Other obligations		7,295			7,505
Total	$	1,369,195		$	1,251,050
Less: current portion		(7,535	)		(3,526	)
Total Long-Term Obligations	$	1,361,660		$	1,247,524

Convertible Debt and Call Spread

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% Notes to repurchase $247.9 million in principal of our 1% Notes for $257.0 million.

At December 31, 2022, we had the following 0% Notes outstanding (in millions except interest rate and price per share data):

	0% Notes
Outstanding principal balance	$	632.5
Unamortized debt issuance costs	$	10.3
Maturity date	April 2026
Interest rate	0 percent
Effective interest rate	0.5 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.

We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in capital in our consolidated balance sheets. Refer to Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, for our Call Spread accounting policy. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.

0.125 Percent Convertible Senior Notes and Call Spread

In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.

At December 31, 2022, we had the following 0.125% Notes outstanding with interest payable semi-annually (in millions except interest rate and price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Unamortized debt issuance costs	$	4.3
Maturity date	December 2024
Interest rate	0.125 percent
Effective interest rate	0.5 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

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, to minimize the impact of potential economic dilution upon conversion of our 0.125% Notes by increasing the effective conversion price on our 0.125% Notes. We increased our effective conversion price to $123.38 with the same number of underlying shares as our 0.125% Notes. The call spread cost us $52.6 million, of which $108.7 million was for the note hedge purchase, offset by $56.1 million we received for selling the warrants. Similar to our 0.125% Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0.125% Notes. The note hedges will expire upon maturity of the 0.125% Notes, or December 2024. The note hedges and warrants are separate transactions and are not part of the terms of our 0.125% Notes. The holders of the 0.125% Notes do not have any rights with respect to the note hedges and warrants.

1 Percent Convertible Senior Notes

In April 2021, we repurchased $247.9 million in aggregate principal amount of our 1% Notes in privately negotiated transactions. As a result of the repurchase, we recognized an $8.6 million loss on early retirement of debt in the second quarter of 2021, reflecting the early retirement of a significant portion of our 1% Notes. The loss on the early retirement of our debt is the difference between the amount paid to retire our 1% Notes and the net carrying balance of the liability at the time that we retired the debt. We paid the remaining principal balance of our 1% Notes with $62.0 million of cash at maturity in November 2021.

Other Terms of Convertible Senior Notes

The 0% and 0.125% 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. The 1% Notes were subject to similar terms.

Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2022, 2021 and 2020 included $5.3 million, $4.9 million and $3.2 million, respectively, of non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.

Financing Arrangements

Operating Facilities

In July 2017, we purchased the building that houses our primary R&D facility for $79.4 million and our manufacturing facility for $14.0 million. We financed the purchase of these two facilities with mortgage debt of $60.4 million in total. Our primary R&D facility mortgage had an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both mortgages, we were only required to make interest payments. We began making principal payments in 2022. Our manufacturing facility mortgage matures in August 2027. We repaid our primary R&D facility mortgage in October 2022 in conjunction with a sale and leaseback transaction.

In October 2022, we concurrently entered into two purchase and sale agreements with a real estate investor. Under the agreements, we sold and leased back the facilities at our headquarters location in Carlsbad, California and will sell, subject to meeting certain closing conditions, two lots of undeveloped land adjacent to our headquarters. We sold the facilities at our headquarters, which includes our primary R&D facility, for a total purchase price of $263.4 million and we expect to receive total proceeds of $33.0 million upon the close of the sale of the two lots. We used a portion of the sale proceeds to extinguish our outstanding mortgage debt on our primary R&D facility of $51.3 million.

Debt Maturity Schedules

Annual convertible and mortgage debt maturities, including fixed and determinable interest, at December 31, 2022 are as follows (in thousands):

2023	$	1,281
2024		550,107
2025		595
2026		633,095
2027		447
Thereafter		8,708
Total debt and mortgage maturities	$	1,194,233
Less: Current portion included in other current liabilities		(151	)
Less: Fixed and determinable interest		(3,526	)
Less: Debt issuance costs		(14,831	)
Total long-term debt	$	1,175,725

Royalty Revenue Monetization

In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. As a result, we received an upfront payment of $500 million and we are eligible to receive up to $625 million in additional milestone payments. Under the terms of the agreement, Royalty Pharma will receive 25 percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion in annual sales. In addition, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen, our medicine in development for lipoprotein(a), or Lp(a), driven cardiovascular disease. Royalty Pharma’s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $475 million or $550 million, depending on the timing and occurrence of FDA approval of pelacarsen. We will begin accounting for the royalty monetization agreement in the first quarter of 2023.

Long-Term Obligations and Commitments

Operating Leases

Carlsbad Leases

We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year period.

We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases. In September 2022, we exercised our option to extend one of these leases, extending our term from January 2023 to May 2027. We have no remaining options to extend this lease. Our other office space lease in Carlsbad has an initial term ending in 2023.

As discussed above in the section titled, Financing Arrangements, we lease our headquarters, which includes our primary R&D facility, as part of a sale and leaseback transaction that closed in October 2022. The initial lease term for our headquarters facilities is 15 years with options to extend the lease for 2 additional terms of five years each. We determined at lease inception that it was not reasonably certain that we would exercise any of the options to extend the lease. We expect our lease payments over the initial term to total approximately $280 million. In connection with the sale of our two undeveloped lots, we will enter into a build-to-suit lease agreement with the same real estate investor who will build a new R&D facility for us on those lots. Once this new facility is completed, our lease will commence.

Oceanside Lease

In October 2022, we entered into a build-to-suit lease agreement to lease a development chemistry and manufacturing facility in Oceanside, California. The lessor will develop and construct a building composed of manufacturing space, office space, research and development space and warehouse space. We will design and construct tenant improvements to customize the facility’s interior space. We will lease the facility for an initial term of 20 years and 3 months with options to extend the lease for two additional terms of 10 years each. The lease will commence when the lessor’s construction is complete and we are able to begin constructing tenant improvements.

Boston Leases

We entered into an operating lease agreement for office space located in Boston, Massachusetts which commenced in August 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under the lease agreement, we received a three-month free rent period.

In January 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement date was in January 2022 when the office space was ready for our tenant’s occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no option to extend the sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced on January 6, 2022. We will receive lease payments over the sublease term totaling $9.6 million.

We entered into an operating lease agreement for another office space located in Boston, Massachusetts which commenced in November 2021. We are leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease commencement date and an option to extend the lease for an additional five-year term. Under the lease agreement, we received a seven-month free rent period, which commenced on November 1, 2021. Our lease payments over the initial term total $6.8 million.

When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we did not include the extension options for these leases in the original lease term because it was not reasonably certain we would exercise those extension options.

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2022
Right-of-use operating lease assets	$	181.5
Operating lease liabilities	$	186.2
Weighted average remaining lease term	13.8 years
Weighted average discount rate		6.9	%

During the years ended December 31, 2022, 2021, and 2020 we paid $4.0 million, $3.3 million and $3.8 million of lease payments, which were included in operating activities in our consolidated statements of cash flows.

As of December 31, 2022, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,
2023	$	20,071
2024		20,391
2025		20,640
2026		20,781
2027		20,800
Thereafter		196,911
Total minimum lease payments		299,594
Less: Imputed interest		(113,438	)
Less: Current portion (included in other current liabilities)		(7,215	)
Total long-term lease liabilities	$	178,941

Rent expense was $8.3 million, $3.4 million and $3.7 million for the years ended December 31, 2022, 2021 and 2020, respectively.

- Definition

The entire disclosure for information about short-term and long-term debt arrangements, which includes amounts of borrowings under each line of credit, note payable, commercial paper issue, bonds indenture, debenture issue, own-share lending arrangements and any other contractual agreement to repay funds, and about the underlying arrangements, rationale for a classification as long-term, including repayment terms, interest rates, collateral provided, restrictions on use of assets and activities, whether or not in compliance with debt covenants, and other matters important to users of the financial statements, such as the effects of refinancing and noncompliance with debt covenants.

+ References

Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 470
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Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 470
-SubTopic 20
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-Paragraph 1B
-Subparagraph (h)
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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
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Reference 4: http://www.xbrl.org/2003/role/disclosureRef
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Reference 5: http://www.xbrl.org/2003/role/disclosureRef
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-Subparagraph (d)
-URI https://asc.fasb.org/extlink&oid=123466505&loc=SL123495371-112611

Reference 6: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 235
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SX 210.4-08(c))
-URI https://asc.fasb.org/extlink&oid=120395691&loc=d3e23780-122690

Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
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Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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-URI https://asc.fasb.org/extlink&oid=123466505&loc=SL123495334-112611

Reference 10: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
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-URI https://asc.fasb.org/extlink&oid=123466505&loc=SL123495323-112611

Reference 12: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 13: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 470
-SubTopic 20
-Section 50
-Paragraph 1B
-Subparagraph (i)
-URI https://asc.fasb.org/extlink&oid=123466505&loc=SL123495323-112611

+ Details

CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($)
$ in Thousands

3 Months Ended

12 Months Ended

Dec. 31, 2022

Dec. 31, 2021

Mar. 31, 2020

Dec. 31, 2022

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Operating activities:

Net loss

$ (52,430)

^[1]

$ 224,613

$ (269,722)

$ (28,597)

$ (479,743)

Adjustments to reconcile net loss to net cash provided by (used in) operating activities:

Depreciation

14,328

15,487

13,365

Amortization of right-of-use operating lease assets

5,362

1,721

1,731

Amortization of other assets

2,415

2,352

2,064

Amortization of premium on investments, net

7,389

17,776

11,521

Amortization of debt issuance costs

5,373

4,958

3,255

Stock-based compensation expense

100,264

120,678

230,117

Loss on early retirement of debt

8,627

Non-cash losses related to disposal of property, plant and equipment

531

Gain on sale of real estate assets

(150,100)

(150,135)

Gain on investments

224

(1,092)

(16,540)

Deferred income taxes, including changes in valuation allowance

341,729

Non-cash losses related to other assets

2,030

2,707

1,948

Changes in operating assets and liabilities:

Contracts receivable

36,358

14,308

(13,170)

Inventories

2,773

(2,841)

(1,261)

Other current and long-term assets

(24,682)

(877)

(9,975)

Long-term income taxes receivable (payable)

1,008

(89)

Accounts payable

1,094

(6,000)

(2,755)

Income taxes

6,213

(1,288)

(31,190)

Accrued compensation

10,368

(26,918)

28,371

Accrued liabilities and other current liabilities

46,695

(8,381)

32,424

Deferred contract revenue

(71,248)

(82,829)

(75,910)

Net cash provided by (used in) operating activities

(274,370)

30,799

35,892

Investing activities:

Purchases of short-term investments

(1,485,772)

(1,124,193)

(1,570,410)

Proceeds from sale of short-term investments

989,152

1,344,185

1,885,935

Purchases of property, plant and equipment

(15,721)

(11,955)

(35,120)

Proceeds from sale of real estate assets

254,083

Acquisition of licenses and other assets, net

(4,378)

(5,946)

(5,928)

Purchases of strategic investments

(7,185)

Net cash provided by (used in) investing activities

(262,636)

194,906

274,477

Financing activities:

Proceeds from equity, net

6,373

11,565

52,036

Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options

(10,953)

(16,725)

(13,411)

Proceeds from the issuance of 0 percent convertible senior notes

632,500

Royalty monetization issuance costs

(29)

0 percent convertible senior notes issuance costs

(15,609)

Repurchase of $247.9 million principal amount of 1 percent convertible senior notes

(256,963)

Repayment of remaining principal amount of 1 percent convertible senior notes at maturity

(61,967)

Proceeds from issuance of warrants

89,752

Purchase of note hedges

(136,620)

Repurchases and retirements of common stock

$ (90,500)

(90,548)

$ (34,400)

Principal payments on debt

(50,686)

Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards

(544,686)

Net cash provided by (used in) financing activities

(55,295)

245,933

(596,609)

Effects of exchange rates on cash

(418)

(111)

617

Net increase (decrease) in cash and cash equivalents

(592,719)

471,527

(285,623)

Cash and cash equivalents at beginning of year

$ 683,287

869,191

397,664

683,287

Cash and cash equivalents at end of year

$ 276,472

$ 869,191

276,472

869,191

397,664

$ 683,287

Supplemental disclosures of cash flow information:

Interest paid

2,898

4,778

6,247

Income taxes paid

5,010

25,855

Supplemental disclosures of non-cash investing and financing activities:

Right-of-use assets obtained in exchange for lease liabilities

168,931

6,641

2,149

Amounts accrued for capital and patent expenditures

$ 4,767

$ 705

$ 4,059

[1]	Our net loss for the three months ended December 31, 2022 includes the $150.1 million gain we recognized from the sale and leaseback transaction for our headquarters in Carlsbad, California.

Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($) $ in Thousands	Dec. 31, 2022	Dec. 31, 2021
Inventory [Abstract]
Raw materials	$ 19,760	$ 18,646
Work in process	2,109	5,770
Finished goods	164	390
Total inventory	22,033	24,806
Clinical [Member]
Inventory [Abstract]
Raw materials	17,061	14,507
Commercial [Member]
Inventory [Abstract]
Raw materials	$ 2,699	$ 4,139

CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares	Dec. 31, 2022	Dec. 31, 2021
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)	142,057,736	141,210,015
Common stock, shares outstanding (in shares)	142,057,736	141,210,015
0 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	0.00%	0.00%
0.125 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	0.125%	0.125%

Fair Value Measurements (Tables)

12 Months Ended

Dec. 31, 2022

Fair Value Measurements [Abstract]

Assets Measured at Fair Value on a Recurring Basis

	At December 31, 2022		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	211,655	$	211,655	$	—
Corporate debt securities (3)		726,950		—		726,950
Debt securities issued by U.S. government agencies (2)		165,055		—		165,055
Debt securities issued by the U.S. Treasury (2)		748,475		748,475		—
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		74,917		—		74,917
Other municipal debt securities (2)		5,994		—		5,994
Publicly traded equity securities included in other current assets (4)		10,539		10,539		—
Total	$	1,943,585	$	970,669	$	972,916

	At December 31, 2021		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	541,199	$	541,199	$	—	$	—
Corporate debt securities (2)		764,059		—		764,059		—
Debt securities issued by U.S. government agencies (2)		120,868		—		120,868		—
Debt securities issued by the U.S. Treasury (2)		182,634		182,634		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (5)		174,464		—		174,464		—
Other municipal debt securities (2)		6,099		—		6,099		—
Publicly traded equity securities included in other current assets (4)		18,205		3,875		—		14,330
Total	$	1,807,528	$	727,708	$	1,065,490	$	14,330

________________

(1)	Included in cash and cash equivalents in our consolidated balance sheets.

(2)	Included in short-term investments.

(3)	$11.0 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.

(4)	Included in other current assets in our consolidated balance sheets.

(5)	$2.3 million included in cash and cash equivalents in our consolidated balance sheets, with the difference included in short-term investments in our consolidated balance sheets.

Organization and Significant Accounting Policies, Call Spread (Details)	Dec. 31, 2022	Dec. 31, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019
0 Percent Convertible Senior Notes [Member]
Call Spread [Abstract]
Interest rate on convertible senior notes	0.00%	0.00%	0.00%		0.00%
0.125 Percent Convertible Senior Notes [Member]
Call Spread [Abstract]
Interest rate on convertible senior notes	0.125%	0.125%		0.125%	0.125%

Organization and Significant Accounting Policies

12 Months Ended

Dec. 31, 2022

Organization and Significant Accounting Policies [Abstract]

Organization and Significant Accounting Policies

1. Organization and Significant Accounting Policies

Basis of Presentation

In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea’s common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger, Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the changes occurred.

Organization and Business Activity

We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.

Use of Estimates

We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S. that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.

Revenue Recognition

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 within deferred revenue in our consolidated balance sheets.

At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808, Collaborative Arrangements, or ASC 808. ASC 808 does not address the recognition and measurement of collaborative arrangements and instead refers companies to use other authoritative accounting literature. For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore are within the scope of ASC 606, Revenue from Contracts with Customers. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.

We evaluate the income statement classification for presentation of amounts due from or owed to other participants associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development activities as revenue; while we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&A expense and research and development expense, respectively.

Steps to Recognize Revenue

For elements of our contractual relationships that we account for under ASC 606, 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:

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.

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 frequently 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. Refer to the section titled, Eplontersen Collaboration with AstraZeneca, below for further discussion of a collaboration that included an upfront license payment.

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.

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;

●

Estimated expenses we may incur;

●

Estimated income taxes; and

●

A discount rate.

We typically estimate the selling price of research and development, or 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 estimated number of internal hours 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.

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.

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:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

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-effect adjustment.

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.

Refer to Part IV, Item 15, Note 7, Collaborative Arrangements and Licensing Agreements, for further discussion of our 2018 Strategic Neurology collaboration with Biogen that included multiple agreements which we negotiated concurrently and in contemplation of one another.

Our Revenue Sources

The following are sources of revenue and when we typically recognize revenue.

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 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

In January 2021 and April 2021, we entered into distribution agreements with Swedish Orphan Biovitrum AB, or Sobi, in which Sobi began commercializing TEGSEDI and WAYLIVRA in Europe and TEGSEDI in North America, respectively. 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 Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. Under our agreement, we started receiving royalties from PTC for TEGSEDI sales in December 2021.

Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics companies, or 3PLs, that took title to TEGSEDI. The 3PLs 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 the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as distributors.

Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi. We are also responsible for maintaining the marketing authorization for TEGSEDI and WAYLIVRA in major markets and for leading the global commercial strategy for each medicine. We view this performance obligation as a series of distinct activities that are substantially the same. 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. Under our agreements with Sobi, Sobi does not generally have a right of return.

Prior to our distribution agreements 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 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.

Research and development revenue under collaboration agreements

We 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, R&D services and manufacturing services.

We provide details about our collaboration agreements in Note 7, Collaborative Arrangements and Licensing Agreements. For each collaboration, we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.

Upfront payments: When we enter into a collaboration agreement and receive 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.

Milestone payments: We 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, when we achieve a milestone payment from a partner for advancing a clinical study under a collaboration agreement, we add the milestone payment to the transaction price if the milestone relates to an ongoing R&D services performance obligation and recognize revenue related to the milestone payment over our estimated period of performance. If we have partially completed our performance obligation, then we record a cumulative-effect adjustment in the period we add the milestone to the transaction price.

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.

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.

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.

Eplontersen Collaboration with AstraZeneca

In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for the treatment of transthyretin amyloidosis, or ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment in 2021.

We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca are performing, (iii) the co-commercialization activities that we and AstraZeneca are performing and (iv) the co-medical affairs activities that we and AstraZeneca are performing.

We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration and therefore do not have a vendor-customer relationship. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 development program, we made an accounting policy election to recognize as non-customer revenue the cost-share funding from AstraZeneca, net of our share of AstraZeneca’s development expenses, in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we made an accounting policy election to recognize cost-share funding we receive from AstraZeneca related to commercial and medical affairs activities as reductions of our SG&A expense and R&D expense, respectively.

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 December 31, 2022, approximately 82.5 percent of our contracts receivables were from one significant customer. As of December 31, 2021, approximately 93.8 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 in our consolidated balance sheets.

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 in our consolidated balance sheets. During the years ended December 31, 2022 and 2021, we recognized $73.5 million and $98.1 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.

Cost of Sales

Our cost of sales is comprised of costs related to our commercial revenue, including 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.

Research, Development and Patent Expenses

Our research, development and patent expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs, patents 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 in our consolidated balance sheets and we expense them as the services are provided. A portion of the costs included in research and development expenses are costs associated with our partner agreements. In 2022, 2021 and 2020, patent expenses were $4.7 million, $5.3 million and $4.1 million, respectively.

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 expected to be realized.

We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.

We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, we can provide no assurance that the final tax outcome of these matters will not be different from that which we have reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which we make such determination.

We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Basic and Diluted Net Loss per Share

Basic net loss per share

We compute basic net loss per share by dividing the total net loss attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. For the years ended December 31, 2022 and 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 years ended December 31, 2022 and 2021 was $1.90 and $0.20, respectively.

For the year ended December 31, 2020, we calculated total net loss attributable to our common stockholders using our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. 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. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share was different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations.

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

Diluted net loss per share

For the years ended December 31, 2022, 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 underlying the following would have had an anti-dilutive effect on net loss per share:

●

0.125 percent convertible senior notes, or 0.125% Notes;

●

Note hedges related to the 0.125% Notes;

●

1 percent convertible senior notes, or 1% Notes;

●

Dilutive stock options;

●

Unvested restricted stock units, or RSUs;

●

Unvested performance restricted stock units, or PRSUs; and

●

Employee Stock Purchase Plan, or ESPP.

For the years ended December 31, 2022 and 2021, common stock underlying the following would also have had an anti-dilutive effect on net loss per share:

●

0 percent convertible senior notes, or 0% Notes; and

●

Note hedges related to the 0% Notes.

Additionally as of December 31, 2022 and 2021, we had warrants related to our 0 percent and 0.125 percent 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.

Stock-Based Compensation Expense

We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs 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 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 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.

Stock Options and Stock Purchase Rights:

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. The expected term of stock options granted represents the period of time that we expect them to be outstanding. Historically, we estimated the expected term of options granted based on historical exercise patterns. In 2021, our Compensation Committee approved an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the 2020 Equity Incentive Plan, or 2020 Plan, that increased the contractual term of stock options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the expected life of stock options granted to employees in the year ended December 31, 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional historical information, we will transition to calculating our expected term based on our historical exercise patterns.

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 to our board of directors after June 2020 fully vest after one year.

PRSU’s:

Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Beginning in 2022, we added PRSU awards to the compensation for our other Section 16 officers. Under the terms of the grants, one third of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to 150 percent of the target number depending on our relative TSR.

We determined the fair value of the 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.

Refer to Part IV, Item 15, Note 5, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Noncontrolling Interest in Akcea Therapeutics, Inc.

Since Akcea’s IPO in July 2017 and prior to the Akcea Merger in October 2020, the shares of Akcea’s common stock third parties owned represented an interest in Akcea’s equity that we did not control. During this period our ownership ranged from 68 percent to 77 percent. However, as we maintained overall control of Akcea through our voting interest, we reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea’s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other owners of Akcea’s common stock on a separate line in our statements of operations and a separate line within stockholders’ equity in our consolidated balance sheets. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders’ equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, we reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the change occurred.

Accumulated Other Comprehensive Loss

Accumulated other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2022, 2021 and 2020 (in thousands):

	Year Ended December 31,
	2022			2021			2020
Beginning balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)
Unrealized gains (losses) on securities, net of tax (1)		(24,395	)		(11,486	)		3,729
Currency translation adjustment		(417	)		(111	)		617
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			—			(127	)
Net other comprehensive income (losses) for the year		(24,812	)		(11,597	)		4,219
Ending balance accumulated other comprehensive loss	$	(57,480	)	$	(32,668	)	$	(21,071	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2022, 2021 and 2020.

Concentration of Credit Risk

Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody’s, Standard & Poor’s, or S&P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.

Fair Value Measurements

We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.

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 consolidated statements 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 December 31, 2022, we held equity investments in three publicly traded companies and eight privately held companies.

We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated statements 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.

Inventories

We reflect our inventory in our consolidated balance sheets 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. Our raw materials- commercial inventory includes API for our commercial medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.

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.

Our inventory consisted of the following (in thousands):

	December 31,
	2022		2021
Raw materials:
Raw materials- clinical	$	17,061	$	14,507
Raw materials- commercial		2,699		4,139
Total raw materials		19,760		18,646
Work in process		2,109		5,770
Finished goods		164		390
Total inventory	$	22,033	$	24,806

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful		December 31,
	Lives (in years)		2022			2021
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	74,351		$	72,802
Building, building improvements and building systems	15 to 40			41,158			144,046
Land improvements		20		-			10,077
Leasehold improvements	5 to 15			28,357			20,144
Furniture and fixtures	5 to 10			9,575			10,591
				153,441			257,660
Less accumulated depreciation				(87,716	)		(102,653	)
				65,725			155,007
Land				8,569			23,062
Total			$	74,294		$	178,069

In October 2022, we sold the facilities and related land at our headquarters for net proceeds of $202.6 million in connection with a sale and leaseback transaction. In connection with the sale of these real estate assets, we de-recognized the related land and improvements, building and building improvements, which resulted in a net gain of $150.1 million that we reported in other income (expense) in our consolidated statements of operations.

We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term. We evaluate long-lived assets, which include property, plant and equipment, 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.

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2022		2021
Clinical expenses	$	116,460	$	65,730
In-licensing expenses		7,945		8,044
Commercial expenses		3,498		2,471
Other miscellaneous expenses		12,198		12,315
Total accrued liabilities	$	140,101	$	88,560

Estimated Liability for Clinical Development Costs

We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.

Convertible Debt

We 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 we did not issue our convertible debt instruments at a substantial premium. We record debt issuance costs as contra-liabilities in our consolidated balance sheets at issuance and amortize them over the contractual term of the convertible debt instrument using the effective interest rate. The balances of our convertible senior notes presented in our consolidated balance sheets represent the principal balance of each convertible debt instrument less debt issuance costs.

As of December 31, 2022, we had two outstanding convertible senior notes, our 0% Notes, which mature in April 2026, and our 0.125% Notes, which mature in December 2024. Refer to Part IV, Item 15, Note 4, Long-Term Obligations and Commitments, for further details on our convertible senior notes.

Call Spread

In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered into call spread transactions, which were 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 consolidated balance sheets. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.

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 in our consolidated balance sheets 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 conclude we are reasonably certain to 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 leases do not provide an interest rate implicit in the lease, we use our incremental borrowing rate, based on the information available 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. Our leases do not include material variable or contingent lease payments. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.

Segment 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. We completed the Akcea Merger in October 2020 and fully integrated Akcea’s operations into ours as of January 1, 2021.

Recently Adopted Accounting Standards

In June 2022, the Financial Accounting Standards Board, or FASB, issued clarifying guidance on fair value measurement of equity securities subject to contractual trading restrictions. The guidance clarifies that contractual trading restrictions are not considered part of the unit of account of equity securities and therefore, are not considered when measuring the fair value of equity securities. This update is effective for interim and annual periods beginning January 1, 2024 on a prospective basis. Early adoption of this guidance is permitted at an interim or annual period. We early adopted this new guidance in the third quarter of 2022. This guidance did not have a material impact on our consolidated financial statements.

We do not expect any other recently issued accounting standards to have a material impact to our financial results.

Long-Term Obligations and Commitments, Debt Maturity Schedules (Details) $ in Thousands	Dec. 31, 2022 USD ($)
Debt Maturities [Abstract]
2023	$ 1,281
2024	550,107
2025	595
2026	633,095
2027	447
Thereafter	8,708
Total debt and mortgage maturities	1,194,233
Less: Current portion included in other current liabilities	(151)
Less: Fixed and determinable interest	(3,526)
Less: Debt issuance costs	(14,831)
Total long-term debt	$ 1,175,725

Document and Entity Information - USD ($)	12 Months Ended
Document and Entity Information - USD ($)	Dec. 31, 2022	Feb. 16, 2023	Jun. 30, 2022
Cover [Abstract]
Document Type	10-K
Amendment Flag	false
Document Annual Report	true
Document Period End Date	Dec. 31, 2022
Current Fiscal Year End Date	--12-31
Document Fiscal Year Focus	2022
Document Fiscal Period Focus	FY
Document Transition Report	false
Entity File Number	000-19125
Entity Registrant Name	Ionis Pharmaceuticals, Inc
Entity Central Index Key	0000874015
Entity Incorporation, State or Country Code	DE
Entity Tax Identification Number	33-0336973
Entity Address, Address Line One	2855 Gazelle Court
Entity Address, City or Town	Carlsbad
Entity Address, State or Province	CA
Entity Address, Postal Zip Code	92010
City Area Code	760
Local Phone Number	931-9200
Title of 12(b) Security	Common Stock, $.001 Par Value
Trading Symbol	IONS
Security Exchange Name	NASDAQ
Entity Well-known Seasoned Issuer	Yes
Entity Voluntary Filers	No
Entity Current Reporting Status	Yes
Entity Interactive Data Current	Yes
Entity Filer Category	Large Accelerated Filer
Entity Small Business	false
Entity Emerging Growth Company	false
ICFR Auditor Attestation Flag	true
Entity Shell Company	false
Entity Public Float			$ 3,804,704,734
Entity Common Stock, Shares Outstanding		142,953,993
Auditor Firm ID	42
Auditor Name	Ernst & Young LLP
Auditor Location	San Diego, California

Stockholders' Equity, Share Repurchase Program (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Mar. 31, 2020	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019	Sep. 30, 2019
Share Repurchase Program [Abstract]
Authorized amount of share repurchase program						$ 125,000
Shares repurchased (in shares)	1,500,000				535,000
Shares repurchased	$ 90,500	$ 0	$ 0	$ 90,548	$ 34,400

CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS [Abstract]
Net loss	$ (269,722)	$ (28,597)	$ (479,743)
Unrealized gains (losses) on investments, net of tax	(24,395)	(11,486)	3,729
Currency translation adjustment	(417)	(111)	617
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.	0	0	(127)
Comprehensive loss	(294,534)	(40,194)	(475,524)
Comprehensive loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.	0	0	(35,480)
Comprehensive loss attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (294,534)	$ (40,194)	$ (440,044)

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.

+ References

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+ Details

Investments, Summary of Investments (Details)
$ in Thousands

12 Months Ended

Dec. 31, 2022

USD ($)

Company

Dec. 31, 2021

USD ($)

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% | Company

Number of publicly held companies in which there is an equity ownership interest of less than 20% | Company

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

$ 1,223,522

$ 612,557

Gross unrealized gains

792

Gross unrealized losses

(12,018)

(345)

Estimated fair value

1,211,568

613,004

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

525,314

638,615

Gross unrealized gains

130

471

Gross unrealized losses

(15,621)

(3,966)

Estimated fair value

509,823

635,120

Available-for-sale Securities [Abstract]

Amortized cost

1,748,836

1,251,172

Gross unrealized gains

194

1,263

Gross unrealized losses

(27,639)

(4,311)

Estimated fair value

1,721,391

1,248,124

Equity Securities [Abstract]

Amortized cost

35,012

27,512

Gross unrealized gains

17,257

23,852

Gross unrealized losses

(1,358)

(837)

Estimated fair value

50,911

50,527

Available-for-sale and Equity Securities [Abstract]

Amortized cost

1,783,848

1,278,684

Gross unrealized gains

17,451

25,115

Gross unrealized losses

(28,997)

(5,148)

Estimated fair value

1,772,302

1,298,651

Corporate Debt Securities [Member]

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

^[1]

513,790

383,870

Gross unrealized gains

728

Gross unrealized losses

(4,365)

(226)

Estimated fair value

509,448

384,372

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

227,631

382,000

Gross unrealized gains

331

Gross unrealized losses

(10,143)

(2,644)

Estimated fair value

217,502

379,687

Debt Securities Issued by U.S. Government Agencies [Member]

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

133,585

48,493

Gross unrealized gains

Gross unrealized losses

(1,829)

(18)

Estimated fair value

131,756

48,494

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

34,339

72,935

Gross unrealized gains

Gross unrealized losses

(1,040)

(561)

Estimated fair value

33,299

72,374

Debt Securities Issued by the U.S. Treasury [Member]

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

^[1]

512,655

45,424

Gross unrealized gains

Gross unrealized losses

(5,124)

(64)

Estimated fair value

507,554

45,360

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

245,030

137,635

Gross unrealized gains

139

Gross unrealized losses

(4,109)

(500)

Estimated fair value

240,921

137,274

Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

57,484

134,770

Gross unrealized gains

Gross unrealized losses

(686)

(37)

Estimated fair value

56,816

134,778

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

18,314

39,909

Gross unrealized gains

116

Gross unrealized losses

(329)

(224)

Estimated fair value

18,101

39,686

Other Municipal Debt Securities [Member]

Available-for-sale Securities with Maturity of One Year or Less [Abstract]

Amortized cost

6,008

Gross unrealized gains

Gross unrealized losses

(14)

Estimated fair value

5,994

Available-for-sale Securities with Maturity of More Than One Year [Abstract]

Amortized cost

6,136

Gross unrealized gains

Gross unrealized losses

(37)

Estimated fair value

6,099

Publicly Traded Equity Securities [Member]

Equity Securities [Abstract]

Amortized cost

^[2]

11,897

Gross unrealized gains

7,145

Gross unrealized losses

(1,358)

(837)

Estimated fair value

10,539

18,205

Available-for-sale and Equity Securities [Abstract]

Unrealized loss on equity investment

(7,700)

Privately Held Equity Securities [Member]

Equity Securities [Abstract]

Amortized cost

^[3]

23,115

15,615

Gross unrealized gains

17,257

16,707

Gross unrealized losses

Estimated fair value

$ 40,372

$ 32,322

[1]	Includes investments classified as cash equivalents in our consolidated balance sheets.
[2]	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. In the year ended December 31, 2022, we recognized a $7.7 million unrealized non-cash loss in our consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.
[3]	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 in our consolidated balance sheets.

Stockholders' Equity (Tables)

12 Months Ended

Dec. 31, 2022

Stockholders' Equity [Abstract]

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2022 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2021		14,089		$	54.04
Granted		2,864		$	34.78
Exercised		(123	)	$	29.35
Cancelled/forfeited/expired		(1,860	)	$	53.96
Outstanding at December 31, 2022		14,970		$	50.57		4.01	$	12,243
Exercisable at December 31, 2022		10,285		$	53.74		2.56	$	1,651

Restricted Stock Unit Activity

The following table summarizes the RSU activity for the year ended December 31, 2022 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2021		2,618		$	58.05
Granted		1,401		$	36.14
Vested		(958	)	$	57.05
Cancelled/forfeited		(295	)	$	48.61
Non-vested at December 31, 2022		2,766		$	48.30

Performance Restricted Stock Unit Activity

The following table summarizes the PRSU activity for the year ended December 31, 2022 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2021		59		$	79.20
Granted		105		$	42.28
Vested		(16	)	$	75.03
Cancelled/forfeited		(5	)	$	79.11
Non-vested at December 31, 2022		143		$	52.59

Stock-Based Compensation Expense

The following table summarizes stock-based compensation expense for the years ended December 31, 2022, 2021 and 2020 (in thousands):

	Year Ended December 31,
	2022		2021		2020
Cost of sales	$	533	$	456	$	1,991
Research, development and patent		73,704		87,522		115,584
Selling, general and administrative		26,027		32,700		112,542
Total	$	100,264	$	120,678	$	230,117

Weighted-Average Assumptions for Stock Options

Ionis Employee Stock Options:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		2.1	%		0.6	%		1.5	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		54.5	%		54.0	%		58.6	%
Expected life	6.3 years			4.9 years			4.7 years

Ionis Board of Director Stock Options:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		2.9	%		1.2	%		0.5	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		56.2	%		55.9	%		57.6	%
Expected life	7.4 years			7.3 years			6.7 years

Weighted-Average Assumptions for ESPP

Ionis ESPP:

	Year Ended December 31,
	2022			2021			2020
Risk-free interest rate		1.2	%		0.1	%		0.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		50.1	%		42.4	%		47.9	%
Expected life	6 months			6 months			6 months

Stockholders' Equity, Preferred and Common Stock (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	142,057,736	141,210,015
Common stock, shares outstanding (in shares)	142,057,736	141,210,015
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 6,373	$ 11,565	$ 52,036
Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares authorized (in shares)	15,000,000
Preferred stock, shares outstanding (in shares)	0
Series C Junior Participating Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares issued (in shares)	0
Preferred stock, shares outstanding (in shares)	0
Common Stock [Member]
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	142,100,000	141,200,000
Common stock, shares outstanding (in shares)	142,100,000	141,200,000
Common shares reserved for future issuance (in shares)	43,200,000
Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)	1,200,000	1,100,000	1,700,000
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 6,400	$ 11,600	$ 52,000

Collaborative Arrangements and Licensing Agreements, Biogen (Details) $ in Thousands	1 Months Ended		3 Months Ended						12 Months Ended
	Sep. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2012 USD ($) Program	Dec. 31, 2022 USD ($) Medicine	Sep. 30, 2022 USD ($)	Dec. 31, 2021 USD ($)	Dec. 31, 2019 USD ($)	Jun. 30, 2018 USD ($)	Dec. 31, 2017 USD ($) PerformanceObligation	Dec. 31, 2022 USD ($) Medicine	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2018 USD ($)	Jan. 31, 2023 USD ($)	Apr. 30, 2018 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									$ 587,367	$ 810,456	$ 729,264
SPINRAZA [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of annual sales on which royalty payments are paid													$ 1,500,000
SPINRAZA [Member] \| Minimum [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Percentage of royalty payments paid to Royalty Pharma on annual sales of medicine													25.00%
Maximum royalty payments made before royalty interest reverts back													$ 475,000
SPINRAZA [Member] \| Maximum [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Percentage of royalty payments paid to Royalty Pharma on annual sales of medicine													45.00%
Maximum royalty payments made before royalty interest reverts back													$ 550,000
SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									242,314	267,776	286,583
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									284,009	468,061	364,565
Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									366,700	428,800	$ 408,600
Deferred revenue			$ 351,200		$ 407,500				$ 351,200	$ 407,500
Biogen [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage									62.00%	53.00%	56.00%
Biogen [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			3,400,000						$ 3,400,000
Biogen [Member] \| SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									242,300	$ 267,800	$ 286,600
Biogen [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue									124,400	161,000	122,000
SPINRAZA [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned			1,800,000						$ 1,800,000
Royalty percentage received on net sales of medicine									11.00%
SPINRAZA [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of medicine									15.00%
SPINRAZA [Member] \| SPINRAZA Royalties [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned			1,400,000						$ 1,400,000
SPINRAZA [Member] \| R&D Revenue [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned			425,000						425,000
New Antisense Medicines for the Treatment of SMA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			85,000						$ 85,000
Royalty percentage received on net sales of medicine									20.00%
Upfront payment received								$ 25,000
Maximum amount of payments receivable over term of collaboration			1,200,000						$ 1,200,000
Maximum amount of upfront payments over term of collaboration			25,000						25,000
Maximum amount of license fees over term of collaboration			110,000						110,000
Maximum amount of development milestone payments over term of collaboration			80,000						80,000
Maximum amount of regulatory milestone payments over term of collaboration			180,000						180,000
Maximum amount of sales milestone payments over term of collaboration			800,000						800,000
Next payment to be achieved			45,000						45,000
Number of separate performance obligations \| PerformanceObligation								1
Transaction price								$ 25,000
New Antisense Medicines for the Treatment of SMA [Member] \| ION306 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration			555,000						555,000
Maximum amount of development milestone payments over term of collaboration			45,000						45,000
Maximum amount of regulatory milestone payments over term of collaboration			110,000						110,000
Maximum amount of sales milestone payments over term of collaboration			400,000						400,000
Revenue					$ 60,000
2018 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			1,100,000						$ 1,100,000
Royalty percentage received on net sales of medicine									20.00%
Upfront payment received							$ 375,000
Next payment to be achieved			7,500						$ 7,500
Number of separate performance obligations \| PerformanceObligation														1
Transaction price														$ 552,000
Term of collaboration agreement									10 years
Upfront payment received, including purchase of stock							1,000,000
Proceeds from issuance of common stock							$ 625,000
Percentage cash premium paid on shares purchased							25.00%
Maximum amount of payments receivable per medicine over term of collaboration			270,000						$ 270,000
Maximum amount of license fees per medicine over term of collaboration			15,000						15,000
Maximum amount of development milestone payments per medicine over term of collaboration			105,000						105,000
Maximum amount of regulatory milestone payments per medicine over term of collaboration			150,000						150,000
Premium paid on shares purchased							$ 177,000
Cumulative payments included in transaction price for performance obligation			616,000						616,000
Milestone payments achieved and included in transaction price for performance obligation										$ 23,000	11,000
2013 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			300,000						300,000
Upfront payment received	$ 100,000
Next payment to be achieved			$ 16,000						$ 16,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 100,000
Number of medicines currently being advanced \| Medicine			5						5
Maximum amount of payments receivable per antisense molecule over term of collaboration			$ 260,000						$ 260,000
Maximum amount of license fees per antisense molecule over term of collaboration			70,000						70,000
Maximum amount of development milestone payments per antisense molecule over term of collaboration			60,000						60,000
Maximum amount of regulatory milestone payments per antisense molecule over term of collaboration			$ 130,000						$ 130,000
Revenue				$ 9,000								$ 35,000
2013 Strategic Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation											145,000
2013 Strategic Neurology [Member] \| Medicines for Parkinson's Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine			1						1
2013 Strategic Neurology [Member] \| Medicines for ALS [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine			2						2
2013 Strategic Neurology [Member] \| Medicines for Multiple System Atrophy [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine			1						1
2013 Strategic Neurology [Member] \| Medicines for Undisclosed Targets [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine			1						1
2013 Strategic Neurology [Member] \| Tofersen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration			$ 110,000						$ 110,000
Maximum amount of license fees over term of collaboration			35,000						35,000
Maximum amount of development milestone payments over term of collaboration			18,000						18,000
Maximum amount of regulatory milestone payments over term of collaboration			55,000						55,000
2012 Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			170,000						170,000
Upfront payment received		$ 30,000
Maximum amount of payments receivable over term of collaboration			210,000						210,000
Maximum amount of license fees over term of collaboration			70,000						70,000
Maximum amount of development milestone payments over term of collaboration			10,000						10,000
Maximum amount of regulatory milestone payments over term of collaboration			130,000						130,000
Next payment to be achieved			25,000						25,000
Number of programs under which medicines are to be developed and commercialized \| Program		2
2012 Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation			40,000						40,000
2012 Neurology [Member] \| IONIS-MAPT [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation			57,000						57,000
Milestone payments achieved and included in transaction price for performance obligation											$ 19,500
Revenue						$ 45,000			10,000
2012 Neurology [Member] \| ION582 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Milestone payments achieved and included in transaction price for performance obligation			$ 14,500
Revenue									$ 20,000

Stockholders' Equity, Restricted Stock Unit Activity (Details) - Restricted Stock Units [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Millions	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Number of Shares [Abstract]
Non-vested at beginning of period (in shares)	2,618
Granted (in shares)	1,401
Vested (in shares)	(958)
Cancelled/forfeited (in shares)	(295)
Non-vested at end of period (in shares)	2,766	2,618
Weighted Average Grant Date Fair Value per Share [Abstract]
Non-vested at beginning of period (in dollars per share)	$ 58.05
Granted (in dollars per share)	36.14	$ 57.02	$ 60.57
Vested (in dollars per share)	57.05
Cancelled/forfeited (in dollars per share)	48.61
Non-vested at end of period (in dollars per share)	$ 48.3	$ 58.05
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested units	$ 45.8
Weighted average period for recognition	1 year 2 months 12 days

Fourth Quarter Financial Data (Unaudited) (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

3 Months Ended

12 Months Ended

Dec. 31, 2022

Dec. 31, 2021

Dec. 31, 2022

Dec. 31, 2021

Dec. 31, 2020

Apr. 30, 2021

Dec. 31, 2019

Fourth Quarter Financial Data (Unaudited) [Abstract]

Revenue

$ 151,890

^[1]

$ 440,006

Operating expenses

359,909

^[2]

219,403

$ 997,558

$ 840,642

$ 901,346

Loss from operations

(208,019)

220,603

(410,191)

(30,186)

(172,082)

Net income (loss)

$ (52,430)

^[3]

$ 224,613

$ (269,722)

$ (28,597)

$ (479,743)

Basic net income (loss) per share (in dollars per share)

$ (0.37)

^[4],[5]

$ 1.59

^[4],[5]

$ (1.9)

$ (0.2)

$ (3.18)

Diluted net income (loss) per share (in dollars per share)

$ (0.37)

^[4]

$ 1.41

^[4],[6]

$ (1.9)

$ (0.2)

$ (3.18)

Gain on sale of real estate assets

$ 150,100

$ 150,135

$ 0

Income (Numerator) [Abstract]

Income (loss) available to Ionis common stockholders

$ 224,612

$ (444,464)

Net income available to Ionis common shareholders

$ 226,210

Shares (Denominator) [Abstract]

Shares used in computing basic net loss per share (in shares)

141,205

141,848

141,021

139,612

Effect of Diluted Securities [Abstract]

Shares issuable related to our ESPP (in shares)

Shares used in computing diluted net income per share (in shares)

160,340

141,848

141,021

139,612

0 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

0.00%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 777

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

10,936

0.125 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

0.125%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 716

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

6,590

1 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

1.00%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 105

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

464

Stock Options [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

Restricted Stock Awards [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

1,065

Eplontersen Collaboration [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Revenue

$ 200,000

Metagenomi License Agreement [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Upfront payment

$ 80,000

[1]	Revenue was lower in the three months ended December 31, 2022 compared to the same period in 2021 due to the $200 million we earned in the fourth quarter of 2021 from AstraZeneca to jointly develop and commercialize eplontersen.
[2]	Operating expenses were higher in the three months ended December 31, 2022 compared to the same period in 2021 primarily due to the $80 million upfront payment we made for our collaboration with Metagenomi in the fourth quarter of 2022.
[3]	Our net loss for the three months ended December 31, 2022 includes the $150.1 million gain we recognized from the sale and leaseback transaction for our headquarters in Carlsbad, California.
[4]	We compute net income (loss) per share independently for each quarter during the year.
[5]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) by our weighted-average number of common shares outstanding during the period.
[6]	We had net income for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period

Stockholders' Equity, Stock-based Valuation Information (Details)	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Employee Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	2.10%	0.60%	1.50%
Dividend yield	0.00%	0.00%	0.00%
Volatility	54.50%	54.00%	58.60%
Expected life	6 years 3 months 18 days	4 years 10 months 24 days	4 years 8 months 12 days
Employee Stock Options [Member] \| 2011 Equity Incentive Plan [Member]
Weighted-Average Assumptions [Abstract]
Award term	7 years
Employee Stock Options [Member] \| 2011 Equity Incentive Plan [Member] \| Issued after December 31, 2021 [Member]
Weighted-Average Assumptions [Abstract]
Award term	10 years
Employee Stock Options [Member] \| 2020 Equity Incentive Plan [Member]
Weighted-Average Assumptions [Abstract]
Award term	7 years
Employee Stock Options [Member] \| 2020 Equity Incentive Plan [Member] \| Issued after December 31, 2021 [Member]
Weighted-Average Assumptions [Abstract]
Award term	10 years
Board of Director Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	2.90%	1.20%	0.50%
Dividend yield	0.00%	0.00%	0.00%
Volatility	56.20%	55.90%	57.60%
Expected life	7 years 4 months 24 days	7 years 3 months 18 days	6 years 8 months 12 days
ESPP [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.20%	0.10%	0.80%
Dividend yield	0.00%	0.00%	0.00%
Volatility	50.10%	42.40%	47.90%
Expected life	6 months	6 months	6 months

Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Number of Shares [Abstract]
Outstanding at beginning of period (in shares)	14,089
Granted (in shares)	2,864
Exercised (in shares)	(123)
Cancelled/forfeited/expired (in shares)	(1,860)
Outstanding at end of period (in shares)	14,970	14,089
Exercisable at end of period (in shares)	10,285
Weighted Average Exercise Price Per Share [Abstract]
Outstanding at beginning of period (in dollars per share)	$ 54.04
Granted (in dollars per share)	34.78
Exercised (in dollars per share)	29.35
Cancelled/forfeited/expired (in dollars per share)	53.96
Outstanding at end of period (in dollars per share)	50.57	$ 54.04
Exercisable at end of period (in dollars per share)	$ 53.74
Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]
Average remaining contractual term, outstanding at end of period	4 years 3 days
Average remaining contractual term, exercisable at end of period	2 years 6 months 21 days
Aggregate intrinsic value, outstanding at end of period	$ 12,243
Aggregate intrinsic value, exercisable at end of period	$ 1,651
Weighted average fair value of options granted (in dollars per share)	$ 18.66	$ 24.35	$ 29.43
Intrinsic value of options exercised	$ 1,400	$ 2,500	$ 15,500
Cash received from exercise of stock options	$ 3,600	$ 8,500	$ 43,700
Weighted-average fair value of options exercised (in dollars per share)	$ 40.71
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested stock options	$ 41,100
Weighted average period for recognition	1 year 1 month 6 days

Investments, Contract Maturity of Available-for-Sale Securities (Details)	12 Months Ended
	Dec. 31, 2022
Contract Maturity of Available-for-Sale Securities [Abstract]
One year or less	70.00%
After one year but within two years	28.00%
After two years but within three and a half years	2.00%
Total	100.00%
Percentage of available-for-sale securities with a maturity of less than two years	98.00%
Maximum contract maturity period, range 1	1 year
Maximum contract maturity period, range 2	2 years
Maximum contract maturity period, range 3	3 years 6 months

Organization and Significant Accounting Policies, Noncontrolling Interest in Akcea Therapeutics, Inc. (Details) - Akcea [Member]	Dec. 31, 2022	Oct. 31, 2020	Jun. 30, 2017
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership	100.00%
Minimum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership		68.00%
Maximum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership		77.00%	100.00%

Income Taxes

12 Months Ended

Dec. 31, 2022

Income Taxes [Abstract]

Income Taxes

6. Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2022			2021			2020
United States	$	(258,493	)	$	(29,966	)	$	(137,222	)
Foreign		508			818			2,670
Income (loss) before income taxes	$	(257,985	)	$	(29,148	)	$	(134,552	)

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2022		2021			2020
Current:
Federal	$	10,522	$	(200	)	$	(837	)
State		1,129		(690	)		3,782
Foreign		86		339			518
Total current income tax expense (benefit)		11,737		(551	)		3,463

Deferred:
Federal		—		—			341,728
State		—		—			—
Total deferred income tax benefit		—		—			341,728
Total income tax expense (benefit)	$	11,737	$	(551	)	$	345,191

	Year Ended December 31,
	2022					2021					2020
Pre-tax income (loss)	$	(257,985	)			$	(29,148	)			$	(134,552	)

Statutory rate		(54,177	)	21.0	%		(6,121	)	21.0	%		(28,256	)	21.0	%
State income tax net of federal benefit		(13,622	)	5.3	%		4,278		(14.7	)%		(37,705	)	28.0	%
Foreign		(49	)	0.0	%		143		(0.5	)%		49		0.0	%
Net change in valuation allowance		104,951		(40.7	)%		2,885		(9.9	)%		460,898		(342.5	)%
Loss on debt transactions		—		—			262		(0.9	)%		—		—
Tax credits		(39,729	)	15.4	%		(23,198	)	79.6	%		(18,774	)	14.0	%
Deferred tax true-up		(20	)	0.0	%		(24	)	0.1	%		(206	)	0.2	%
Tax rate change		(3,091	)	1.2	%		12,838		(44.0	)%		(32,951	)	24.5	%
Non-deductible compensation		3,023		(1.2	)%		5,085		(17.4	)%		7,931		(5.9	)%
Other non-deductible items		57		0.0	%		84		(0.3	)%		193		(0.1	)%
Stock-based compensation		14,030		(5.4	)%		4,720		(16.2	)%		17,435		(13.0	)%
Impacts from Akcea Merger		—		—			—		—			(22,032	)	16.4	%
Other		364		(0.1	)%		(1,503	)	5.1	%		(1,391	)	0.9	%
Effective rate	$	11,737		(4.5	)%	$	(551	)	1.9	%	$	345,191		(256.5	)%

Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes.

Significant components of our deferred tax assets and liabilities as of December 31, 2022 and 2021 are as follows (in thousands):

	Year Ended December 31,
	2022			2021
Deferred Tax Assets:
Net operating loss carryovers	$	87,802		$	85,600
Tax credits		277,436			269,538
Deferred revenue		85,700			104,330
Stock-based compensation		86,983			86,611
Intangible and capital assets		104,649			92,542
Convertible debt		34,384			45,681
Interest expense limitation		—			6,996
Capitalized research and development expenses		119,635			—
Long-term lease liabilities		45,612			5,119
Other		15,813			9,929
Total deferred tax assets	$	858,014		$	706,346

Deferred Tax Liabilities:
Fixed assets		(4,475	)		(3,303	)
Right-of-use assets		(44,504	)		(4,159	)
Other		(313	)		(1,111	)
Net deferred tax asset	$	808,722		$	697,773
Valuation allowance		(808,722	)		(697,773	)
Total net deferred tax assets and liabilities	$	—		$	—

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. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.

Our valuation allowance increased by $111 million from December 31, 2021 to December 31, 2022. The increase was primarily related to increases in our deferred tax asset for capitalized research and development expenses.

At December 31, 2022, we had federal and state, primarily California, tax net operating loss carryforwards of $242.8 million and $461.3 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2022, we also had federal and California research and development tax credit carryforwards of $224.9 million and $110.7 million, respectively. Our federal research and development tax credit carryforwards will begin to expire in 2035. Our California research and development tax credit carryforwards are available indefinitely.

Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.

We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2022			2021			2020
Beginning balance of unrecognized tax benefits	$	55,085		$	54,163		$	69,784
Decrease for prior period tax positions		(267	)		(695	)		(24,154	)
Increase for prior period tax positions		259			263			7,023
Increase for current period tax positions		1,490			1,354			1,510
Ending balance of unrecognized tax benefits	$	56,567		$	55,085		$	54,163

Included in the balance of unrecognized tax benefits at December 31, 2022, 2021 and 2020 was $6.2 million, $6.2 million and $6.4 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.

We estimate that it is reasonably possible that the balance of our gross unrecognized tax benefits may decrease by approximately $15.0 million within the next 12 months due to the lapse of statute of limitations on underlying tax positions primarily related to tax credits.

We recognize interest and/or penalties related to income tax matters in income tax expense. During the years ended December 31, 2022, 2021 and 2020, we recognized $0.8 million, $0.5 million and $0.3 million, respectively, of accrued interest and penalties related to gross unrecognized tax benefits.

We are subject to taxation in the U.S. and various state and foreign jurisdictions. The tax years 2018 through 2021 remain open to examination by major taxing jurisdictions, primarily federal and California, although net operating loss and credit carryforwards generated prior to 2018 may still be adjusted upon examination by the Internal Revenue Service or state tax authorities if they have been used in an open period or are used in a future period.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax liabilities associated with these earnings.

- Definition

The entire disclosure for income taxes. Disclosures may include net deferred tax liability or asset recognized in an enterprise's statement of financial position, net change during the year in the total valuation allowance, approximate tax effect of each type of temporary difference and carryforward that gives rise to a significant portion of deferred tax liabilities and deferred tax assets, utilization of a tax carryback, and tax uncertainties information.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 740
-SubTopic 10
-Section 50
-Paragraph 21
-URI https://asc.fasb.org/extlink&oid=121826272&loc=d3e32857-109319

Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 740
-SubTopic 10
-Section S99
-Paragraph 2
-Subparagraph (SAB Topic 11.C)
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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
-Topic 740
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-Section 50
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-Subparagraph (b)
-URI https://asc.fasb.org/extlink&oid=121826272&loc=d3e32809-109319

Reference 4: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
-Topic 740
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-Section S99
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Reference 5: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
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Reference 6: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
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Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 740
-URI https://asc.fasb.org/topic&trid=2144680

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 740
-SubTopic 30
-Section 50
-Paragraph 2
-Subparagraph (a)
-URI https://asc.fasb.org/extlink&oid=6424122&loc=d3e41874-109331

Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 235
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SX 210.4-08(h)(2))
-URI https://asc.fasb.org/extlink&oid=120395691&loc=d3e23780-122690

+ Details

Stockholders' Equity, Stock-based Compensation Expense (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020	Oct. 31, 2020
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ 100,264	$ 120,678	$ 230,117
Cost of Sales [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	533	456	1,991
Research, Development and Patent [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	73,704	87,522	115,584
Selling, General and Administrative [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ 26,027	$ 32,700	$ 112,542
Akcea [Member]
Stock-Based Compensation [Abstract]
Unrecognized compensation cost related to non-vested units				$ 59,300

Collaborative Arrangements and Licensing Agreements, GSK (Details) $ in Thousands	1 Months Ended	3 Months Ended	12 Months Ended
	Jan. 31, 2023 USD ($)	Sep. 30, 2019 USD ($)	Dec. 31, 2022 USD ($) Medicine	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 587,367	$ 810,456	$ 729,264
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 284,009	468,061	$ 364,565
GSK [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being developed \| Medicine			2
Maximum amount of payments receivable over term of collaboration			$ 260,000
Maximum amount of license fees over term of collaboration			25,000
Maximum amount of development milestone payments over term of collaboration			42,500
Maximum amount of regulatory milestone payments over term of collaboration			120,000
Maximum amount of sales milestone payments over term of collaboration			70,000
Cumulative payments received			50,000
Next payment to be achieved			15,000
Revenue		$ 25,000
Deferred revenue			$ 0	$ 0
GSK [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage			0.00%	0.00%	0.00%
GSK [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue	$ 15,000
GSK [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 0	$ 0	$ 200

Organization and Significant Accounting Policies, Revenue Recognition (Details) $ in Thousands	12 Months Ended
	Dec. 31, 2022 USD ($)	Dec. 31, 2021 USD ($) Component PerformanceObligation	Dec. 31, 2020 USD ($)
Revenue Recognition [Abstract]
Revenue	$ 587,367	$ 810,456	$ 729,264
Eplontersen Collaboration with AstraZeneca [Member]
Revenue Recognition [Abstract]
Revenue		$ 200,000
Number of material components \| Component		4
Number of separate performance obligations \| PerformanceObligation		1
Transaction price		$ 200,000
Percentage of costs associated with ongoing global Phase 3 development program paid by AstraZeneca	55.00%

- Definition

Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 30
-Subparagraph (a)
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e8906-108599

Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
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-Subparagraph (a)
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Reference 4: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (b)
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e8933-108599

Reference 5: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (a)
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e8933-108599

Reference 6: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 4
-Subparagraph (a)
-URI https://asc.fasb.org/extlink&oid=126920106&loc=SL49130543-203045

Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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-SubTopic 10
-Section 50
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-Subparagraph (b)
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e8736-108599

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-Subparagraph (a)
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e8736-108599

Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 42
-URI https://asc.fasb.org/extlink&oid=126901519&loc=d3e9054-108599

Reference 10: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 5
-URI https://asc.fasb.org/extlink&oid=126920106&loc=SL49130545-203045

Reference 11: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 924
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SAB Topic 11.L)
-URI https://asc.fasb.org/extlink&oid=6472922&loc=d3e499488-122856

+ Details

Organization and Significant Accounting Policies, Accrued Liabilities (Details) - USD ($) $ in Thousands	Dec. 31, 2022	Dec. 31, 2021
Accrued Liabilities [Abstract]
Clinical expenses	$ 116,460	$ 65,730
In-licensing expenses	7,945	8,044
Commercial expenses	3,498	2,471
Other miscellaneous expenses	12,198	12,315
Total accrued liabilities	$ 140,101	$ 88,560

Long-Term Obligations and Commitments, Future Payments for Operating Lease Liabilities (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Future Payments for Operating Lease Liabilities [Abstract]
2023	$ 20,071
2024	20,391
2025	20,640
2026	20,781
2027	20,800
Thereafter	196,911
Total minimum lease payments	299,594
Less: Imputed interest	(113,438)
Less: Current portion (included in other current liabilities)	(7,215)
Total long-term lease liabilities	$ 178,941	$ 19,432
Operating Lease, Liability, Current, Statement of Financial Position [Extensible Enumeration]	Other current liabilities
Rent expense	$ 8,300	$ 3,400	$ 3,700

CONSOLIDATED STATEMENTS OF CASH FLOWS (Parenthetical) - USD ($) $ in Millions	Dec. 31, 2022	Dec. 31, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019
0 Percent Convertible Senior Notes [Member]
Financing activities:
Interest rate on convertible senior notes	0.00%	0.00%	0.00%		0.00%
1 Percent Convertible Senior Notes [Member]
Financing activities:
Interest rate on convertible senior notes	1.00%	1.00%	1.00%	1.00%	1.00%
Principal amount repurchased		$ 247.9	$ 247.9		$ 375.6

Collaborative Arrangements and Licensing Agreements, AstraZeneca (Details) $ in Thousands	1 Months Ended		3 Months Ended	12 Months Ended
	Dec. 31, 2021 USD ($) Component PerformanceObligation	Jul. 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2021 USD ($) Component PerformanceObligation	Dec. 31, 2022 USD ($)	Dec. 31, 2021 USD ($) Component PerformanceObligation	Dec. 31, 2020 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 587,367	$ 810,456	$ 729,264
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				284,009	468,061	$ 364,565
AstraZeneca [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue	$ 0		$ 0	$ 0	$ 0
AstraZeneca [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				13.00%	31.00%	12.00%
AstraZeneca [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 79,200	$ 254,600	$ 88,000
Eplontersen Collaboration [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration				3,600,000
Upfront payment received	$ 200,000
Maximum amount of development milestone payments over term of collaboration				485,000
Maximum amount of sales milestone payments over term of collaboration				$ 2,900,000
Royalty percentage received on sales of medicine in U.S.				20.00%
Number of material components \| Component	4		4		4
Number of separate performance obligations \| PerformanceObligation	1		1		1
Transaction price	$ 200,000		$ 200,000		$ 200,000
Percentage of costs associated with ongoing global Phase 3 development program paid by AstraZeneca				55.00%
Next payment to be achieved				$ 50,000
Revenue					$ 200,000
Eplontersen Collaboration [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received				260,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable over term of collaboration				5,800,000
Upfront payment received		$ 65,000
Maximum amount of license fees over term of collaboration				290,000
Maximum amount of development milestone payments over term of collaboration				1,100,000
Maximum amount of regulatory milestone payments over term of collaboration				2,900,000
Maximum amount of sales milestone payments over term of collaboration				1,500,000
Number of separate performance obligations \| PerformanceObligation		1
Transaction price		$ 65,000
Next payment to be achieved				10,000
Revenue			$ 30,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received				280,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation				$ 90,000

Organization and Significant Accounting Policies, Basis of Presentation (Details) - Akcea [Member]	Dec. 31, 2022	Oct. 31, 2020	Jun. 30, 2017
Basis of Presentation [Abstract]
Percentage ownership	100.00%
Maximum [Member]
Basis of Presentation [Abstract]
Percentage ownership		77.00%	100.00%

Collaborative Arrangements and Licensing Agreements, Alnylam Pharmaceuticals, Inc. (Details) $ in Thousands	3 Months Ended	12 Months Ended
	Dec. 31, 2020 USD ($)	Dec. 31, 2022 USD ($)	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2015 Program Target
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 587,367	$ 810,456	$ 729,264
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		284,009	468,061	$ 364,565
Alnylam [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of therapeutic programs \| Program					4
Number of therapeutic targets granted to Ionis \| Target					4
Number of unnamed therapeutic targets granted to Ionis \| Target					2
Number of therapeutic targets granted by Ionis \| Target					4
Award from arbitration panel	$ 41,200
Revenue	$ 41,200
Deferred revenue		$ 0	$ 0
Alnylam [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage		4.00%	0.00%	7.00%
Alnylam [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 21,400	$ 0	$ 47,900

Long-Term Obligations and Commitments, Convertible Debt and Call Spread (Details) - USD ($) $ / shares in Units, $ in Thousands, shares in Millions	1 Months Ended			12 Months Ended
	Nov. 30, 2021	Apr. 30, 2021	Dec. 31, 2019	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Convertible Debt [Abstract]
Repurchase of convertible notes				$ 0	$ 61,967	$ 0
Unamortized debt issuance costs				14,831
Purchase of note hedges				0	136,620	0
Proceeds from issuance of warrants				0	89,752	0
Loss on early retirement of debt				0	(8,627)	0
Amortization of debt issuance costs				5,373	4,958	3,255
Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Amortization of debt issuance costs				5,300	$ 4,900	$ 3,200
0% Notes [Member]
Convertible Debt [Abstract]
Face amount of offering		$ 632,500
Outstanding principal balance				632,500
Unamortized debt issuance costs				$ 10,300
Maturity date				Apr. 30, 2026
Interest rate		0.00%	0.00%	0.00%	0.00%
Effective interest rate				0.50%
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
Cost of call spread		$ 46,900
Purchase of note hedges		136,700
Proceeds from issuance of warrants		89,800
Percentage of principal amount used as purchase price upon occurrence of fundamental change				100.00%
0.125% Notes [Member]
Convertible Debt [Abstract]
Outstanding principal balance				$ 548,800
Unamortized debt issuance costs				$ 4,300
Maturity date				Dec. 31, 2024
Interest rate			0.125%	0.125%	0.125%	0.125%
Effective interest rate				0.50%
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
Cost of call spread			$ 52,600
Purchase of note hedges			108,700
Proceeds from issuance of warrants			56,100
Percentage of principal amount used as purchase price upon occurrence of fundamental change				100.00%
0.125% Convertible Senior Notes Issued in Exchange for 1 Percent Notes [Member]
Convertible Debt [Abstract]
Face amount of offering			439,300
0.125% Convertible Senior Notes Issued under Subscription Agreements [Member]
Convertible Debt [Abstract]
Face amount of offering			109,500
1% Notes [Member]
Convertible Debt [Abstract]
Principal amount repurchased		247,900	$ 375,600		$ 247,900
Repurchase of convertible notes	$ 62,000	$ 257,000
Interest rate		1.00%	1.00%	1.00%	1.00%	1.00%
Loss on early retirement of debt		$ 8,600

Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Research, Development and Patent Expenses [Abstract]
Patent expenses	$ 4.7	$ 5.3	$ 4.1

Income Taxes, Tax Credit Carryforwards (Details) $ in Millions	Dec. 31, 2022 USD ($)
Federal [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	$ 242.8
Federal [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	224.9
California [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	461.3
California [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	$ 110.7

Organization and Significant Accounting Policies (Policies)

12 Months Ended

Dec. 31, 2022

Organization and Significant Accounting Policies [Abstract]

Basis of Presentation

Use of Estimates

Revenue Recognition

Steps to Recognize Revenue

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.

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.

Determine the transaction price

Allocate the transaction price

●

Estimated future product sales;

●

Estimated royalties we may receive from future product sales;

●

Estimated contractual milestone payments we may receive;

●

Estimated expenses we may incur;

●

Estimated income taxes; and

●

A discount rate.

●

The estimated number of internal hours 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.

Recognize revenue

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:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

If the goods and/or services are sold at a stand-alone selling price.

Multiple 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.

Our Revenue Sources

The following are sources of revenue and when we typically recognize revenue.

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.

Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

Research and development revenue under collaboration agreements

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.

Eplontersen Collaboration with AstraZeneca

We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca are performing, (iii) the co-commercialization activities that we and AstraZeneca are performing and (iv) the co-medical affairs activities that we and AstraZeneca are performing.

We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration and therefore do not have a vendor-customer relationship. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 development program, we made an accounting policy election to recognize as non-customer revenue the cost-share funding from AstraZeneca, net of our share of AstraZeneca’s development expenses, in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we made an accounting policy election to recognize cost-share funding we receive from AstraZeneca related to commercial and medical affairs activities as reductions of our SG&A expense and R&D expense, respectively.

Contracts Receivable

Unbilled SPINRAZA Royalties

Deferred Revenue

Cost of Sales

Research, Development and Patent Expenses

Income Taxes

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Basic and Diluted Net Loss per Share

Basic net loss per share

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

Diluted net loss per share

●

0.125 percent convertible senior notes, or 0.125% Notes;

●

Note hedges related to the 0.125% Notes;

●

1 percent convertible senior notes, or 1% Notes;

●

Dilutive stock options;

●

Unvested restricted stock units, or RSUs;

●

Unvested performance restricted stock units, or PRSUs; and

●

Employee Stock Purchase Plan, or ESPP.

For the years ended December 31, 2022 and 2021, common stock underlying the following would also have had an anti-dilutive effect on net loss per share:

●

0 percent convertible senior notes, or 0% Notes; and

●

Note hedges related to the 0% Notes.

Stock-Based Compensation Expense

Stock Options and Stock Purchase Rights:

RSU’s:

PRSU’s:

Refer to Part IV, Item 15, Note 5, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Noncontrolling Interest in Akcea Therapeutics, Inc.

Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2022			2021			2020
Beginning balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)
Unrealized gains (losses) on securities, net of tax (1)		(24,395	)		(11,486	)		3,729
Currency translation adjustment		(417	)		(111	)		617
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			—			(127	)
Net other comprehensive income (losses) for the year		(24,812	)		(11,597	)		4,219
Ending balance accumulated other comprehensive loss	$	(57,480	)	$	(32,668	)	$	(21,071	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2022, 2021 and 2020.

Concentration of Credit Risk

Fair Value Measurements

Cash, Cash Equivalents and Investments

Inventories

Our inventory consisted of the following (in thousands):

	December 31,
	2022		2021
Raw materials:
Raw materials- clinical	$	17,061	$	14,507
Raw materials- commercial		2,699		4,139
Total raw materials		19,760		18,646
Work in process		2,109		5,770
Finished goods		164		390
Total inventory	$	22,033	$	24,806

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful		December 31,
	Lives (in years)		2022			2021
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	74,351		$	72,802
Building, building improvements and building systems	15 to 40			41,158			144,046
Land improvements		20		-			10,077
Leasehold improvements	5 to 15			28,357			20,144
Furniture and fixtures	5 to 10			9,575			10,591
				153,441			257,660
Less accumulated depreciation				(87,716	)		(102,653	)
				65,725			155,007
Land				8,569			23,062
Total			$	74,294		$	178,069

Estimated Liability for Clinical Development Costs

Recently Adopted Accounting Standards

We do not expect any other recently issued accounting standards to have a material impact to our financial results.

CONSOLIDATED BALANCE SHEETS - USD ($) $ in Thousands	Dec. 31, 2022	Dec. 31, 2021
Current assets:
Cash and cash equivalents	$ 276,472	$ 869,191
Short-term investments	1,710,397	1,245,782
Contracts receivable	25,538	61,896
Inventories	22,033	24,806
Other current assets	168,254	143,374
Total current assets	2,202,694	2,345,049
Property, plant and equipment, net	74,294	178,069
Right-of-use assets	181,544	17,974
Deposits and other assets	75,344	70,598
Total assets	2,533,876	2,611,690
Current liabilities:
Accounts payable	17,921	11,904
Accrued compensation	49,178	38,810
Accrued liabilities	140,101	88,560
Income taxes payable	6,249	36
Current portion of deferred contract revenue	90,577	97,714
Other current liabilities	7,535	3,526
Total current liabilities	311,561	240,550
Long-term deferred contract revenue	287,768	351,879
Long-term lease liabilities	178,941	19,432
Long-term mortgage debt	8,847	59,713
Long-term obligations	7,126	6,946
Total liabilities	1,960,989	1,839,953
Stockholders' equity:
Common stock, $0.001 par value; 300,000,000 shares authorized, 142,057,736 and 141,210,015 shares issued and outstanding at December 31, 2022 and December 31, 2021, respectively	142	141
Additional paid-in capital	2,059,850	1,964,167
Accumulated other comprehensive loss	(57,480)	(32,668)
Accumulated deficit	(1,429,625)	(1,159,903)
Total stockholders' equity	572,887	771,737
Total liabilities and stockholders' equity	2,533,876	2,611,690
0 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net	622,242	619,119
0.125 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net	$ 544,504	$ 542,314

Income Taxes, Reconciliation of Statutory to Effective Tax Rate (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Reconciliation Between Effective and Statutory Tax Rate [Abstract]
Pre-tax income (loss)	$ (257,985)	$ (29,148)	$ (134,552)
Statutory rate	(54,177)	(6,121)	(28,256)
State income tax net of federal benefit	(13,622)	4,278	(37,705)
Foreign	(49)	143	49
Net change in valuation allowance	104,951	2,885	460,898
Loss on debt transactions	0	262	0
Tax credits	(39,729)	(23,198)	(18,774)
Deferred tax true-up	(20)	(24)	(206)
Tax rate change	(3,091)	12,838	(32,951)
Non-deductible compensation	3,023	5,085	7,931
Other non-deductible items	57	84	193
Stock-based compensation	14,030	4,720	17,435
Impacts from Akcea Merger	0	0	(22,032)
Other	364	(1,503)	(1,391)
Total income tax expense (benefit)	$ 11,737	$ (551)	$ 345,191
Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]
Statutory rate	21.00%	21.00%	21.00%
State income tax net of federal benefit	5.30%	(14.70%)	28.00%
Foreign	0.00%	(0.50%)	0.00%
Net change in valuation allowance	(40.70%)	(9.90%)	(342.50%)
Loss on debt transactions	0.00%	(0.90%)	0.00%
Tax credits	15.40%	79.60%	14.00%
Deferred tax true-up	0.00%	0.10%	0.20%
Tax rate change	1.20%	(44.00%)	24.50%
Non-deductible compensation	(1.20%)	(17.40%)	(5.90%)
Other non-deductible items	0.00%	(0.30%)	(0.10%)
Stock-based compensation	(5.40%)	(16.20%)	(13.00%)
Impacts from Akcea Merger	0.00%	0.00%	16.40%
Other	(0.10%)	5.10%	0.90%
Effective rate	(4.50%)	1.90%	(256.50%)

Collaborative Arrangements and Licensing Agreements, PTC Therapeutics (Details)	12 Months Ended
	Dec. 31, 2022
PTC Therapeutics [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of each medicine from PTC	20.00%

Organization and Significant Accounting Policies, Deferred Revenue (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021
Deferred Revenue [Abstract]
Revenue recognized from amounts in beginning deferred revenue balance	$ 73.5	$ 98.1

Income Taxes, Income (Loss) Before Income Taxes (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Income Taxes [Abstract]
United States	$ (258,493)	$ (29,966)	$ (137,222)
Foreign	508	818	2,670
Loss before income tax benefit (expense)	$ (257,985)	$ (29,148)	$ (134,552)

- Definition

Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
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Reference 2: http://www.xbrl.org/2003/role/disclosureRef
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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
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Reference 5: http://www.xbrl.org/2003/role/disclosureRef
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Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef
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Reference 8: http://www.xbrl.org/2003/role/disclosureRef
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Reference 9: http://www.xbrl.org/2003/role/exampleRef
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-Name Accounting Standards Codification
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+ Details

Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($) $ in Thousands	Dec. 31, 2022	Dec. 31, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019
Long-Term Obligations [Abstract]
Lease liabilities	$ 186,156	$ 22,058
Mortgage debt	8,998	60,054
Other obligations	7,295	7,505
Total	1,369,195	1,251,050
Less: current portion	(7,535)	(3,526)
Total Long-Term Obligations	1,361,660	1,247,524
0 Percent Convertible Senior Notes [Member]
Long-Term Obligations [Abstract]
Convertible senior notes	$ 622,242	$ 619,119
Interest rate on convertible senior notes	0.00%	0.00%	0.00%		0.00%
0.125 Percent Convertible Senior Notes [Member]
Long-Term Obligations [Abstract]
Convertible senior notes	$ 544,504	$ 542,314
Interest rate on convertible senior notes	0.125%	0.125%		0.125%	0.125%

Organization and Significant Accounting Policies (Tables)

12 Months Ended

Dec. 31, 2022

Organization and Significant Accounting Policies [Abstract]

Basic Net Loss per Share

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

Changes in Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2022			2021			2020
Beginning balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)
Unrealized gains (losses) on securities, net of tax (1)		(24,395	)		(11,486	)		3,729
Currency translation adjustment		(417	)		(111	)		617
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			—			(127	)
Net other comprehensive income (losses) for the year		(24,812	)		(11,597	)		4,219
Ending balance accumulated other comprehensive loss	$	(57,480	)	$	(32,668	)	$	(21,071	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2022, 2021 and 2020.

Inventory

Our inventory consisted of the following (in thousands):

	December 31,
	2022		2021
Raw materials:
Raw materials- clinical	$	17,061	$	14,507
Raw materials- commercial		2,699		4,139
Total raw materials		19,760		18,646
Work in process		2,109		5,770
Finished goods		164		390
Total inventory	$	22,033	$	24,806

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful		December 31,
	Lives (in years)		2022			2021
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	74,351		$	72,802
Building, building improvements and building systems	15 to 40			41,158			144,046
Land improvements		20		-			10,077
Leasehold improvements	5 to 15			28,357			20,144
Furniture and fixtures	5 to 10			9,575			10,591
				153,441			257,660
Less accumulated depreciation				(87,716	)		(102,653	)
				65,725			155,007
Land				8,569			23,062
Total			$	74,294		$	178,069

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2022		2021
Clinical expenses	$	116,460	$	65,730
In-licensing expenses		7,945		8,044
Commercial expenses		3,498		2,471
Other miscellaneous expenses		12,198		12,315
Total accrued liabilities	$	140,101	$	88,560

Organization and Significant Accounting Policies, Segment Information (Details) - Segment	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2020
Segment Information [Abstract]
Number of operating segments	1	2

Legal Proceedings (Details) - John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al. [Member] $ in Millions			12 Months Ended
	Jun. 03, 2022 USD ($)	Aug. 05, 2021 Plaintiff	Dec. 31, 2022 USD ($)
Legal Procedings [Abstract]
Number of plaintiffs \| Plaintiff		4
Settlement agreement	$ 12.5
Other Expense [Member]
Legal Procedings [Abstract]
Net settlement expense			$ 7.7

Fourth Quarter Financial Data (Unaudited) (Tables)

12 Months Ended

Dec. 31, 2022

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

Three Months Ended December 31,	2022			2021
Revenue (1)	$	151,890		$	440,006
Operating expenses (2)	$	359,909		$	219,403
Income (loss) from operations	$	(208,019	)	$	220,603
Net income (loss) (3)	$	(52,430	)	$	224,613
Basic net income (loss) per share (4) (5)	$	(0.37	)	$	1.59
Diluted net income (loss) per share (4) (6)	$	(0.37	)	$	1.41

________________

(1)	Revenue was lower in the three months ended December 31, 2022 compared to the same period in 2021 due to the $200 million we earned in the fourth quarter of 2021 from AstraZeneca to jointly develop and commercialize eplontersen.

(2)	Operating expenses were higher in the three months ended December 31, 2022 compared to the same period in 2021 primarily due to the $80 million upfront payment we made for our collaboration with Metagenomi in the fourth quarter of 2022.

(3)	Our net loss for the three months ended December 31, 2022 includes the $150.1 million gain we recognized from the sale and leaseback transaction for our headquarters in Carlsbad, California.

(4)	We compute net income (loss) per share independently for each quarter during the year.

(5)	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) by our weighted-average number of common shares outstanding during the period.

(6)	We had net income for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):

Three Months Ended December 31, 2021	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	224,612		141,205	$	1.59
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		46
Shares issuable upon restricted stock award issuance		—		1,065
Shares issuable related to our ESPP		—		34
Shares issuable related to our 0 percent convertible notes		777		10,936
Shares issuable related to our 0.125 percent convertible notes		716		6,590
Shares issuable related to our 1 percent convertible notes		105		464
Income available to Ionis common stockholders, plus assumed conversions	$	226,210		160,340	$	1.41

CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($) shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021	Dec. 31, 2020
Revenue:
Revenue	$ 587,367	$ 810,456	$ 729,264
Expenses:
Cost of sales	14,116	10,842	11,947
Research, development and patent	833,147	643,453	535,077
Selling, general and administrative	150,295	186,347	354,322
Total operating expenses	997,558	840,642	901,346
Loss from operations	(410,191)	(30,186)	(172,082)
Other income (expense):
Investment income	25,331	10,044	30,562
Interest expense	(8,122)	(9,349)	(9,510)
Gain (loss) on investments	(7,333)	10,103	16,540
Gain on sale of real estate assets	149,604	0	0
Other expenses	(7,274)	(9,760)	(62)
Loss before income tax benefit (expense)	(257,985)	(29,148)	(134,552)
Income tax benefit (expense)	(11,737)	551	(345,191)
Net loss	(269,722)	(28,597)	(479,743)
Net loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.	0	0	35,480
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (269,722)	$ (28,597)	$ (444,263)
Basic net loss per share (in dollars per share)	$ (1.9)	$ (0.2)	$ (3.18)
Shares used in computing basic net loss per share (in shares)	141,848	141,021	139,612
Diluted net loss per share (in dollars per share)	$ (1.9)	$ (0.2)	$ (3.18)
Shares used in computing diluted net loss per share (in shares)	141,848	141,021	139,612
Commercial Revenue [Member]
Revenue:
Revenue	$ 303,358	$ 342,395	$ 364,699
SPINRAZA Royalties [Member]
Revenue:
Revenue	242,314	267,776	286,583
TEGSEDI and WAYLIVRA Revenue, Net [Member]
Revenue:
Revenue	30,051	55,500	69,999
Licensing and Other Royalty Revenue [Member]
Revenue:
Revenue	30,993	19,119	8,117
Research and Development Revenue [Member]
Revenue:
Revenue	284,009	468,061	364,565
Collaborative Agreement Revenue [Member]
Revenue:
Revenue	207,222	468,061	364,565
Eplontersen Joint Development Revenue [Member]
Revenue:
Revenue	$ 76,787	$ 0	$ 0

Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2022	Dec. 31, 2021
Deferred Tax Assets [Abstract]
Net operating loss carryovers	$ 87,802	$ 85,600
Tax credits	277,436	269,538
Deferred revenue	85,700	104,330
Stock-based compensation	86,983	86,611
Intangible and capital assets	104,649	92,542
Convertible debt	34,384	45,681
Interest expense limitation	0	6,996
Capitalized research and development expenses	119,635	0
Long-term lease liabilities	45,612	5,119
Other	15,813	9,929
Total deferred tax assets	858,014	706,346
Deferred Tax Liabilities [Abstract]
Fixed assets	(4,475)	(3,303)
Right-of-use assets	(44,504)	(4,159)
Other	(313)	(1,111)
Net deferred tax asset	808,722	697,773
Valuation allowance	(808,722)	(697,773)
Total net deferred tax assets and liabilities	0	$ 0
Increase in valuation allowance	$ 111,000

Long-Term Obligations and Commitments, Financing Arrangements (Details) $ in Thousands	1 Months Ended		2 Months Ended	12 Months Ended
	Oct. 31, 2022 USD ($) Agreement Lot	Jul. 31, 2017 USD ($) Facility	Feb. 22, 2023 USD ($)	Dec. 31, 2022 USD ($) Lot	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)
Operating Facilities [Abstract]
Number of purchased facilities financed with mortgage debt \| Facility		2
Number of purchase and sale agreements entered into with real estate investor \| Agreement	2
Proceeds from sale of real estate assets				$ 254,083	$ 0	$ 0
Payment of mortgage debt				$ 50,686	$ 0	$ 0
Long-term Mortgage Debt [Member]
Operating Facilities [Abstract]
Face amount		$ 60,400
Primary R&D Facility Mortgage [Member]
Operating Facilities [Abstract]
Period to make interest only payments on mortgage loan				5 years
Payment of mortgage debt	$ 51,300
Manufacturing Facility Mortgage [Member]
Operating Facilities [Abstract]
Period to make interest only payments on mortgage loan				5 years
Primary R&D Facility [Member]
Operating Facilities [Abstract]
Payment to acquire building		$ 79,400
Interest rate		3.88%
Manufacturing Facility [Member]
Operating Facilities [Abstract]
Payment to acquire building		$ 14,000
Interest rate		4.20%
Headquarters Location in Carlsbad, California [Member]
Operating Facilities [Abstract]
Number of lots of undeveloped land included in purchase and sale agreement \| Lot				2
Proceeds from sale of real estate assets	$ 263,400
Undeveloped Land in Carlsbad, California [Member]
Operating Facilities [Abstract]
Number of lots of undeveloped land included in purchase and sale agreement \| Lot	2
Undeveloped Land in Carlsbad, California [Member] \| Forecast [Member]
Operating Facilities [Abstract]
Proceeds from sale of real estate assets			$ 33,000

Organization and Significant Accounting Policies, Convertible Debt (Details) - Note	Dec. 31, 2022	Dec. 31, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019
Convertible Debt [Abstract]
Number of outstanding convertible notes	2
0 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes	0.00%	0.00%	0.00%		0.00%
0.125 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes	0.125%	0.125%		0.125%	0.125%

Long-Term Obligations and Commitments, Operating Leases (Details) $ in Thousands	1 Months Ended		12 Months Ended
	Sep. 30, 2022 Lease	Jan. 31, 2022 USD ($)	Dec. 31, 2022 USD ($) Lot Option	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)
Operating Leases [Abstract]
Lease payments to be made over initial term of lease			$ 299,594
Right-of-use operating lease assets			181,544	$ 17,974
Operating lease liabilities			$ 186,156	22,058
Weighted average remaining lease term			13 years 9 months 18 days
Weighted average discount rate			6.90%
Operating lease cash payments			$ 4,000	$ 3,300	$ 3,800
Carlsbad Facility [Member]
Operating Leases [Abstract]
Number of options to extend lease \| Option			1
Term of lease extension			5 years
Carlsbad Office Spaces [Member]
Operating Leases [Abstract]
Number of leases that were extended \| Lease	1
Number of options to extend lease \| Option			0
Headquarters Location in Carlsbad, California [Member]
Operating Leases [Abstract]
Initial term of operating lease			15 years
Number of options to extend lease \| Option			2
Term of lease extension			5 years
Lease payments to be made over initial term of lease			$ 280,000
Number of lots of undeveloped land included in purchase and sale agreement \| Lot			2
Development Chemistry and Manufacturing Facility in Oceanside, California [Member]
Operating Leases [Abstract]
Initial term of operating lease			20 years 3 months
Number of options to extend lease \| Option			2
Term of lease extension			10 years
Boston Office Space [Member]
Operating Leases [Abstract]
Initial term of operating lease			123 months
Term of lease extension			5 years
Period of free rent under lease			3 months
Subleased Office Space in Boston [Member]
Operating Leases [Abstract]
Term of sublease		83 months
Period of free rent under sublease		7 months
Lease payments to be received over term of sublease		$ 9,600
Another Office Space in Boston [Member]
Operating Leases [Abstract]
Initial term of operating lease			91 months
Number of options to extend lease \| Option			1
Term of lease extension			5 years
Period of free rent under lease			7 months
Lease payments to be made over initial term of lease			$ 6,800