FORWARD-LOOKING STATEMENTS
This report on Form 10-K and the information incorporated herein by reference includes forward-looking statements regarding our business and the therapeutic and commercial potential of SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen) and our technologies and productscommercial medicines, additional medicines in development including the business of Akcea Therapeutics, Inc., our wholly owned subsidiary.and technologies. Any statement describing our goals, expectations, financial or other projections, intentions or beliefs, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those related to the impact of COVID-19 could have on our business, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in this report on Form 10-K, including those identified in Item 1A entitled “Risk Factors”. Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements.
In this report, unless the context requires otherwise, “Ionis,” “Company,” “we,” “our,” and “us” refers to Ionis Pharmaceuticals, Inc. and its subsidiaries.
Summary of Risk Factors
There are a number of risks related to our business and our securities. Below is a summary of material factors that make an investment in our securities speculative or risky. Importantly, this summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, as well as other risks that we face, can be found in this report on Form 10-K in Item 1A entitled “Risk Factors.”Factors”:
| ● |
| ● |
| ● | Our and our partners’ ability to compete effectively; |
| ● | Our ability to successfully manufacture our medicines; |
| ● |
| ● |
| ● |
| ● |
| ● |
| ● | The impacts of pandemics, climate change, wars and other global events. |
TRADEMARKS
“Ionis,” the Ionis logo, and other trademarks or service marks of Ionis Pharmaceuticals, Inc. appearing in this report are the property of Ionis Pharmaceuticals, Inc. “Akcea,” the Akcea logo, and other trademarks or service marks of Akcea Therapeutics, Inc. appearing in this report are the property of Akcea Therapeutics, Inc,Inc., Ionis’ wholly owned subsidiary. This report contains additional trade names, trademarks and service marks of others, which are the property of their respective owners. Solely for convenience, trademarks and trade names referred to in this report may appear without the ® or TM symbols.
CORPORATE INFORMATION
We incorporated in California in 1989 and in January 1991 we changed our state of incorporation to Delaware. In December 2015, we changed our name to Ionis Pharmaceuticals, Inc. from Isis Pharmaceuticals, Inc. Our principal offices are in Carlsbad, California. In December 2014, we formed Akcea Therapeutics, Inc., as a Delaware corporation, with its principal office in Boston, Massachusetts. Prior to Akcea’s initial public offering, or IPO, in July 2017, we owned 100 percent of Akcea’s stock. In October 2020, we acquired the remaining shares of Akcea.
We make available, free of charge, on our website, www.ionispharma.com, our reports on Forms 10-K, 10-Q, 8-K and amendments thereto, as soon as reasonably practicalpracticable after we file such materials with, or furnish such materials to, the Securities and Exchange Commission.Commission, or SEC. Periodically, we provide updates about the company in the Newsroom section of the Investors & Media page of our website. Any information that we include on or link to our website is not a part of this report or any registration statement that incorporates this report by reference.
FORM 10-K
For the Fiscal Year Ended December 31, 20202023
Table of Contents
| Page | ||
| Item 1. | 4 | |
| Item 1A. | ||
| Item 1B. | ||
| Item 1C. | 65 | |
| Item 2. | ||
| Item 3. | ||
| Item 4. | ||
| Item 5. | ||
| Item 6. | ||
| Item 7. | ||
| Item 7A. | ||
| Item 8. | 79 | |
| Item 9. | 79 | |
| Item 9A. | ||
| Item 9B. | ||
| Item 9C. | 82 | |
| Item 10. | ||
| Item 11. | ||
| Item 12. | ||
| Item 13. | ||
| Item 14. | ||
| Item 15. | ||
| 91 |
Overview
We currently have five marketed medicines address a broad range of diseases. We are primarily focused on two core franchises: neurology and cardiometabolic. Our commercial productsto treat serious diseases: SPINRAZA (nusinersen), QALSODY (tofersen), WAINUA (eplontersen), TEGSEDI (inotersen) and WAYLIVRA are approved(volanesorsen). We also have a rich innovative late- and mid-stage pipeline in major markets around the world. Within our late-stage pipeline, weneurology, cardiology and other areas of high patient need. We currently have sixnine medicines in Phase 3 studies underway with five medicines: tofersen for SOD1-ALS, tominersen for Huntington’s disease, IONIS-TTR-LRx for transthyretin, or TTR, amyloidosis, IONIS-APOCIII-LRx for familial chylomicronemia syndrome, or FCS,development and pelacarsen for lipoprotein(a), or Lp(a), driven cardiovascular disease.multiple additional medicines in early and mid-stage development.
We accomplished all of this and achieved our 2020 financial guidance, with while earning revenues of $729.3$788 million for 2023 and ending the year with a year-end cash and short-term investment balance of $1.9 billion, even in the challenging COVID-19 pandemic environment.
$2.3 billion. Our multiple sources of revenue provide us with substantial financial strength. Our financial strength enablesand capital structure enable us to execute on our capital allocation strategy, which is focused on internal investmentcontinue investing in three key areas: our wholly owned pipeline, building our commercial capabilitiesreadiness efforts for multiple late-stage programs, our innovative pipeline and broadening the reach of our technology. WeBy continuing to focus on these priorities, we believe investing in these areas moves us closerwe are well positioned to our goal of 12 or more marketed products in 2026drive future growth and will drive the greatestto bring next-level value forto patients and shareholders.
SPINRAZA is the global foundation-of-caremarket leader for the treatment of patients of all ages with spinal muscular atrophy, or SMA, a progressive, debilitating and often fatal genetic disease. Our partner, Biogen, our partneris responsible for commercializing SPINRAZA worldwide, reported that as of December 31, 2020, over 11,000 patients were on SPINRAZA therapy in markets around the world. SPINRAZA is approved in over 50 countries with formal reimbursement in over 40 countries.worldwide. From inception through December 31, 2020,2023, we have earned $1.3more than $2.1 billion in revenues from our SPINRAZA collaboration, including more than $930 million$1.6 billion in royalties on sales of SPINRAZA.
QALSODY is an antisense medicine that received accelerated approval in April 2023 from the FDA for the treatment of adult patients with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS, a rare, neurodegenerative disorder that causes progressive loss of motor neurons leading to death. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. The European Medicines Agency, or EMA, is currently reviewing QALSODY for approval in the European Union, or EU.
WAINUA is a once monthly, self-administered subcutaneous LIgand-Conjugated Antisense, or LICA, medicine that received FDA approval in December 2023 for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTRv-PN, a debilitating, progressive, and fatal disease. WAINUA is the only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector. We and AstraZeneca are commercializing WAINUA in the U.S. with the launch having commenced in January 2024. We and AstraZeneca are seeking regulatory approval for WAINUA in Europe and other parts of the world. AstraZeneca has exclusive rights to commercialize WAINUA outside of the U.S.
TEGSEDI is a once weekly, self-administered subcutaneous medicine approved in the U.S., Europe, Canada and Brazil for the treatment of patients with polyneuropathy caused by hereditary TTR amyloidosis, or hATTR, a debilitating, progressive, and fatal disease. As of December 31, 2020, TEGSEDI was commercially available in 15 countries. In 2021, we began sellingATTRv-PN. We sell TEGSEDI in the U.S. and Canada (collectively, North America) and Europe through aour distribution modelagreement with Swedish Orphan Biovitrum AB, or Sobi. In October 2023, our agreement for TEGSEDI in North America was terminated. As a result, Sobi is transitioning responsibilities to us. In February 2024, we began the process to withdraw the TEGSEDI New Drug Application, or NDA. In Latin America, PTC Therapeutics International Limited, or PTC, through its exclusive license agreement with us, is commercializing TEGSEDI in Brazil and is working towardspursuing access in additional Latin American countries.countries through its exclusive license agreement with us.
WAYLIVRA is a once weekly, self-administered, subcutaneous medicine that received conditional marketing authorizationapproved in May 2019 from the European Commission, or EC,Europe and Brazil as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis. We launchedsell WAYLIVRA in the EUEurope through our distribution agreement with Sobi. In Latin America, PTC is commercializing WAYLIVRA in the third quarter of 2019. In 2021, we began selling WAYLIVRABrazil for two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through a distributor, Sobi. Through ourits exclusive license agreement with PTC, we are working to expand access to WAYLIVRA across Latin America, beginning in Brazil. In the second quarter of 2020, PTC submitted the WAYLIVRA marketing application for approval in Brazil to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária), or ANVISA.us.
Medicines in Registration and Phase 3 Studies
We advanced our pipeline ofcurrently have nine medicines that we believe will pioneer new markets and change standards of care. Ourin registration or Phase 3 medicines include:studies for eleven indications, which are:
Olezarsen is our medicine in development for FCS, an ultra-rare indication and severe hypertriglyceridemia, or SHTG, a much broader indication. In September 2023, we reported positive results from the Phase 3 Balance study in patients with FCS showing statistically significant triglyceride lowering and a substantial reduction in acute pancreatitis events in addition to a favorable safety and tolerability profile. Based on our positive Phase 3 results in FCS patients we are preparing regulatory submissions to the FDA and EMA. In January 2023, the FDA granted fast track designation to olezarsen for the treatment of patients with FCS. Additionally, we are currently conducting a broad Phase 3 development program for olezarsen for the treatment of SHTG including three Phase 3 studies supporting development (CORE, CORE2 and ESSENCE). In February 2024, the FDA granted Breakthrough Therapy designation and orphan drug designation to olezarsen for the treatment of FCS. Additionally, in January 2023, the FDA granted olezarsen Fast Track designation for the treatment of patients with FCS.
Donidalorsen is our medicine in development for hereditary angioedema, or HAE.In January 2024, we reported positive data from the Phase 3 OASIS-HAE study in patients treated every four weeks or patients treated every eight weeks. We are currently conducting OASIS-Plus, our open-label study in patients who were either previously treated with other prophylactic therapies or who have completed OASIS-HAE. Throughout 2022 and 2023, we reported positive data from the Phase 2 study and Phase 2 open-label extension, or OLE, study, including two-year OLE data. In December 2023, we licensed European commercialization rights of donidalorsen to Otsuka Pharmaceutical Co., Ltd., or Otsuka. We are preparing to submit an NDA to the FDA. Otsuka is preparing to submit a Marketing Authorization Application, or MAA, to the EMA. In September 2023 and February 2024, the FDA and EMA, respectively, granted orphan drug designation to donidalorsen.
Zilganersen is our medicine in development for Alexander disease, or AxD. In September 2023, we advanced zilganersen into the Phase 3 portion of its ongoing study for patients with AxD. In September 2020 and October 2019, the FDA and EMA, respectively, granted orphan drug designation to zilganersen. Additionally in August 2020, the FDA granted rare pediatric designation to zilganersen.
Ulefnersen is our medicine in development for amyotrophic lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS. We are currently conducting a Phase 3 study of ulefnersen in juvenile and adult patients with FUS-ALS. In August 2023 and September 2023, the FDA and EMA, respectively, granted orphan drug designation to ulefnersen.
QALSODY (tofersen) is our medicine to treat patients with SOD1-ALS. In April 2023, the FDA granted Biogen accelerated approval of QALSODY for tominersen in April 2020
Pelacarsen is our medicine in development to treat patients with elevated lipoprotein(a), or Lp(a)-driven cardiovascular disease, or CVD. Novartis is developing pelacarsen, including conducting the ongoing Lp(a) HORIZON Phase 3 cardiovascular outcome study and in patients with elevated Lp(a)-driven CVD, which achieved full enrollment in July 2022 with more than 8,000 patients. In April 2020, the U.S. Food and Drug Administration, or FDA granted pelacarsen Fast Track Designation as a potential treatment for people at significant risk for cardiovascular disease duedesignation to elevated levelspelacarsen.
Our Marketed Medicines – Transformational Medicines Bringing–Bringing Value to Patients Today
SPINRAZA – SPINRAZA (nusinersen) injection for intrathecal use is a survival motor neuron-2, or SMN2, directed antisense medicine indicated for the treatment of SMA in pediatric and adult patients.
SPINRAZA continues to demonstrate substantial benefit in SMA patients of all ages, supporting its position as ais the global foundation of caremarket leader for the treatment of SMA.patients with SMA, a progressive, debilitating and often fatal genetic disease. Our partner, Biogen, our worldwide commercial partner, reported that as of December 31, 2020, there were more than 11,000 patients onis responsible for commercializing SPINRAZA therapy with approval in over 50 countries around the world.worldwide.
SMA is characterized by loss of motor neurons in the spinal cord and lower brain stem,stem. People with SMA have a deletion or defect in their SMN1 gene and rely on their SMN2 gene to produce functional SMN protein, which motor neurons need to maintain motor function and muscle strength. However, in untreated people the SMN2 gene can only produce approximately 10% of the SMN protein critical for motor neurons, resulting in severe and progressive muscular atrophy and weakness. Ultimately, if untreated, individuals with the most severe type of SMA, infantile-onset, or Type 1, SMA, can become paralyzed and have difficulty performing the basic functions of life, like breathing and swallowing. Due to a loss of or defect in, the SMN1 gene, people with SMA do not produce enough SMN protein, which is critical for the maintenance of motor neurons. function and strength.
The rate and severity of SMA correlates withdegeneration varies depending on the amount of functional SMN protein a patient can produce on his/her own. Patients withproduce. Type 1, or infantile-onset, SMA is the most severe form of the disease. Type 1 SMA patients produce very little SMN protein and do not achieveoften progress to death or permanent ventilation by the ability to sit without support or live beyond two years without respiratory support.age of 2. Patients with later-onset, or Type 2 or Type 3, or later-onset, SMA suffer from less severe, but still life-altering, forms of SMA. These patients produce greater amounts ofmore SMN protein, but also experiencesuffer from a progressive degeneration dueloss of muscle strength and function and a reduced life expectancy.
Biogen continues to expand the body of evidence supporting SPINRAZA’s durable efficacy and well-established safety profile to address the remaining needs of SMA patients of all ages. This includes the following ongoing studies:
DEVOTE: In the Phase 2/3 DEVOTE study, Biogen is evaluating the safety and potential to achieve increased efficacy with a higher dose of SPINRAZA compared to the disease.currently approved dose. In 2022, Biogen reported final data from Part A of the ongoing, three-part DEVOTE study. Results from Part A, an open-label safety evaluation period in children and teens with later-onset SMA, suggest that the higher dosing regimen of SPINRAZA leads to higher levels of the drug in the cerebrospinal fluid, or CSF, supporting further development of a higher dose of SPINRAZA. Additionally, the results indicated that SPINRAZA was generally well-tolerated.
RESPOND: In the Phase 4 RESPOND study, Biogen is evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to the gene therapy, onasemnogene abeparvovec. In 2023, Biogen presented interim results from the RESPOND study that showed improved motor function in most participants treated with SPINRAZA following treatment with onasemnogene abeparvovec.
ASCEND: In the Phase 3b ASCEND study, Biogen is evaluating the clinical outcomes and assessing the safety of a higher dose of SPINRAZA in children, teens and adults with later-onset SMA following treatment with risdiplam.
Additionally, Biogen continues to conduct the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA. NURTURE was the first study to investigate the potential to slow or stop SMA disease progression in presymptomatic SMA patients. In 2022, Biogen reported new NURTURE study data, showing that early and sustained treatment with SPINRAZA helped participants to maintain and/or make progressive gains in motor function. These data showed that after 11 months of additional follow-up since the 2020 interim analysis, all children who were able to walk alone maintained this ability and one child gained the ability to walk alone, increasing the total percentage of study participants able to walk from 92% to 96%. Further, most children achieved motor milestones within age-appropriate timelines and no major motor milestones were lost. The safety of SPINRAZA over this extended follow-up period was consistent with previously reported findings.
The approval of SPINRAZA was based on safetyefficacy and efficacysafety data from multiple clinical studies, including two randomized, placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an ongoing open label extension, or OLE study for patients with SMA who participated in prior SPINRAZA studies.
QALSODY – QALSODY (tofersen) is conducting DEVOTE,an antisense medicine used to treat ALS in adults who have a Phase 2/3 study evaluatingmutation in the safety and potential to achieve increased efficacy with a higher dose of SPINRAZA compared to the currently approved dose.superoxide dismutase 1, or SOD1, gene, or SOD1-ALS. The DEVOTE study is enrolling SMA patients of all ages, including adults. We and Biogen believe that SPINRAZA’s favorable long-term safety and tolerability profileFDA granted QALSODY accelerated approval based on reduction in plasma neurofilament light chain, or NfL, observed in over 11,000 SMA patients of all ages, with some patients treated with QALSODY. Continued approval for up to 7 years, supports evaluationthis indication may be contingent upon verification of higher SPINRAZA dosing.clinical benefit in confirmatory trial(s).
SOD1-In January 2021, ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the SOD1 gene leading to a progressive loss of motor neurons. As a result, people with SOD1-ALS experience increasing muscle weakness, loss of movement, difficulty breathing and swallowing and eventually succumb to the disease. Current treatment options for people with SOD1-ALS are extremely limited. It is estimated that there are approximately 1,400 patients with SOD1-ALS in the G7 countries (comprised of Canada, France, Germany, Italy, Japan, the United Kingdom and the U.S.).
Biogen initiatedis also evaluating QALSODY for treatment of presymptomatic individuals who have a SOD1 genetic mutation. See the global“Tofersen” description under “Our Phase 4 RESPOND3 Pipeline” section below for further information on the development program for presymptomatic individuals. Tofersen is one of three medicines we have in development to treat ALS.
QALSODY received accelerated approval from the U.S. FDA in April 2023 and is currently under regulatory review in the EU. The QALSODY NDA and MAA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the benefitPhase 3 VALOR study, and the Phase 3 OLE study, as well as 12-month integrated results from the Phase 3 VALOR study and the Phase 3 OLE study. The 12-month integrated data show that earlier initiation of SPINRAZAQALSODY, compared to delayed initiation, slowed declines in infantsclinical function, respiratory function, muscle strength and children with a suboptimal clinical response to the gene therapy, onasemnogene abeparvovec. RESPOND is a two-year, open-label study that Biogen is conducting at approximately 20 sites worldwidequality of life and is expecting to enroll approximately 60 children with SMA. The primary endpoint is the total scorebuild on the Hammersmith Infant Neurological Examination.results previously observed in the initial readout. The 12-month data compare patients with early initiation of QALSODY (at the start of VALOR) to those who had a delayed initiation of QALSODY (six months later, in the OLE).
33% and 21% reduction in SOD1 protein, the intended target for QALSODY, respectively
51% and 41% reduction in plasma neurofilament, a marker of neuron injury, respectively
QALSODY had a favorable safety and tolerability profile.
The FDA and EMA granted QALSODY orphan drug designation for the patientstreatment of ALS in the study were able to sit without supportSeptember 2016 and 96 percent of the patients were able to walk either with assistance or independently. No new safety concerns were identified.August 2016, respectively.
In NovemberDecember 2018, SPINRAZA was recognized with the International Prix Galien Best Biotechnology Product award. The prestigious honor marks the seventh Prix Galien awardBiogen exercised its option to license QALSODY. As a result, Biogen is responsible for SPINRAZA, following country recognitions in the U.S., Germany, Italy, Belgium-Luxembourg, the Netherlandsglobal development, regulatory and the U.K. The International Prix Galien award is given every two years by Prix Galien International Committee members in recognition of excellence in scientific innovation to improve human health.commercialization activities, and costs for QALSODY.
ATTR amyloidosis is a systemic, progressive and fatal disease in which patients experience multiple overlapping clinical manifestations caused by the inappropriate formation and aggregation of TTR amyloid deposits in various tissues and organs, including peripheral nerves, heart, intestinal track, and central nervous system. There are an estimated 250,000 people worldwide with TTR amyloidosis.
ATTRv-PN is caused by the normal functionaccumulation of these tissues. As themisfolded mutated TTR protein fibrils enlarge, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death. We designed TEGSEDI to reduce the production of the TTR protein, the underlying cause of hATTR.
Often, patients with ATTRv-PN will have TTR build up in the Prix Galien USA awardheart and experience cardiomyopathy symptoms. Similarly, patients with ATTR-CM may often have TTR build up in their peripheral nerves and experience nerve damage and a variety of symptoms, including progressive difficulty with motor functions. As a result, we are developing WAINUA to treat all types of ATTR. See the “WAINUA” description under “Our Phase 3 Pipeline” section below for the Best Biotechnology Product in 2020. TEGSEDI is the second offurther information on our products to receive this prestigious honor.development program for ATTR-CM.
Additionally, in April 2023, we presented positive data that WAINUA met all co-primary and secondary endpoints in the NEURO-TTRansform study at the final analysis at week 66. At week 66:
WAINUA achieved a LS mean reduction of 82% in serum TTR concentration from baseline, compared to an 11% reduction from baseline in the external placebo group (p<0.0001).
WAINUA stopped disease progression as measured by mNIS+7 resulting in a 0.28 point LS mean increase compared to a 25.06 point increase for the external placebo group from baseline (24.8 point LS mean improvement; p<0.0001).
WAINUA improved quality of life demonstrating a 5.5 point LS mean decrease (improvement) on the Norfolk QoL-DN, compared to a 14.2 point increase (worsening) in the external placebo group (19.7 point LS mean improvement; p<0.0001).
And in July 2023, we reported that WAINUA continued to halt neuropathy disease progression and improve quality of life in patients with ATTRv-PN through the end of treatment analysis at week 85.
WAINUA is currently under regulatory review in the EU and other countries for the treatment of patients with ATTRv-PN.
In January 2022 and October 2023, the FDA and EMA, respectively, granted orphan drug designation to WAINUA for the treatment of ATTR.
In December 2021, we entered into an agreement with AstraZeneca to jointly develop and commercialize WAINUA in the U.S. We initially granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S., except for certain Latin American countries. In July 2018,2023, we expanded those rights to include Latin America.
TEGSEDI – TEGSEDI (inotersen) injection is an antisense medicine indicated for the final results fromtreatment of ATTRv-PN in adults. TEGSEDI prevents the NEURO-TTR pivotal study were published in The New England Journalproduction of Medicine.TTR protein, reducing the amount of amyloid buildup that damages organs and tissues.
TEGSEDI is commercially available in numerous countries, including the U.S., many European countries, Canada, and Latin America. We also conducted an OLElaunched TEGSEDI in the U.S. and EU in late 2018. In 2021, we began selling TEGSEDI in the U.S., Canada and Europe through our distribution agreement with Sobi. Refer to the section titled, Overview, for further details on our distribution agreement with Sobi. In Latin America, PTC is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.
The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with hATTR treated with TEGSEDI. This study was intended to evaluate the long-term efficacy and safety profileATTRv-PN.
WAYLIVRA – WAYLIVRA (volanesorsen) is an antisense medicine indicated as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for acute, potentially fatal pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.WAYLIVRA reduces triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein that is a key regulator of triglyceride levels.
FCS is a rare, genetic disease estimated to affect one to two individuals per million and characterized by extremely elevated triglyceride levels, that is estimated to affect 3,000 to 5,000 people worldwide.typically greater than 1,000 mg/dl. FCS can lead to many chronic health issues including severe, recurrent abdominal pain, fatigue, high risk of life-threatening pancreatitis and abnormal enlargement of the liver or spleen. In addition, people with FCS are often unable to work, adding to their disease burden. In severe cases, patients can have bleeding into the pancreas, serious tissue damage, infection, and cyst formation, as well as damage to other vital organs such as the heart, lungs, and kidneys.
WAYLIVRA reduces triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein that is a key regulator of triglyceride levels. People who have low levels of apoC-III or reduced apoC-III function have lower levels of triglycerides and a lower incidence of cardiovascular disease, or CVD. By inhibiting the production of apoC-III, WAYLIVRA is able to reduce triglyceride levels in people with high levels of triglycerides.
WAYLIVRA’s conditional marketing authorization in the EU for FCS and approval in Brazil for FCS were based on resultsefficacy and safety data from the Phase 3 APPROACH study, the ongoing APPROACH OLE study and supported by results from the Phase 3 COMPASS study. The pivotal APPROACH studyWAYLIVRA’s approval in Brazil for FPL was a one-year, randomized, placebo-controlled based on efficacy and safety data from the Phase 3 BROADEN study in 66 patients with FCS (average baseline triglycerides of 2,209 mg/dL, or 25.0 mmol/L). The study achieved its primary endpoint of reduction in triglycerides at three months, with a 77 percent mean reduction in triglycerides, which translated into a 1,712 mg/dL (19.3 mmol/L) mean absolute triglyceride reduction in WAYLIVRA-treated patients. We observed 50 percent of treated patients achieved triglyceride levels below 500 mg/dL, a commonly accepted threshold for pancreatitis risk. In addition, treatment with WAYLIVRA was associated with a statistically significant reduced rate of pancreatitis attacks in the group of patients who had the highest incidence of pre-study pancreatitis and reduced abdominal pain in patients reporting pain before treatment in the study. In August 2019, the final results from the APPROACH pivotal study were published in FPL.The New England Journal of Medicine.
Our Development Projects
The above table below lists the medicines in our clinical pipeline. We categorize patient studies to establish a medicine’s safety profile as Phase 1/2pipeline and those studies in healthy volunteers as Phase 1. The table includes the disease indication, athe partner (if the medicine is partnered), and the development status of each medicine. We categorize first-in-patient studies to establish a medicine’s safety profile as Phase 1/2 and in the table below these are listed in the Phase 2 column. Studies in patients that are designed to establish an investigational medicine’s proof of concept and additional safety profile are also listed in Phase 2. Pivotal studies designed to enable registrational filing for marketing authorization are listed in Phase 3. We have included descriptions for each of our medicines in Phase 2 and Phase 3 development below.
We entered into a collaboration with Roche to develop and commercialize antisensecurrently have nine medicines to treat HD in April 2013. In December 2017, Roche exercised its option to license tominersen. As a result, Roche is responsible for global development, regulatory and commercialization activities and costs for tominersen.our Phase 3 pipeline:
1Granted Otsuka exclusive rights to commercialize donidalorsen in Europe.
Eplontersen (TTR) – Eplontersen (TTR) – Eplontersen (formerlyIONIS-TTR-LRx – IONIS-TTR-LRx) is an investigational LICA medicine we designed to inhibit the production of transthyretin, the same protein inhibited by TEGSEDI (inotersen). There are two types of ATTR amyloidosis: hATTR amyloidosis and wt-ATTR amyloidosis. WeTTR protein. As discussed above under “WAINUA” in our “Marketed Medicines” section, we are developing IONIS-TTR-LRxeplontersen as a monthly self-administered subcutaneous injection forto treat all types of ATTR, including ATTR-CM.
ATTR-CM is caused by the treatmentaccumulation of peoplemisfolded TTR protein in the cardiac muscle. Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death within three to five years from disease onset. ATTR-CM includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to 500,000 patients with all formsATTR-CM worldwide.
Often, patients with ATTRv-PN will have TTR build up in the heart and experience cardiomyopathy symptoms. Similarly, patients with ATTR-CM may often have TTR build up in their peripheral nerves and experience nerve damage and a variety of TTR amyloidosis. See the TEGSEDI summary under “Our Marketed Medicines” section for more information about hATTR amyloidosis and wt-ATTR amyloidosis.symptoms, including progressive difficulty with motor functions.
In January 2022 and October 2023, the FDA and EMA, respectively, granted orphan drug designation to WAINUA for the treatment of cardiovascular death and frequencyATTR.
We are currently conducting a broad development program for olezarsen that includes the only medicine approvedPhase 3 Balance study in patients with FCS and three Phase 3 studies supporting development for the treatment of people with FCS. SeeSHTG: CORE, CORE2 and ESSENCE.
In September 2023, we reported positive topline data from the WAYLIVRA summary under “Our Marketed Medicines” section for more information about FCS.
We are also conducting ongoing Phase 2 data described below. We believe that3 studies for the enhancements offered by our LICA technology canexpanded SHTG patient population. CORE and CORE2 are global, multi-center, randomized, double-blind, placebo-controlled studies enrolling approximately 540 and 390 patients, respectively, designed to assess the efficacy, safety and tolerability of olezarsen in patients with SHTG. The CORE and CORE2 studies compare olezarsen to placebo in patients with triglyceride levels equal to or greater than 500 mg/dL who are on currently available therapies for elevated triglycerides. The primary endpoint of the studies is the percent change in fasting triglycerides from baseline at month six. Additionally, in November 2022, we initiated ESSENCE, a global, multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 1,300 patients to provide greater reductionsa robust safety database. The primary endpoint of the study is the percent change in fasting triglycerides significantly lower doses and less frequent administration, compared to WAYLIVRA.from baseline at month six.
In January 2020, we reported positive results from a Phase 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established CVD. Patients were treated with multiple doses of IONIS-APOCIII-LRx administered weekly, bi-weekly, or monthly. IONIS-APOCIII-LRxOlezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels. Additionally, at the highest monthly dose, 91 percent of patients achieved serum triglycerides of ≤ 150 mg/dL, the recognized threshold for cardiovascular risk, compared to less than 5 percent of patients in the placebo group. IONIS-APOCIII-LRxOlezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III, very low-density lipoprotein cholesterol,apoC-III. Olezarsen had a favorable safety and tolerability profile supportive of continued development.
In February 2024, the FDA granted Breakthrough Therapy designation and orphan drug designation to olezarsen for the treatment of FCS. Additionally, in January 2023, the FDA granted olezarsen Fast Track designation for the treatment of patients with FCS.
Donidalorsen (PKK)– Donidalorsen (formerly IONIS-PKK-LRx) is an investigational LICA medicine we designed to inhibit the production of prekallikrein, or VLDL-C,PKK. HAE is a rare genetic disease that is characterized by severe and remnant cholesterol,potentially fatal swelling of the arms, legs, face and throat. PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. By inhibiting the production of PKK, donidalorsen could be an effective prophylactic approach to preventing HAE attacks. It is estimated that there are more than 20,000 patients with HAE in the U.S. and Europe.
In January 2024, we reported positive topline data from the Phase 3 OASIS-HAE study in patients with HAE. The study met its primary efficacy endpoint with a statistically significant increasereduction in high-density lipoprotein cholesterol,the rate of HAE attacks in patients treated with 80 mg of donidalorsen via subcutaneous injection dosed every four weeks, or HDL-C. IONIS-APOCIII-LRxQ4W, (p<0.001) or every eight weeks, or Q8W, (p=0.004) compared to placebo. In addition, the trial showed donidalorsen achieved statistical significance on all secondary endpoints in the Q4W group and key secondary endpoints in the Q8W group. Donidalorsen demonstrated a favorable safety and tolerability profile in the study. Based on the positive results, we plan to file a NDA in 2024 with the U.S. FDA. Otsuka, which has exclusive rights to commercialize donidalorsen in Europe, is preparing to submit a Marketing Authorization Application to the European Medicines Agency, or EMA.
In May 2022, we initiated OASIS-Plus, a multi-center, open-label, global study in approximately 110 patients who were either previously treated with other prophylactic therapies or who have completed OASIS-HAE.
In 2021 and 2022 we reported positive results from the Phase 2 clinical study of donidalorsen in patients with HAE. And in 2022 and 2023, we presented positive results from the Phase 2 OLE study of donidalorsen in patients with HAE. Following the 13-week blinded, placebo-controlled Phase 2 study with a fixed 13-week dosing period where they received donidalorsen 80 mg every four weeks, patients were eligible for enrollment in the OLE study. Of the 20 Phase 2 study participants, 17 entered the OLE study and were on a fixed 13-week dosing period where they received 80 mg every four weeks. From week 17 through two years, patients entered a flexible dosing period where they either received donidalorsen 80 mg every four weeks, 80 mg every eight weeks, or 100 mg every four weeks.Over the two years, patients treated with donidalorsen via subcutaneous injection showed an overall sustained mean reduction in HAE attack rates of 96% from baseline, from 2.70 to 0.06 attacks per month, across all dosing groups. Furthermore, all patients treated with donidalorsen reported a clinically meaningful improvement in quality of life as measured by the Angioedema Quality of Life Questionnaire (AE-QoL) over two years. Donidalorsen had a favorable safety and tolerability profile in the study.
In September 2023 and February 2024, the FDA and EMA granted orphan drug designation to donidalorsen.
In December 2023, we granted Otsuka exclusive rights to commercialize donidalorsen in Europe.
Pelacarsen (Apo(a)) (IONIS-APO(a)-LRx or TQJ230)(TQJ230) – Pelacarsen (formerly IONIS-APO(a)-LRx) is an investigational LICA antisense medicine we designed to inhibit the production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD. Lp(a) levels are determined at birth and lifestyle modification, including diet and exercise, do not impact Lp(a) levels. It is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a). Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing cardiovascular diseaseCVD in people with hyperlipoproteinemia(a), a condition in which individuals have levels of Lp(a) greater than 50 mg/dL, the recognized threshold for risk of CVD.
We believe antisense technology is well suited to address hyperlipoproteinemia(a) because antisense technologyit specifically targets the RNA that codes for all forms of the Apo(a) molecule. Furthermore, we believe addressingIt is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a) is the next important horizon in CVD risk reduction..
In December 2019, Novartis initiated the Phase 3 Lp(a)HORIZON study of pelacarsen, a global, randomized, blinded, placebo-controlled outcomes studyLp(a) HORIZON, in approximately 7,500 patients with elevated Lp(a) levels and a prior cardiovascular event, based onevent. Lp(a) HORIZON is a global, multi-center, randomized, double-blind, placebo-controlled cardiovascular outcomes study in more than 8,000 patients designed to assess the Phase 2 data described below.efficacy, safety and tolerability of pelacarsen. Patients will beare treated with 80 mg of pelacarsen administered monthly by subcutaneous injection. The primary endpoint in Lp(a)HORIZON is the time to occurrence of first major adverse cardiovascular event, or MACE.In July 2022, we announced that the Lp(a) HORIZON study had completed enrollment.
Ulefnersen (FUS) (BIIB101) – ION464Ulefnersen (formerly ION363) is an investigational antisense medicine we designed to inhibitreduce the production of the alpha-synucleinFUS protein as a potential therapy for PD, Multiple System Atrophy, or MSA, and related synucleinopathies. Alpha-synuclein protein abnormally accumulatesto treat people with ALS caused by mutations in the brainsFUS gene. Because antisense-mediated reduction of PD and MSA patients and is thoughtmutant FUS protein in a FUS-ALS mouse model demonstrated the ability to be one of the key drivers of these diseases. It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations as well as the primary pathology in PD and MSA patients without alpha-synuclein mutations.
In August 2020, Bayer initiated2023 and September 2023, the Phase 2b RE-THINc clinical study of IONIS-FXI-LRx, a randomized, blinded, placebo-controlled study in approximately 290 patients with ESRD on hemodialysis. The study is designedFDA and EMA, respectively, granted orphan drug designation to evaluate multiple monthly doses administered subcutaneously. The primary endpoint is incidence of major bleeding and clinically relevant non-major bleeding. The study will also assess numerous secondary endpoints, and safety and tolerability of IONIS-FXI-LRx.
In October 2018, we announced data from a Phase 1/2 study of danvatirsen in combination with durvalumab in recurrent metastatic head and neck cancer. The combination treatment resulted in seven percent of patients achieving a complete tumor response and 23 percent achieving either a partial or complete tumor response. This response rate is estimated to be double that with durvalumab alone, based on previous studies in this difficult to treat patient population. Results from this study demonstrated a safety and tolerability profile supportive of continued development.
HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world.world, affecting nearly 300 million people and resulting in approximately 900,000 deaths annually. Currently available therapies, although effective in reducing circulating HBV in the blood, do not effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.
In January 2023, GSK reported results ofinitiated the Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV. B-Well 1 and B-Well 2 are global, multi-center, randomized, double-blind, placebo-controlled studies enrolling more than 500 patients each. GSK designed these studies to assess the efficacy, safety and tolerability of bepirovirsen. The arms will be stratified based on HBsAg levels at screening. The primary endpoint is the number of patients achieving functional cure with baseline HBsAg ≤ 1,000 IU/mL. Functional cure is defined as a sustained suppression (24 weeks or longer) of HBV DNA (< Lower Limit of Quantification, or LLOQ) while off all HBV treatments with HBsAg loss (<0.05 IU/mL) with or without HBsAg after a finite duration of therapy.
In June 2022, GSK presented positive results from the Phase 2b B-CLEAR study with IONIS-HBVRxof bepirovirsen in patients with chronic hepatitis B virusHBV infection. The end of study results showed that treatment with bepirovirsen in some patients resulted in sustained clearance of HBsAg and HBV DNA for 24 weeks after end of bepirovirsen treatment in people with chronic HBV infection. Treatment with bepirovirsen that was administered weekly at a dose of 300 mg per week for 24 weeks, with loading doses administered on day four and 11 (treatment arm 1), resulted in 9% of patients on NA treatment and 10% of patients not on NA treatment both achieving the primary outcome of HBsAg levels and HBV DNA levels below the LLOQ. This is defined as a sustained response and was observed for 24 weeks post last dose. Patients with low baseline HBsAg levels responded best to treatment with bepirovirsen with 16% and 25% of patients achieving the primary outcome in treatment arm one of the on NA and not on NA cohorts, respectively. Additionally in June 2023, GSK presented durable response data from the Phase 2 B-Sure long-term follow-up study of bepirovirsen in complete responder patients from the Phase 2b B-Clear study of patients with HBV. Bepirovirsen had a favorable safety and tolerability profile supportive of continued development.
In October 2023, GSK reported data from the B-Together Phase 2b study of bepirovirsen in patients with chronic HBV infection at the American Association forAASLD Liver Meeting. The data showed that between 9-15% of patients attained the Studyprimary outcome of Liver Diseases annual meeting in November 2019. In the Phase 2 study with IONIS-HBVRx, the medicine demonstrated target engagement with dose dependent declines in HBsAg with up to 3-log reductions in HBsAg at one month, including two patients who achieved reductions in HBsAg and HBV DNA below levelsthe LLOQ for 24 weeks after planned end of detection.sequential treatment with pegylated interferon, in the absence of newly initiated antiviral therapy. Additionally, IONIS-HBVRxall patients who achieved the primary endpoint had a baseline HBsAg ≤3000 IU/mL. Bepirovirsen demonstratedhad a favorable safety and tolerability profile.profile supportive of continued development.
In August 2019, GSK exercised its option to license our HBV program following the positive results of the Phase 2 results described above.2a study of bepirovirsen in patients with chronic HBV infection. As a result, GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.
In August 2020, GSK launched a broad Phase 2 program and initiatedFebruary 2024, the Phase 2b B-Clear clinical studyFDA granted bepirovirsen Fast Track designation for the treatment of IONIS-HBVRx in patients with chronic hepatitis B virus. The Phase 2b B-Clear study is a randomized, blinded, placebo-controlled study in approximately 440 patients with chronic hepatitis B virusHBV infection. The primary endpoint is the percentage of patients achieving HBV surface antigen and HBV DNA less than the lower limit of quantitation. The study will also assess multiple secondary endpoints and the safety and tolerability of IONIS-HBVRx.
IONIS-FB-LRx (IgAN) (RG6299)–IONIS-FB-LRx is an investigational LICA medicine we designed to inhibit the production of complement factor B, or FB. FB, is produced predominantly inand the liver and circulates at high levels throughout the vascular system where it plays a pivotal role in an innate immunogenic cascade.alternative complement pathway. Genetic association studies have shown that overactivityoveraction of this cascadethe alternative complement pathway has been associated with the development of several complement-mediated diseases, including dryIgAN. As discussed below under the “IONIS-FB-LRx” section in our “Other Medicines in Development” section, we are also developing IONIS-FB-LRx for GA, secondary to age-related macular degeneration, or AMD, and IgA nephropathy, or IgAN.AMD.
IgAN is one of the most common causes of inflammation that impairs the filtering ability of kidneys and is an important cause of chronic kidney disease and renalkidney failure. Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage.
In April 2023, Roche initiated a Phase 3 study of IONIS-FB-LRx, called IMAGINATION, in patients with IgAN. IMAGINATION is a multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 430 patients designed to assess the efficacy, safety and tolerability of IONIS-FB-LRx. The clinical presentation, disease progression and histologic findings are highly variable.primary endpoint is the change from baseline in the urine protein-to-creatinine ratio, or UPCR, at week 37.
In May 2017,November 2022, we reported datapresented positive results from a randomized, placebo-controlled, dose-escalationthe Phase 12 open-label study evaluatingof IONIS-FB-LRx in 54 healthy volunteers. Subjectspatients with IgAN at the American Society of Nephrology’s, or ASN, Kidney Week. In the Phase 2 study, which included results from the first 10 patients treated with IONIS-FB-LRx, IONIS-FB-LRx met its primary endpoint of change in 24-hour urinary protein, demonstrating a single dose44% mean reduction in proteinuria from baseline to week 29. Kidney function, as measured by estimated glomerular filtration rate, or eGFR, was maintained in all patients in the study. The results from the Phase 2 study provided proof-of-concept for the potential of IONIS-FB-LRx achieved dose-dependent reductionsto treat patients with IgAN by inhibiting complement FB and the alternative complement pathway. Additionally, in plasma FB of up to 50 percent. Treatment with multiple doses ofNovember 2023 at ASN Kidney Week, we presented new positive interim results from the ongoing Phase 2 study, which included results from 13 patients. The results showed that IONIS-FB-LRx during a six-week period resulted in greater reductions ineffectively and selectively reduced circulating FB, levels. In this study,Alternate Pathway Activity, or AH50 and urinary complement Ba. Additionally, IONIS-FB-LRx demonstratedreduced established proteinuria in patients with IgAN after six-months of treatment. The Phase 2 open-label study remains ongoing and will evaluate IONIS-FB-LRx in approximately 25 patients with IgAN. IONIS-FB-LRx had a favorable safety and tolerability profile.profile supportive of continued development.
In July 2022, Roche exercised its option to license IONIS-FB-LRx following the positive Phase 2 results described above. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-LRx, 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.
Our Neurological Medicines in Development
We have a leading neurology franchise that includes three approved medicines for serious neurological diseases and Rochea pipeline of investigational potential disease-modifying treatments for a broad range of neurological diseases. As we look to expand our wholly owned pipeline, we are collaboratingfocused on four pillars within our neurology franchise. We are first focusing on two areas: rare pediatric neurology and dementia, with plans to develop IONIS-FB-Lmove into neuromuscular and peripheral neuropathies and motor diseases and then common neurological diseases in the future. We recently added ION717 for prion disease to our pipeline with plans to add three additional medicines by the end of 2024.
Zilganersen – See the medicine description under “Our Phase 3 Pipeline” section above.
Ulefnersen – See the medicine description under “Our Phase 3 Pipeline” section above.
Tofersen – See the medicine description under “Our Phase 3 Pipeline” section above.
ION717 (PRNP)– ION717 is an investigational antisense medicine we designed to inhibit the production of prion protein, or PrP, for the potential treatment of prion disease. Prion disease is a rare, fatal neurodegenerative disease caused by misfolding of PrP which accumulates in the brain. People with prion disease often experience progressive memory impairment, personality changes, difficulties with movement and loss of independence. There are currently no effective disease-modifying treatments for prion disease. In most cases, a person succumbs to prion disease within a year following symptom onset.
In December 2023, we initiated the Phase 1/2, PrProfile, study of ION717 in patients with prion disease. The current study is a randomized, multi-center, double-blind, placebo-controlled study in approximately 55 patients designed to assess the safety, tolerability and pharmacokinetics of multiple dose levels of ION717 administered intrathecally.
IONIS-MAPTRx for(TAU) (BIIB080) – IONIS-MAPTRx is an investigational antisense medicine we designed to selectively inhibit production of the treatmentmicrotubule-associated protein tau (MAPT), or tau protein in the brain. We are developing IONIS-MAPTRx to treat people with Alzheimer’s disease, or AD.
AD is characterized predominantly by memory impairment and behavioral changes, resulting in a person’s inability to independently perform daily activities. AD generally occurs late in life and may progress to death in five to 20 years after the onset of complement-mediated diseases. the disease.
In June 2019, weDecember 2022, Biogen initiated a Phase 2 clinical study evaluating IONIS-FB-Lof IONIS-MAPTRx in patients with geographic atrophy secondarymild cognitive impairment or mild dementia due to age-related macular degeneration.AD. The study is a randomized, masked,double-blinded, placebo-controlled, dose-escalation study in approximately 735 patients designed to assess the efficacy, safety and tolerability of IONIS-MAPTRx administeredintrathecally. The primary endpoint is the change from baseline to week 76 on the Clinical Dementia Rating scale Sum of Boxes, or CDR-SB.
In March 2023, Biogen presented new data from the Phase 1/2 study at the International Conference on Alzheimer's and Parkinson's Diseases. The data showed that IONIS-MAPTRx reduced soluble tau protein in CSF in a dose-dependent and sustained manner in patients with early-stage AD. IONIS-MAPTRx also reduced aggregated tau pathology, as measured by positron emission tomography, or PET, in all brain composites assessed. In October 2023, these data were published in JAMA. Additionally in October 2023, Biogen presented new data from the Phase 1/2 study at The Clinical Trials on Alzheimer’s Disease, or CTAD, conference. The data showed a numerical difference favoring IONIS-MAPTRx on multiple cognitive and functional scales for the patients receiving higher doses of IONIS-MAPTRx throughout the multiple ascending dose and long-term extension compared to matched external control patients receiving placebo. The assessments included: Clinical Dementia Rating Sum of Boxes, or CDR-SB, Mini-Mental State Examination, or MMSE and, Functional Activities Questionnaire, or FAQ.
In July 2021, we and Biogen reported positive topline data from our Phase 1/2 study of IONIS-MAPTRx in patients with mild AD at the Alzheimer’s Association International Conference, or AAIC. The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation study of IONIS-MAPTRx to evaluate the safety and activity of once-monthly intrathecal injections of IONIS-MAPTRx in patients with mild AD. The study showed that IONIS-MAPTRx met its primary objective of safety and tolerability in patients with mild AD. The study demonstrated robust time and dose dependent lowering of tau protein in CSF over the three-month treatment period and sustained reductions during the six-month post-treatment period. IONIS-MAPTRx had a favorable safety and tolerability profile supportive of continued development.
In December 2019, Biogen exercised its option to license IONIS-MAPTRx. Biogen has responsibility for global development, regulatory and commercialization activities, and costs for IONIS-MAPTRx.
ION859 (LRRK2) (BIIB094) – ION859 is an investigational antisense medicine we designed to inhibit the production of the Leucine Rich Repeat Kinase 2, or LRRK2, protein as a potential therapy for Parkinson’s disease, or PD. The most common genetic mutations in PD are found in the LRRK2 protein. It is believed that increased LRRK2 protein activity could be one of the key drivers for developing PD. PD is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patients with PD can experience tremors, loss of balance and coordination, stiffness, slowing of movement, changes in speech and in some cases cognitive decline. PD is ultimately fatal. There are treatments that can relieve symptoms, but there are no approved disease modifying therapies.
In August 2019, Biogen initiated a Phase 1/2 study evaluating ION859 in patients with PD. The Phase 1/2 study is a global, multi-center, randomized, double-blinded, placebo-controlled study in approximately 80 patients designed to assess the safety, tolerability and activity of multiple ascending doses of ION859 administered intrathecally.
ION859 is being developed under our 2013 Strategic Neurology collaboration with Biogen.
ION464 (SNCA) (BIIB101) – ION464 is an investigational antisense medicine we designed to inhibit the production of the alpha-synuclein protein as a potential therapy for PD, Multiple System Atrophy, or MSA, and related synucleinopathies. Alpha-synuclein protein abnormally accumulates in the brains of PD and MSA patients and is thought to be one of the key drivers of these diseases. It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations.
In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA. The current study is a multi-center, randomized, double-blinded, placebo-controlled study in approximately 40 patients designed to assess the safety and tolerability of multiple ascending doses of ION464 administered intrathecally.
ION464 is being developed under our 2013 Strategic Neurology collaboration with Biogen.
ION541 (ATXN2) (BIIB105) – ION541 is an investigational antisense medicine we designed to reduce the production of the ataxin-2, or ATXN2, protein for the potential treatment of ALS. The reduction of ATXN2 has been shown to decrease toxic aggregation of TDP-43, an RNA binding protein found in most patients with ALS, including the approximately 90% of the ALS population with no known family history of ALS.
In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in patients with ALS. The current study is a randomized, blinded, placebo-controlled study in approximately 110 patients designed to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of IONIS-FB-LRxION541 administered subcutaneously in adults with geographic atrophy.intrathecally.
In December 2021, we initiated the Phase 1/2 study, HALOS, of ION582 in patients with AS. The study is an open label dose-escalation study enrolling approximately 50 patients designed to assess the safety, tolerability and activity of multiple ascending doses of ION582 administered intrathecally. In November 2023, we announced that the HALOS study had completed enrollment.
In November 2023, we presented initial observations from the ongoing Phase 1/2 study at the Foundation for Angelman Syndrome, or FAST, summit. The data demonstrated that approximately 70% of patients showed a genetic formreduction in slow-wave electroencephalogram, or EEG, delta activity and over 80% showed an increase in faster frequency rhythms. Additionally, a majority of autosomal dominant retinitis pigmentosapatients showed improvement in overall functioning on the SAS-CGI-C scale. A majority of patients also showed improvement on the total Bayley score, which is a direct assessment of clinical functioning.
In May 2022 and June 2022, the FDA and EMA, respectively, granted orphan drug designation to ION582. Additionally in July 2022 and May 2022, the FDA granted Fast Track designation and rare pediatric designation to ION582, respectively.
ION582 is being developed under our 2012 Neurology collaboration with Biogen.
Tominersen (HTT) (RG6042) – Tominersen (formerly IONIS-HTTRx) is an investigational antisense medicine we designed to target the underlying cause of Huntington’s disease, or HD, by inhibitingreducing the production of all forms of the rhodopsin P23H mutanthuntingtin protein, or HTT, including its mutated variant, or mHTT. HD is an inherited genetic brain disorder that results in the eye while allowing normalprogressive loss of both mental faculties and physical control. It is caused by the expansion of the cytosine-adenine-guanine, or CAG, trinucleotide sequence in the HTT gene. The resulting mutant HTT protein is toxic and gradually destroys neurons. Symptoms usually appear between the ages of 30 and 50 and worsen over a 10 to be expressed.25-year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective treatment or cure for the disease, and currently available medicines only mask the patient’s symptoms but do not slow down the underlying loss of neurons.
Roche conducted the Phase 3 study, GENERATION HD1, of tominersen in patients with HD. The Phase 3 study was a randomized, multicenter, double-blind, placebo-controlled study that recruited 791 participants. In March 2021, Roche announced that dosing would be stopped in the study following a recommendation from the independent data monitoring committee, or iDMC, based on an overall benefit/risk assessment. In January 2022, Roche announced findings from a post-hoc analysis of the GENERATION HD1 study that suggested tominersen may benefit younger adult patients with lower disease burden.
In December 2015 and March 2015, the FDA and EMA, respectively, granted orphan drug designation to tominersen. Additionally in August 2018, the EMA granted PRIME designation to tominersen.
In December 2017, Roche exercised its option to license tominersen. As a result, Roche is responsible for converting light into signalsglobal development, regulatory and commercialization activities, and costs for tominersen.
Our Cardiovascular Medicines in Development
Our cardiovascular franchise includes investigational medicines that are sent totarget the brain. Photoreceptors provide us our color and night vision. Affected patients first experience defective dark adaptation during adolescence or young adulthood, followed by lossmajor risk factors of peripheral visual field. Patients eventually have limited residual central vision, which ultimately leads to complete blindness around the age of 60.CVD.
Eplontersen – See the medicine description under “Our Phase 3 Pipeline” section above.
Olezarsen – See the medicine description under “Our Phase 3 Pipeline” section above.
Pelacarsen – See the medicine description under “Our Phase 3 Pipeline” section above.
Fesomersen (FXI) – Fesomersen (formerly IONIS-FXI-LRx) is an investigational LICA medicine we designed to inhibit the production of Factor XI. Factor XI is a clotting factor produced in the liver that is important in the growth of blood clots. Thrombosis, characterized by the formation of a blood clot inside blood vessels, can cause heart attacks and strokes. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased bleeding, which can be fatal. By inhibiting Factor XI production, we believe that fesomersen can be used for the treatment of a number of non-acute forms of thrombosis where additional safe and well tolerated anti-thrombotic medicines are needed.
In November 2022, Bayer presented positive results from the RE-THINc Phase 2b study of fesomersen in patients with end-stage renal disease, or ESRD, on hemodialysis at the ASN Kidney Week. In the study, fesomersen achieved its primary endpoint, demonstrating no increase in the incidence of the composite of major bleeding and clinically relevant non-major bleeding with 24 weeks of treatment. Fesomersen also achieved dose-dependent and sustained median reductions in steady-state FXI levels of 53.1%, 72.2% and 86.6% in the 40 mg, 80 mg, and 120 mg doses of fesomersen, respectively, administered once every four weeks. Incidences of dialysis circuit clotting and arteriovenous access, or AV-access, thrombosis diminished significantly with decreasing FXI levels, both of which were exploratory efficacy endpoints. Fesomersen had a favorable safety and tolerability profile supportive of continued development.
In November 2022, we regained all rights to fesomersen, which we had previously licensed to Bayer in February 2017.
ION904 (AGT) – ION904 is an investigational next-generation LICA medicine designed to inhibit the production of angiotensinogen to decrease blood pressure in people with uncontrolled hypertension. ION904 is a follow-on medicine targeting AGT, designed to enable less frequent dosing compared to IONIS-AGT-LRx.
In November 2023 at the AHA annual meeting we presented positive results from the Phase 2 clinical study of ION904 in patients with mild to moderate uncontrolled hypertension on one or more anti-hypertensive medications for at least one month. ION904 significantly reduced AGT levels compared to placebo. ION904 had a favorable safety and tolerability profile supportive of continued development.
Other Medicines for High Patient Need in Development
We also have other medicines for high patient need in development that are outside of our cardiovascular and ProQRneurological franchises that we believe could represent compelling opportunities for us, including our Specialty Rare medicines, donidalorsen and sapablursen.
1 Granted Otsuka exclusive rights to commercialize donidalorsen in Europe.
Donidalorsen – See the medicine description under “Our Phase 3 Pipeline” section above.
Sapablursen (TMPRSS6) – Sapablursen (formerly IONIS-TMPRSS6-LRx) is an investigational LICA medicine we designed to target the TMPRSS6 gene to modulate the production of hepcidin, which is the key regulator of iron homeostasis. By modulating hepcidin expression, sapablursen has the potential to positively impact diseases characterized by iron deficiency, such as polycythemia vera, or PV.
PV is a rare disease driven by a mutation in the JAK2 gene that is potentially fatal and characterized by overproduction of red blood cells. This overproduction leads to a thickening of the blood, which increases patients’ risk of life-threatening blood clots, including in the lungs, heart and brain. Patients with PV also experience severe iron deficiency and symptoms such as fatigue and impaired cognitive function. There are collaboratingno approved disease-modifying treatments for PV.
In January 2022, we initiated a Phase 2 study evaluating sapablursen in patients with phlebotomy dependent PV, or PD-PV. The Phase 2 study is a multi-center, randomized, open-label study in approximately 40 patients designed to develop assess the efficacy, safety and tolerability of sapablursen. The primary endpoint is the change in the frequency of phlebotomy comparing baseline with the last 20 weeks of the 37-week treatment period.
In December 2018, we presented positive data from our Phase 1 study of sapablursen in healthy volunteers at the American Society of Hematology Annual Meeting. The Phase 1 study demonstrated dose-dependent reductions of serum iron and serum transferrin saturation with sapablursen. Additionally, we observed an increase in serum hepcidin and predicted changes in hemoglobin. Sapablursen had a favorable safety and tolerability profile supportive of continued development.
In September 2020, the FDA granted Fast Track designation to sapablursen for polycythemia vera.
IONIS-FB-LRx (IgAN) – See the medicine description under “Our Phase 3 Pipeline” section above.
ION224(DGAT2) – ION224 is an investigational LICA medicine we designed to reduce the production of diacylglycerol acyltransferase 2, or DGAT2, to treat patients with RP.nonalcoholic steatohepatitis, or NASH. NASH is a common liver disease characterized by liver steatosis, inflammation and scarring and can lead to increased risk of CVD, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. In November 2019, ProQRanimal studies, antisense inhibition of DGAT2 significantly improved liver steatosis, lowered blood lipid levels and reversed diet-induced insulin resistance.
Nonalcoholic fatty liver disease, or NAFLD, describes the full spectrum of liver disease progression from fatty liver to NASH to cirrhosis to hepatocellular carcinoma. NASH epidemiology studies have estimated 13% to 32% of the global population has NAFLD, 1.5% to 6.5% have NASH, and up to 10% of NASH patients progress to advanced liver disease. There are currently no commercially available medications to treat NASH.
NASH is sometimes considered a “silent” liver disease because people with early-stage NASH feel well, even though they are starting to accumulate fat in their livers and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.
In June 2021, we initiated a Phase 1/2 clinical study evaluating ION357of ION224 in patients with RP.confirmed non-alcoholic steatohepatitis. The currentPhase 2 study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 160 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous doses of ION224 on NASH histologic improvement.
IONIS-FB-LRx – IONIS-FB-LRx (RG6299) is an investigational LICA medicine we designed to inhibit the production of FB, and the alternative complement pathway. Genetic association studies have shown that overaction of the alternative complement pathway has been associated with the development of several complement-mediated diseases, including IgAN (see section above “Our Phase 3 Pipeline” for discussion of IgAN) and GA secondary to AMD.
AMD is the leading cause of central vision loss in developed countries. GA is an advanced form of AMD.
In June 2019, we initiated a Phase 2 GOLDEN study evaluating IONIS-FB-LRx in patients with GA secondary to AMD. The study is a randomized, masked, placebo-controlled study in approximately 330 patients designed to assess the efficacy, safety and tolerability of multiple ascending doses of IONIS-FB-LRxION357 administered subcutaneously in adults with GA. The primary endpoint is the absolute change from baseline in adultGA area at week 49. In August 2023, we announced that the GOLDEN study had completed enrollment.
In July 2022, Roche exercised its option to license IONIS-FB-LRx following the positive Phase 2 results for IgAN. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-LRx, except for the open label Phase 2 study in patients with RP.IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding.
In March 2023, AstraZeneca initiated a Phase 2b study of ION839 in patients with confirmed NASH with fibrosis and who are carriers of the PNPLA3 mutation. The efficiencyPhase 2b study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 180 patients designed to assess the efficacy, safety and broad applicabilitytolerability of multiple subcutaneous doses of ION839. The primary endpoint is the proportion of patients achieving NASH resolution without worsening of fibrosis based on histology after 52 weeks of treatment.
In April 2018, AstraZeneca exercised its option to license ION839. As a result, AstraZeneca is responsible for global development, regulatory and commercialization activities, and costs for ION839.
Our Technology
For three decades through our innovations in science and technology, enableswe have enhanced the profiles of RNA-targeted medicines and pursued new opportunities in emerging areas of genetic medicine.Our recent technology advancements have enabled us to developadvance programs with the potential for extended dosing and delivery to new tissues, such as muscle. We have also added capabilities to utilize RNA interference, or RNAi, and potentially gene editing in addition to our novel antisense technology, which gives us the potential to deliver medicines forto a broad rangegreater number of people living with serious diseases. In 2020, we initiated six Phase 1 or Phase 1/2 studies.
Our advanced LICA technology is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors on the surfacessurface of cells in a highly specific manner. Because these receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with higher specificity to certain cell types that express these receptors relative to non-conjugated antisense medicines. As of December 2020, weWe currently have an integrated assessment of data from multiple LICA medicines and over 1,200 subjects who have been treated with our LICA medicines,clinical programs which demonstrates that our LICA technology for liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines.
Emerging Technology Advancements
Our recent technology advancements have enabled us to create even more potent medicines amenable to more potential targets and tissue types. We have also diversified the Phase 2 study. The study includedapproaches we can use in designing our medicines in order to reach more than 280 patients with 98 percent of patients insevere diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including our Bicycle LICA technology, siRNA technology and MsPA backbone chemistry. And through our Metagenomi collaboration, we added the high dose group achieving levels below 50 mg/dL, the recognized risk threshold for CVD.potential to use gene editing, which modifies DNA.
Mesyl phosphoramidate Backbone Chemistry
We designed our MsPA backbone chemistry to improve both therapeutic index and durability. It does this by increasing metabolic stability relative to the other backbone chemistries we utilize. We have also shown it can also combineimprove potency in certain circumstances and reduce non-specific interactions with proteins that can cause undesirable effects, such as proinflammatory effects. We currently have multiple new programs using our MsPA backbone, designed to improve both efficacy and durability, in preclinical development.
Bicycle Collaboration
In 2021, we entered into a collaboration with Bicycle Therapeutics that we expect can expand our LICA technologyplatform to target both skeletal and cardiac muscle, and potentially deliver medicines across the blood brain barrier. Bicycles are small, bicyclic peptides that have high affinity and selectivity for protein targets. Our collaboration with our Generation 2.5 chemistry, further increasing potency. This increase in potency may enable oralBicycle allows us to utilize Bicycles that bind transferrin receptor 1 to facilitate the tissue specific delivery of oligonucleotide drugs (both antisense and siRNAs). We advanced our antisense medicines. In addition to thefirst Bicycle LICA technology for liver targets, we are also developing LICA conjugation technology that we can use to target other tissues, such as muscle, and initial results are promising.program into preclinical development in 2023.
Gene editing is highly complementary and synergistic with RNA-targeted therapeutics. Both platforms rely on the same nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H mechanismand siRNA drugs, or to DNA in the case of action.Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems. This enables us to leverage our expertise in nucleic acids and modified nucleic acid chemistry with the goal to enhance gene editing’s ability to treat diseases for which there are limited treatment options.
Collaborative Arrangements
We have established alliances with a cadre of leading global pharmaceutical companies. Our partners include the following companies, among others: AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, PfizerOtsuka and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments. In 2020,addition, we recognized nearly $730 million in revenue, the majority of which was fromare eligible to receive royalties under our partnered medicines and programs. We have the potential to earn more than $20 billion in future milestone payments, licensing fees and other payments from our current partnerships, not including potential royalties.partnerships. Below, we include the significant terms of our collaboration agreements. For additional details, including other financial information, seerefer to Part IV, Item 15, Note 6,4, Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial Statements.
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. WeIn April 2023, the FDA granted accelerated approval for QALSODY (tofersen) in the U.S. to treat patients with SOD1-ALS. Biogen developed QALSODY under our 2013 strategic neurology collaboration. In addition, we and Biogen are currently developing eightnumerous other investigational medicines to treat neurodegenerative diseases, under these collaborations, including medicines in development to treat people with ALS, Alzheimer’s diseaseSMA, AS, AD, and 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.PD. From inception through December 2020,31, 2023, we have received $2.8generated more than $3.8 billion in payments 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, an RNA-targeted therapy for the treatment of SMA.SPINRAZA is approved in over 50 countries around the world. From inception through December 2020, we generated more than $1.3 billion in total revenue under our SPINRAZA collaboration, including more than $930 million in revenue from SPINRAZA royalties and more than $435 million in R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on 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. Under our agreement, Biogen is responsible for global development, regulatory and commercialization activities and costs for SPINRAZA. From inception through December 31, 2023, we recognized more than $2.0 billion in total revenue under our SPINRAZA collaboration, including more than $1.6 billion in revenue from SPINRAZA royalties and more than $425 million in R&D revenue.
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. 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 therapiestherapies.
In 2021, Biogen exercised its option to license ION306. . UnderBiogen is solely responsible for the collaboration agreement, we received acosts and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. $25 million upfront payment in December 2017. We will receive development and regulatory milestone payments from Biogen if new medicines, including ION306, advance towards marketing approval.In total over
Over the term of ourthis collaboration, we are eligible to receive up to $1.2 billion in license fees,development, regulatory and sales milestone payments and other payments. In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we have generated $85 million in payments 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 anddiseases. We also entered into a Stock Purchase Agreement, or SPA. As a result, we received a payment related to the SPA in addition to an upfront payment at the commencement of this collaboration. 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 targets.targets. In most cases, Biogen iswill be responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will havehas 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,
For each medicine under this collaboration, 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. We are eligible to receive up to $270 million ina license fee, development milestone payments for each medicine that achieves marketing approval. and regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration.We We are currently advancing eightmultiple programs under this collaboration andcollaboration. From inception through December 2020,31, 2023, we have generated over $1.05nearly $1.1 billion in payments.payments under this collaboration.
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 beIn most cases, we are responsible for drug discovery and early development of antisense medicines and Biogen will havehas 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 sixfour investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease three(ION859), two medicines for ALS (QALSODY and ION541) and a medicine for multiple system atrophy and a medicine for an undisclosed target.(ION464). In December 2018, Biogen exercised its option to license QALSODY, our most advanced ALS medicine tofersen, and asthat received accelerated approval in April 2023 from the FDA for the treatment of adult patients with SOD1-ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.QALSODY.
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.
Over the term of the collaboration for QALSODY, we are eligible to receive a license fee, development milestone payments and regulatory milestone payments. In addition, we are eligible to receive tiered royalties ranging from 11 percent to 15 percent on net sales of QALSODY.
For each of the other antisense moleculemolecules that isare chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee, anddevelopment milestone payments per program.and regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that Biogen successfully commercializes under this collaboration. Throughcollaboration. From inception through December 2020,31, 2023, we have generated over $270more than $325 million in payments under this collaboration, including $28 million we received from Biogen in 2020 when Biogen initiated Phase 1/2 trials for ION464, our investigational medicine for MSA and Parkinson’s disease and ION541, our investigational medicine for ALS.2013 strategic neurology collaboration.
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-MAPTRx study for AD and we are currently advancing IONIS-MAPTRx for Alzheimer’s disease and ION582 for Angelman syndrome.AS. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In December 2019, Biogen exercised its option to license IONIS-MAPTRx and as a result Biogen is now responsible for global development, regulatory and commercialization activities and costs for IONIS-MAPTRx.
Joint Development and Commercialization Arrangement
AstraZeneca
WAINUA (Eplontersen) Collaboration
In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. In December 2023, the FDA approved eplontersen with the brand name, WAINUA, in the U.S. for ATTRv-PN. We are jointly developing and commercializing WAINUA with AstraZeneca in the U.S. We initially granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S., except for certain Latin American countries. In July 2023, we expanded those rights to include Latin America.
The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S.
Over the term of the collaboration, we are eligible to receive an upfront payment, license fee, development and approval milestone payments and sales milestone payments. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties ranging from mid to high teens for sales outside the U.S. From inception through December 31, 2023, we have generated more than $425 million in payments under this collaboration, including $19.5 milliona milestone payment for the approval of WAINUA in the U.S. and revenue we receivedearned from Biogen for advancing IONIS-MAPTRx during 2020.cost sharing provisions.
Research Development and CommercializationDevelopment Partners
AstraZeneca
us. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed and any medicines AstraZeneca licenses in the future.from us.
GSK
In December 2012,2010, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer. We and AstraZeneca also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if AstraZeneca exercises its option to license a medicine, it will be responsible for global development, regulatory and commercialization activities and costs for such medicine. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer.
Novartis
Pelacarsen Collaboration
In January 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen. We received a $75 million upfront payment in the first quarter of 2017. In February 2019, Novartis licensed pelacarsen and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study whichthat Novartis initiated in December 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.
New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease
In conjunction with this collaboration,August 2023, 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 2017collaboration and purchased $50 million of Akcea’s common stock at the IPO price concurrent with Akcea’s IPO in July 2017.
Roche
Huntington’s Disease
In April 2013, we formedentered into an allianceagreement with Hoffman-LaHoffmann-La Roche Inc.Inc and F. Hoffmann-La Roche Ltd.,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 stageearly-stage HD. In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersenandtominersen. As a result, Roche is now responsible for theall global development, regulatory and commercialization activities and costs for tominersen.
IONIS-FB-LRx for Complement-Mediated Diseases
In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-LRx for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-LRx, one for the treatment of patients with IgAN and one for the treatment of patients with GA, the advanced stage of dry AMD, andAMD. In April 2023, Roche initiated a second for the treatmentPhase 3 study of IONIS-FB-LRx in patients with IgA nephropathy. Roche has the option to license IONIS-FB-LRx at the completion of these studies. Upon licensing, IgAN.
After positive data from a Phase 2 clinical study in patients with IgAN, Roche will belicensed IONIS-FB-LRx in 2022. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs.costs for IONIS-FB-LRx, 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.
RNA-Targeting Medicines for Alzheimer's Disease and Huntington's Disease
In September 2023, we entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-targeting investigational medicines for the treatment of AD and HD. Under the agreement, we are responsible for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the medicines if they receive regulatory approval.
Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments and sales milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2023, we have generated $60 million in payments under this collaboration.
Commercialization Partnerships
Otsuka
In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe. We are responsible for the ongoing development of donidalorsen. We retained the rights to commercialize donidalorsen in the U.S. and in the rest of the world assuming regulatory approval.
Over the term of the collaboration, we are eligible to receive an upfront payment, regulatory milestone payments and sales milestone payments. In addition, we are eligible to receive tiered royalties ranging from 20 percent to 30 percent on net sales of donidalorsen in Europe. From inception through December 31, 2023, we have generated $65 million in payments under this collaboration.
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 and September 2023, we started receiving royalties from PTC for TEGSEDI and WAYLIVRA sales, respectively.
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. Refer to the section titled, Overview, for further details on our distribution agreement with Sobi.
Technology Enhancement Collaborations
Bicycle Therapeutics
In 2020, we entered into a collaboration agreement with Bicycle Therapeutics, or Bicycle, and obtained an option to license its peptide technology to potentially increase the delivery capabilities of our LICA medicines. In 2021, we exercised our option to license Bicycle's technology. Our payment to Bicycle for licensing its technology included an equity investment in Bicycle.
Metagenomi
In 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 Metagenomi to license its technologies and will pay Metagenomi certain fees for the selection of genetic targets. In addition, we will pay Metagenomi milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. We will also reimburse Metagenomi for certain of its costs in conducting its research and drug discovery activities under the collaboration.
Vect-Horus
In December 2023, we entered into a license agreement with Vect-Horus to provide us with worldwide, exclusive license for a specified number of targets using Vect-Horus’ platform technology ”VECTrans” for systemic delivery of RNA-targeted therapeutics that can cross the blood-brain barrier and address targets in the central nervous system. As a result, we paid Vect-Horus to license its technologies. In addition, we will pay Vect-Horus milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events.
Other Agreements
Alnylam Pharmaceuticals, Inc.
Under the terms of our agreement with Alnylam, we exclusivelyco-exclusively (with ourselves) licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, inwith 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 medicinestherapeutics 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 four 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.
Manufacturing
We manufacture most of the drug productactive pharmaceutical ingredient, or API, we use for our research and development, or R&D, activities ourselves. We have also manufactured API and commercial supply for our approved medicines. We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same nucleotide building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our antisenseother medicines. By developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly reduced the cost of producing oligonucleotide medicines. For example, we have significantly reduced the cost of raw materials through improved yield efficiency, while at the same time increasing our capacity to make our medicines. Through both our internal research and development programs and collaborations with outside vendors, we may achieve even greater efficiency and further cost reductions.
Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building in 2017. In addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this facility under a lease that has a term ending in August 2026 with an option to extend the lease for an additional five-year period. Our manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in compliance with current Good Manufacturing Practices, or cGMP, requirements.
As part of our collaborations, we may agree to manufacture clinical trial materialsmaterial and/or commercial drug supply for our partners. For example, in the past we have manufactured clinical supply materialstrial material for AstraZeneca, Bayer, Biogen, GSK and Novartis and commercial drug supply materials for Biogen.
We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or CMOs, to meet our current internal research, development and potential commercial needs, as well as our obligations under existing agreements with our partners for research, development and commercial needs.material. We and/or our CMOs manufacture process performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory approval, commercial sale. We believe our current network of CMO partnersCMOs are capable of providing sufficient quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional suppliers to increase overall capacity and diversify our supply chain. While we believe that there are alternate sources of supply that can satisfy our commercial requirements, it is possible that identifying and establishing relationships with such sources, if necessary, could result in significant delay or material additional costs. We also could experience a disruption in supply from our current CMO partners.CMOs.
CMOs are subject to the FDA’s cGMP requirements and other rules and regulations prescribed by foreign regulatory authorities. We depend on our CMO partnersCMOs for continued compliance with cGMP requirements and applicable foreign standards.
Specifically, we have the following in place for our approvedcommercial medicines SPINRAZA, TEGSEDI and WAYLIVRA and our medicines in Phase 3 development: tominersen, tofersen, pelacarsen, IONIS-TTR-LRx and IONIS-APOCIII-LRx:development.
SPINRAZA
QALSODY
Biogen has an oligonucleotide synthesis manufacturing facility that gives itis responsible for QALSODY drug supply.
WAINUA
AstraZeneca is responsible for WAINUA's commercial drug supply. Our CMOs supplied the capabilityAPI and the finished drug product for WAINUA’s Phase 3 program. Pursuant to our collaboration with AstraZeneca, we will manufacture SPINRAZA.and supply WAINUA using CMOs for the ongoing clinical trials, process performance qualification batches and pre-approval inspection batches.
TEGSEDI and WAYLIVRA
For TEGSEDI’s commercial drug supply, we are using CMOs to produce custom raw materials, active pharmaceutical ingredient, or API and finished goods. For WAYLIVRA’s commercial drug supply, we are using API that we have manufactured custom raw materials and API. We are using CMOs to produce the finished goods for WAYLIVRA. Our CMO partners have extensive technical expertise and cGMP experience. We believe our current network of CMO partners are capable of providing sufficient quantities to meet anticipated commercial demands.
We and/or our CMOs have supplied the API and the finished drug product for olezarsen, donidalorsen, zilganersen and ulefnersen that we believe will be sufficient through the completion of the Phase 3 programs for each medicine, including process performance qualification batches and pre-approval inspection batches. We plan to leverage our relationships with CMOs to maintain long-term supply at competitive prices in the future.
Pelacarsen
We supplied API and finished drug product for pelacarsen’s Phase 3 study.program. Pursuant to our collaboration with Novartis, Novartis is responsible for any further pelacarsen drug supply.
We supplied API for bepirovirsen’s Phase 3 Medicines: IONIS-TTR-LRx,IONIS-APOCIII-L1 and Phase 2 programs. Pursuant to our collaboration with GSK, GSK is responsible for any further bepirovirsen drug supply.
IONIS-FB-LRx
We have supplied API for the API and the finished drug product for IONIS-TTR-LIONIS-FB-LRx Phase 1 and IONIS-APOCIII-LPhase 2 IgAN programs. Pursuant to our collaboration with Roche, Roche is responsible for any further drug supply for the IONIS-FB-LRx that we believe will be sufficient through the completion of the Phase 3 programs for each medicine. We plan to leverage our relationships with CMOs to procure long-term raw material and drug supplies at competitive prices in the future.program.
We have manufacturedestablished sales and used CMOsmarketing capabilities to manufacturesupport our LICA medicines for our preclinical and clinical studies. LICA enables lower doses than unconjugated oligonucleotides. With our expertise in optimizing manufacturingcommercial launch of oligonucleotides, we believe we can scale up manufacturing of our LICA medicines at commercially competitive prices or use CMO’s.
As we approach our first potential independent commercial launches of olezarsen and donidalorsen in the U.S., we have been refining our portfolio strategy and recruiting experienced professionals with relevant backgrounds in sales, marketing, patient education, market access, portfolio planning and market insight, new product commercial strategy and commercial operations in the pharmaceutical industry. We are focused on developing a unique and innovative approach to bring our medicines to patients living with serious diseases. We have built core capabilities and a commercial platform with the ability to scale as needed to meet our current and future commercialization needs. We plan to build our field sales teams as we approach each of our launches.
In addition, we recently entered into a European licensing agreement with Otsuka for donidalorsen in HAE in which we will leverage Otsuka's strong commercial infrastructure and rare disease experience to reach European HAE patients.
Medical Affairs
We have built medical affairs capabilities to disseminate information about our medicines and increase disease awareness through various channels of communication with key stakeholders. Our medical affairs function is responsible for funding and coordinating investigator-sponsored trials, communicating scientific and clinical information to healthcare providers, medical professionals and patients, and managing publications.
Intellectual Proprietary Rights
We rely on patents, trademarks, trade secrets, and proprietary know-how to develop and maintain a competitive position in RNA-targeted therapeutics generally and to protect our investment in specific products. To this end, we focus our resources on patents and new patent applicationsintellectual property, or IP, that drivedrives value for our company.
Product-Specific IP
Each of our medicines is protected worldwide by product-specific patents claiming oligonucleotides having the nucleobase sequences and chemical modifications of our medicines; and methods of achieving cellular or clinical endpoints using such oligonucleotides. We pursue such patents in significant markets and/or countries for each medicine in development. We also seek to maximize patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during regulatory review. Expiration dates listed below do not reflect any such extensions.
Commercial products are also protected by trademarks filed throughout the world.
Marketed Products
SPINRAZA and Survival Motor Neuron 2
Patents
We own or controlbelieve SPINRAZA (nusinersen) is protected from generic competition in the U.S. until at least 2035 and in Europe until at least 2030 by a suite of patents. These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification, and uses of such compounds for treating SMA, (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2’-MOE compounds targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions; and (iii) dosing and therapeutic methods of using such compounds and compositions. With Biogen’s license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 10,266,822 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2025 | Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA | ||||
| United States | 8,110,560 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2025 | Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA | ||||
| Europe | 1910395 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2026 | Sequence and chemistry (full 2’-MOE) of SPINRAZA | ||||
| Europe | 3308788 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2026 | Pharmaceutical compositions that include SPINRAZA | ||||
| United States | 7,838,657 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2027 | Oligonucleotides having sequence of SPINRAZA | ||||
| United States | 8,361,977 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2030 | Sequence and chemistry (full 2’-MOE) of SPINRAZA | ||||
| United States | 8,980,853 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Methods of administering SPINRAZA | ||||
| United States | 9,717,750 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Methods of administering SPINRAZA to a patient | ||||
| Europe | 3449926 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Pharmaceutical compositions that include SPINRAZA for treating SMA | ||||
| Europe | 3305302 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Antisense compounds including SPINRAZA for treating SMA | ||||
| United States | 9,926,559 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2034 | SPINRAZA doses for treating SMA | ||||
| United States | 10,436,802 | METHODS FOR TREATING SPINAL MUSCULAR ATROPHY | 2035 | SPINRAZA dosing regimen for treating SMA |
Trademarks
The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen. Particulars for the United States and European marks are listed below:
| Jurisdiction | Registration No. | Mark | ||||
| United States | 5156572 | SPINRAZA | _ | (word mark) | ||
| Europe | 013388145 | SPINRAZA | (word mark) | |||
| Europe | 014812291 and 015309941 |  | (design mark) | |||
QALSODY and SOD-1
Patents
We believe QALSODY is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications designed to protect QALSODY in other foreign jurisdictions are being pursued. With Biogen’s license of QALSODY, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting QALSODY in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
United States | 10,385,341 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Composition of QALSODY | ||||
United States | 10,669,546 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Methods of treating a SOD-1 associated neurodegenerative disorder by administering QALSODY | ||||
| United States | 10,968,453 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Methods of treating a SOD-1 associated neurodegenerative disorder by administering a pharmaceutical composition of QALSODY | ||||
| Europe | 3126499 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Composition of QALSODY |
Trademarks
The name “QALSODY” is protected throughout the world by trademarks owned by our commercial partner Biogen. Particulars for the United States and European marks are listed below:
| Jurisdiction | Registration No. | Mark | ||||
| United States | 7164425 | QALSODY | _ | (word mark) | ||
| United States | 7116182 |  | (design mark) | |||
| Europe | 1542485 | QALSODY | (word mark) | |||
| Europe | 018517819 | | (design mark) | |||
WAINUA and Transthyretin
Patents
We believe WAINUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect WAINUA in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 10,683,499 | COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION | 2034 | Composition of eplontersen | ||||
| Europe | 3524680 | COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION | 2034 | Composition of eplontersen |
Trademarks
The name “WAINUA” is protected by trademarks owned by our commercial partner Astra Zeneca. Particulars for the United States marks are listed below:
| Jurisdiction | Application No. | Mark | ||||
| United States | 98054331 | WAINUA | _ | (word mark) | ||
| United States | 98228658 |  | (design mark) | |||
TEGSEDI and Transthyretin
Patents
We believe TEGSEDI (inotersen) is protected from generic competition in the U.S. and Europe until at least 2031. The table below lists some key issued patents protecting TEGSEDIin the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 8,101,743 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2025 | Antisense sequence and chemistry of TEGSEDI | ||||
| United States | 8,697,860 | DIAGNOSIS AND TREATMENT OF DISEASE | 2031 | Composition of TEGSEDI | ||||
| United States | 9,061,044 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Sodium salt composition of TEGSEDI | ||||
| United States | 9,399,774 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Methods of treating transthyretin amyloidosis by administering TEGSEDI | ||||
| Europe | 2563920 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Composition of TEGSEDI |
Trademarks
The name “TEGSEDI” is protected by trademark throughout the world. Particulars for the United States and European marks are listed below:
| Jurisdiction | Registration No. | Mark | ||||
| United States | 5740635 | TEGSEDI | _ | (word mark) | ||
| Europe | 017224742 | TEGSEDI | (word mark) | |||
WAYLIVRA and Apolipoprotein C-III
Patents
We believe WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034. We have obtained patent claims in the U.S. and Europe drawn to the use of antisense compounds complementary to a broad active region of human apoC-III, including the site targeted by WAYLIVRA. We have also obtained issued patents claiming the specific sequence and chemical composition of WAYLIVRA in the U.S. and Europe. The table below lists some key issued patents protecting WAYLIVRA in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| Europe | 1622597 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Antisense sequence and chemistry of WAYLIVRA | ||||
| Europe | 2441449 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Antisense compounds that hybridize within the nucleotide region of apo-CIII targeted by WAYLIVRA | ||||
| Europe | 3002007 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Antisense compounds complementary to an apo-CIII nucleic acid for use in therapy | ||||
| United States | 9,157,082 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION | 2032 | Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL | ||||
| United States | 9,593,333 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS | 2034 | Methods of treating lipoprotein lipase deficiency with an apo-CIII specific inhibitor wherein triglyceride levels are reduced | ||||
| Europe | 2956176 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS | 2034 | Apo-CIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or FCS |
Trademark
The name “WAYLIVRA” is protected by trademark in Europe. Particulars for the European mark are listed below:
| Jurisdiction | Registration No. | Mark | ||||
| Europe | 016409609 | WAYLIVRA | (word mark) | |||
Phase 3 Programs
Olezarsen and ApoC-III
We believe olezarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect olezarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting olezarsen in the U.S. and Europe.
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,163,239 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION | 2034 | Composition of olezarsen | ||||
| Europe | 2991656 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION | 2034 | Composition of olezarsen |
Donidalorsen and PKK
We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications to protect donidalorsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting donidalorsen in the U.S. and Europe.
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,315,811 | METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION | 2032 | Methods of treating HAE | ||||
| Europe | 2717923 | METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION | 2032 | Compounds for use in treating an inflammatory condition, including HAE | ||||
| United States | 10,294,477 | COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION | 2035 | Composition of donidalorsen | ||||
| Europe | 3137091 | COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION | 2035 | Composition of donidalorsen |
Zilganersen and GFAP
We believe zilganersen is protected from generic competition in the U.S. until at least 2041. A patent application designed to protect zilganersenfrom generic competition is being pursued in Europe; a patent issuing from that provideapplication would have term until at least 2041. The table below lists a key issued patent protecting zilganersen in the U.S. and a pending application in Europe:
| Jurisdiction | Patent No. (Patent Application No.) | Title | Expiration | Description of Claims | ||||
| United States | 11,786,546 | COMPOUNDS AND METHODS FOR MODULATING GFAP | 2041 | Composition of zilganersen | ||||
| Europe | (20846055.0) | COMPOUNDS AND METHODS FOR MODULATING GFAP | 2041 | Composition of zilganersen |
Ulefnersen and FUS
Patent applications designed to protect ulefnersen from generic competition are being pursued in the U.S. and Europe. Patents issued from these applications would have terms until at least 2040. The table below lists some key pending patent applications designed to protect ulefnersen in the U.S. and Europe:
| Jurisdiction | Patent Application No. | Title | Expiration | Description of Claims | ||||
| United States | 17/613,183 | COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION | 2040 | Composition of ulefnersen | ||||
| Europe | 20815459.1 | COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION | 2040 | Composition of ulefnersen |
Pelacarsen and Apo(a)
We believe pelacarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent protection designed to protect pelacarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting pelacarsen in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,574,193 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Methods of lowering Apo(a) and/or Lp(a) levels with an oligonucleotide complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
United States | 10,478,448 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Methods of treating hyperlipidemia with an oligonucleotide complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
United States | 9,884,072 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
| Europe | 2855500 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen for decreasing Apo(a) expression | ||||
United States | 9,181,550 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION | 2034 | Composition of pelacarsen | ||||
| Europe | 2992009 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION | 2034 | Composition of pelacarsen |
Bepirovirsen and Hepatitis B Virus
We believe bepirovirsen is protected from generic competition in the U.S. and Europe until at least 2032. Additional patent protection designed to protect bepirovirsen in other foreign jurisdictions are being pursued. With GSK’s license of bepirovirsen, we assigned our interest in these patents to GSK. The table below lists some key issued patents protecting bepirovirsen in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 8,642,752 | MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION | 2032 | Composition of bepirovirsen | ||||
Europe | 3505528 | MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION | 2032 | Composition of bepirovirsen |
IONIS-FB-LRx and Factor B
We believe IONIS-FB-LRx is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent protection designed to protect IONIS-FB-LRx in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting IONIS-FB-LRx in the U.S. and Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
Europe | 3043827 | MODULATORS OF COMPLEMENT FACTOR B | 2034 | Compound comprising the antisense oligonucleotide portion of IONIS-FB-LRx. | ||||
| United States | 10,280,423 | COMPOSITIONS AND METHODS FOR MODULATING COMPLEMENT FACTOR B EXPRESSION | 2035 | Composition of IONIS-FB-LRx. | ||||
| Europe | 3137596 | COMPOSITIONS AND METHODS FOR MODULATING COMPLEMENT FACTOR B EXPRESSION | 2035 | Composition of IONIS-FB-LRx. |
Platform IP
In addition to the IP that provides exclusivity for specific products, in our pipeline and patentswe also pursue IP that provideprovides exclusivity for our core technology in the field of antisenseoligonucleotides and RNA-targeting therapeutics more generally. Our core technology patents include claims to chemically modified nucleosides and oligonucleotides as well as antisense medicine designs utilizing these chemically modified nucleosides. Thesechemical modifications. Because these core claims are independent of specific therapeutic target, nucleic acid sequence, or clinical indication. We also own a large number of patents claiming antisense compounds having nucleic acid sequences complementary to therapeutic target nucleic acids, independent of the particular chemical modifications incorporated into the antisense compound. Most importantly, we seek and obtain issued patent claims to specifically protect each of our medicines. For example, we file and seek to obtain claims covering each drug’s nucleic acid sequence and precise drug design. In sum, we maintain our competitive advantage in the field of antisense technology by protecting our core platform technology and by creating multiple layers of patent protection for each of our specific medicines in development.indication, they may reach several products.
 |
Chemically Modified Nucleosides and Oligonucleotides
The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the modified nucleosides that we incorporate into our antisense medicines to increase their therapeutic efficacy. Nucleosides and chemically modified nucleosides are the basic building blocks of our antisense medicines. Therefore claims that cover any oligonucleotide incorporating one of our proprietary modified nucleosides can apply to a wide array of antisense mechanisms of action as well as several therapeutic targets. Of particular note are our patents covering our proprietary 2’-O-(2-methoxy) ethyl, or “MOE,” modified nucleosides, incorporated into many of our second-generation development compounds, as well as our constrained-ethyl nucleosides, or “cEt” nucleosides incorporated into our Generation 2.5 compounds. The following are some of our patents in this category in key jurisdictions (U.S., Europethe U.S. and Japan):Europe:
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 7,101,993 | OLIGONUCLEOTIDES CONTAINING 2’-O-MODIFIED PURINES | 2023 | Certain MOE nucleosides and oligonucleotides containing these nucleotides | ||||
| United States | 7,399,845 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| United States | 7,741,457 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| United States | 8,022,193 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Oligonucleotides containing cEt nucleoside analogs | ||||
| Europe | 1984381 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| Europe | 2314594 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Oligonucleotides containing cEt nucleoside analogs and methods of use | ||||
| Japan | 5342881 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| United States | 7,569,686 | COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Methods of synthesizing cEt nucleosides |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 7,399,845 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| United States | 7,741,457 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| United States | 8,022,193 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Oligonucleotides containing cEt nucleoside analogs | ||||
| Europe | 1984381 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | cEt nucleosides and oligonucleotides containing these nucleoside analogs | ||||
| Europe | 2314594 | 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Oligonucleotides containing cEt nucleoside analogs and methods of use | ||||
| United States | 7,569,686 | COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Methods of synthesizing cEt nucleosides | ||||
| Europe | 2092065 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having 2’-modifed and LNA nucleosides | ||||
| Europe | 2410053 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides | ||||
| Europe | 2410054 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing | ||||
| United States | 9,550,988 | ANTISENSE COMPOUNDS | 2028 | Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides | ||||
| United States | 10,493,092 | ANTISENSE COMPOUNDS | 2028 | Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides | ||||
| Europe | 3067421 | OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF | 2032 | Gapmer oligonucleotides having at least one bicyclic, one 2’-modified nucleoside and one 2’-deoxynucleoside | ||||
| United States | 11,629,348 | LINKAGE MODIFIED OLIGONUCLEOTIDES AND USES THEREOF | 2040 | Gapmer oligonucleotides having 2-4 mesyl phosphoramidate internucleoside linkages at specified positions in the gap |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 7,015,315 | GAPPED OLIGONUCLEOTIDES | 2023 | Gapmer oligonucleotides having 2’-O-alkyl-O-alkyl nucleosides | ||||
| United States | 7,750,131 | 5’-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS | 2027 | Oligonucleotides having 5’-methyl BNA nucleosides | ||||
| Europe | 2092065 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having 2’-modifed and LNA nucleosides | ||||
| Europe | 2410053 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides | ||||
| Europe | 2410054 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing | ||||
| Japan | 5665317 | ANTISENSE COMPOUNDS | 2027 | Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides | ||||
| United States | 9,550,988 | ANTISENSE COMPOUNDS | 2028 | Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides | ||||
| United States | 10,493,092 | ANTISENSE COMPOUNDS | 2028 | Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides | ||||
| Europe | 3067421 | OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF | 2032 | Gapmer oligonucleotides having at least one bicyclic, one 2’-modified nucleoside and one 2’-deoxynucleoside |
LIgand-Conjugated Antisense (LICA) Technology
We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties. We designed our N-acetyl-galactosamine, or GalNAc LICA medicines to provide an increase in potency for targets in the liver. We have successfully obtained issued patent claims covering our LICA technology conjugated to any modified oligonucleotide, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some examples of our issued patents in this category:
| Jurisdiction | Patent | Title | Expiration | Description of Claims | ||||
| United States | 9,127,276 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides | ||||
| United States | 9,181,549 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any nucleoside having a 2’-MOE modification or a cEt modification | ||||
| Europe | 2991661 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 10,266,822 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2025 | Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA | ||||
| United States | 8,110,560 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2025 | Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA | ||||
| Europe | 1910395 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2026 | Sequence and chemistry (full 2’-MOE) of SPINRAZA | ||||
| Europe | 3308788 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2026 | Pharmaceutical compositions that include SPINRAZA | ||||
| United States | 7,838,657 | SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES | 2027 | Oligonucleotides having sequence of SPINRAZA | ||||
| United States | 8,361,977 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING | 2030 | Sequence and chemistry (full 2’-MOE) of SPINRAZA | ||||
| United States | 8,980,853 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Methods of administering SPINRAZA | ||||
| United States | 9,717,750 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Methods of administering SPINRAZA to a patient | ||||
| Europe | 3449926 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Pharmaceutical compositions that include SPINRAZA for treating SMA | ||||
| Europe | 3305302 | COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT | 2030 | Antisense compounds including SPINRAZA for treating SMA |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 8,101,743 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2025 | Antisense sequence and chemistry of TEGSEDI | ||||
| United States | 8,697,860 | DIAGNOSIS AND TREATMENT OF DISEASE | 2031 | Composition of TEGSEDI | ||||
| United States | 9,061,044 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Sodium salt composition of TEGSEDI | ||||
| United States | 9,399,774 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Methods of treating transthyretin amyloidosis by administering TEGSEDI | ||||
| Europe | 2563920 | MODULATION OF TRANSTHYRETIN EXPRESSION | 2031 | Composition of TEGSEDI |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,624,496 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2023 | Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA | ||||
| United States | 7,598,227 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2023 | Methods of treating hyperlipidemia, lowering cholesterol levels or lowering triglyceride levels with WAYLIVRA | ||||
| United States | 7,750,141 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2023 | Antisense sequence and chemistry of WAYLIVRA | ||||
| Europe | 1622597 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Antisense sequence and chemistry of WAYLIVRA | ||||
| Europe | 2441449 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA | ||||
| Europe | 3002007 | MODULATION OF APOLIPOPROTEIN C-III EXPRESSION | 2024 | Compounds complementary to an ApoCIII nucleic acid for use in therapy | ||||
| United States | 9,157,082 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION | 2032 | Methods of using ApoCIII antisense oligonucleotides for reducing pancreatitis and chylomicronemia and increasing HDL | ||||
| United States | 9,593,333 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS | 2034 | Methods of treating lipoprotein lipase deficiency with an ApoCIII specific inhibitor wherein triglyceride levels are reduced | ||||
| Europe | 2956176 | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS | 2034 | ApoCIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or familial chylomicronemia syndrome |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 7,951,934 | COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN | 2027 | Antisense sequence of tominersen | ||||
| United States | 8,952,145 | COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN | 2027 | Antisense compound specifically hybridizable within the nucleotide region of HTT targeted by tominersen | ||||
| Europe | 2161038 | COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN | 2027 | Antisense sequence of tominersen | ||||
| United States | 9,273,315 | MODULATION OF HUNTINGTIN EXPRESSION | 2030 | Composition of tominersen | ||||
| United States | 8,906,873 | MODULATION OF HUNTINGTIN EXPRESSION | 2030 | Methods of treating Huntington’s disease by administering tominersen | ||||
| Europe | 2475675 | MODULATION OF HUNTINGTIN EXPRESSION | 2030 | Composition of tominersen |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 8,993,529 | ANTISENSE MODULATION OF SUPEROXIDE DISMUTASE 1, SOLUBLE EXPRESSION | 2021 | Pharmaceutical compositions that include antisense compounds specifically hybridizable within nucleotide region of SOD-1 targeted by tofersen | ||||
| Europe | 2270024 | ANTISENSE MODULATION OF SUPEROXIDE DISMUTASE 1, SOLUBLE EXPRESSION | 2022 | Antisense compound specifically hybridizable within nucleotide region of SOD-1 targeted by tofersen | ||||
United States | 10,385,341 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Composition of tofersen | ||||
United States | 10,669,546 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Methods of treating a SOD-1 associated neurodegenerative disorder by administering tofersen | ||||
| Europe | 3126499 | COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION | 2035 | Composition of tofersen |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,574,193 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Methods of lowering Apo(a) and/or Lp(a) levels with an oligonucleotide complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
United States | 10,478,448 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Methods of treating hyperlipidemia with an oligonucleotide complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
United States | 9,884,072 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen | ||||
| Europe | 2855500 | METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION | 2033 | Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen for decreasing Apo(a) expression | ||||
United States | 9,181,550 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION | 2034 | Composition of pelacarsen | ||||
| Europe | 2992009 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION | 2034 | Composition of pelacarsen |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 10,683,499 | COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION | 2034 | Composition of IONIS-TTR-LRx | ||||
| Europe | 3524680 | COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION | 2034 | Composition of IONIS-TTR-LRx |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,163,239 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION | 2034 | Composition of IONIS-APOCIII-LRx | ||||
| Europe | 2991656 | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION | 2034 | Composition of IONIS-APOCIII-LRx |
| Jurisdiction | Patent No. | Title | Expiration | Description of Claims | ||||
| United States | 9,127,276 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides | ||||
| United States | 9,181,549 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any nucleoside having a 2’-MOE modification or a cEt modification | ||||
| Europe | 2991661 | CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE | 2034 | Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides |
Manufacturing Patents
We also own patents claiming methods of manufacturing and purifying oligonucleotides.oligonucleotides and related compounds. These patents claim methods for improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification. These methods allow us to manufacture oligonucleotides at lower cost by, for example, eliminating expensive manufacturing steps.
Government Regulation
Regulation by government authorities in the U.S. and other countries is a significant component in the development, manufacture and commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act, the Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future federal, state and local regulations.
Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our medicines. In particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we conduct business. The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval monitoring and reporting, sampling, quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing facilities and procedures.
Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to ensure that they are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict regulations regarding changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.
The FDA must approve any new medicine before a manufacturer can market it in the U.S. In order to obtain approval, we and our partners must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation strategy, or REMS, to help ensure the benefits of the medicine outweigh the potential risks. For example, TEGSEDI has a REMS program. The requirements for REMS can materially affect the potential market and profitability of our medicines. In foreign jurisdictions, the drug approval process is similarly demanding.
Pricing and Reimbursement
For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of coverage and adequate reimbursement by third-party payors,payers, including governments and private health plans. The process for determining whether a payorpayer will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payorpayer will pay for the product, or procedures whichthat utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations. For example, third-party payorspayers may limit coverage to specific products on an approved list, or formulary, which might not include all of U.S. FDA-approved products for a particular indication. Moreover, a payer's decision to provide coverage for a medicine does not imply that an adequate reimbursement rate will be approved. Additionally, coverage and reimbursement for drugs can differ significantly from payer to payer. One third-party payer's decision to cover a particular medicine does not ensure that other payers will also provide coverage for the medicine or will provide coverage at an adequate reimbursement rate.
Third-party payers are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medicines and services, in addition to their safety and efficacy. To obtain coverage and reimbursement for any medicine that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies to demonstrate the medical necessity and cost-effectiveness of our medicine. These studies will be in addition to the studies required to obtain regulatory approvals. If third-party payers do not consider a medicine to be cost-effective compared to other available therapies, they may not cover the medicine after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to sell such medicine at a profit.
In certain jurisdictions, governments may also regulate or influence coverage, reimbursement and/or pricing of our medicines to control cost or affect use. WithinIn the EU a varietyEuropean community, governments influence the price of payors pay for medicines, with governments being the primary source of payment. Negotiating pricing with governmental authorities can delay commercialization. Suchdrugs through their pricing and reimbursement factors could impact our abilityrules and control of national health care systems that fund a large part of ourthe cost of those medicines to consumers. Some jurisdictions operate positive and negative list systems under which medicines may only be marketed once a reimbursement price has been agreed to by the government. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical studies that compare the cost effectiveness of a particular drug candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines but monitor and control company profits.
The marketability of any medicine for which we receive regulatory approval for commercial partnerssale may suffer if the government and third-party payers fail to successfully commercialize approved medicines. Further, it is possible that additional governmental action is takenprovide adequate coverage and reimbursement. In addition, the focus on cost containment measures in responsethe U.S. and other countries has increased and we expect will continue to increase the COVID-19 pandemic.pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if we attain favorable coverage and reimbursement status for one or more medicines for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in efforts to bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for medicines. Further, itFor example, in August 2022, President Biden signed the Inflation Reduction Act of 2022, or the IRA, into law, which includes key actions aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price cap on such drugs, known as the Maximum Fair Price. There are important exemptions to the Maximum Fair Price, including for medications that are orphan drug designated and approved for only one rare disease, and drugs with low Medicare spend as defined by the Centers for Medicare & Medicaid Services. Specifically, in an effort to curb Medicare patients’ out-of-pocket costs for prescription drugs, the Part D redesign legislation under the IRA requires, among other things, (1) a cap on out-of-pocket drug spending under Part D, (2) drug manufacturers to pay a rebate to the federal government if prices for drugs covered under Part D and Part B increase faster than the rate of inflation, and (3) drug manufacturers to contribute to the catastrophic coverage phase for Part D drugs as discounts through a manufacturer discount program. The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. These provisions take effect progressively starting in fiscal year 2023. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is possible that additional governmental action is taken incurrently subject to legal challenges. In response to the COVID-19 pandemic.Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care. It is unclear whether the models will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.
Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payers. Our future product sales may be subject to additional discounts from list price in the form of rebates and discounts provided to 340B covered entities. Changes to the 340B program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.
In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCA, which regulateregulates the distribution and tracing of prescription drugs and prescription drug samples at the federal level and setsets minimum standards for the regulation of drug distributors by the states. The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
Other healthcare laws that may affect our ability to operate include, for example, the following:
| ● | The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; |
| ● | Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and |
| ● | The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the |
Sales and Marketing
Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid Services, other divisions of the U.S. Department of Health and Human Services,HHS, the U.S. Department of Justice, and similar foreign, state and local government authorities, regulate sales, promotion and other activities following drug approval. As described above, the FDA regulates all advertising and promotion activities for drugs under its jurisdiction both prior to and after approval. Only those claims relating to safety and efficacy that the FDA has approved may be used in labeling. Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those we tested and the FDA approved. Such off-label uses are common across medical specialties and often reflect a physician’s belief that the off-label use is the best treatment for the patients. The FDA does not regulate the behavior of physicians in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers’ communications regarding off-label uses. If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA. Promotion of off-label uses of drugs can also implicate the false claims laws described below.
In the U.S., sales, marketing and scientific/educational programs must also comply with various federal and state laws pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal for a prescription drug manufacturer to solicit, offer, receive, or pay any remuneration in exchange for, or to induce, the referral of business, including the purchase or prescription of a particular drug. Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, recent healthcare reform legislation has strengthened these laws. For example, the PPACAPatient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or Affordable Care Act, among other things, amends the intent requirement of the federal anti-kickback and criminal healthcare fraud statutes to clarify that a person or entity does not need to have actual knowledge of this statute or specific intent to violate it. In addition, PPACAthe Affordable Care Act clarifies that the government may assert that a claim that includes items or services resulting from a violation of the federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the false claims statutes. False claims laws prohibit anyone from knowingly and willingly presenting, or causing to be presented for payment, to third-party payers (including Medicare and Medicaid) claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed, or claims for medically unnecessary items or services. Our activities relating to the sale and marketing of our drugs may be subject to scrutiny under these laws. Further, HIPAA also prohibits, among other things, executing or attempting to execute a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters. Violations of fraud and abuse laws may be punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid) and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies. Similar sanctions and penalties also can be imposed upon executive officers and employees, including criminal sanctions against executive officers under the so-called “responsible corporate officer” doctrine, even in situations where the executive officer did not intend to violate the law and was unaware of any wrongdoing.
Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of such violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, and corporate integrity agreements.agreements, and could include criminal penalties. If the government were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions. Our activities could be subject to challenge for the reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law enforcement authorities. OtherAs described above, other healthcare laws that may affect our ability to operate include the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; analogous state laws governing the privacy and security of health information, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report annually to the U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.Act. Further, there are an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. Many of these laws contain ambiguities as to what is required to comply with the laws. Given the lack of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities.
Similar rigid restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries. Even in those countries where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us.
As discussed above, both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations designed to contain or reduce the cost of healthcare, including new models aimed to lower of cost of drugs, promote accessibility, and improve quality of care and initiatives to control the price of prescription drugs using march-in rights under the Bayh-Dole Act.
The Foreign Corrupt Practices Act
The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising, paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to obtain or retain business or an improper advantage. If we violate the FCPA, it could result in large civil and criminal penalties as well as an adverse effect on our reputation, operations, and financial condition. We could also face collateral consequences such as debarment and the loss of export privileges. In addition, in many other countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is no certainty that all employees and third-party business partners (including our contract research organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions.
Competition
Our Business in General
Some of our medicines may compete with existing therapies for market share and some of our medicines in development may compete for patients in studyclinical trials. In addition, there are a number of companies pursuing the development of oligonucleotide-based technologiesgenetic medicines and the development of pharmaceuticals utilizing these technologies. These companies include biopharmaceutical companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, and formulations.
Our approved productscommercial medicines and our products undermedicines in development address numerous markets. The diseases our medicines target for which we have or may receive marketing authorization will determine our competition. For some of our products,medicines, an important factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can develop products,medicines, complete the clinical trials and marketing authorization processes and supply commercial quantities of the productsmedicines to the market are important competitive factors. We expect to compete with products approved for sale based on a variety of factors, including, among other things, product efficacy, safety, mechanism of action, dosing convenience,administration, marketing and sales strategy and tactics, availability, price, and reimbursement.
Below we have included what we believe to be the competitive landscape formedicines that compete or may compete directly with our marketed medicines and for the medicines we currently have in Phase 3 trials. We have included medicines that we believe compete or may compete directly with our medicines. We included competitors, potential competitors that are past Phase 1 development or potential competitors that plan to start a pivotal study this year. We do not believe that any medicines meet these criteria to compete with pelacarsen.
SPINRAZA
We consider the following medicines as competitors and potential future competitors to SPINRAZA for the indication of SMA:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
Zolgensma (Onasemnogene | Novartis | Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene | Approved for | Intravenous infusion | ||||
Evrysdi (Risdiplam) | A small molecule medicine that modulates splicing of the SMN2 gene | Approved for SMA in | Oral | |||||
OAV101 (Onasemnogene abeparvovec) | Novartis | Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene | Phase 3 | Intrathecal injection |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
We considerbelieve that the following medicines as competitors and potential future competitors to TEGSEDI and IONIS-TTR-LRx for the indication of hATTR amyloidosis and/or ATTR cardiomyopathy:medicine could compete with QALSODY in SOD1-ALS:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
Phase 2 | Intravenous | |||||||
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
We believe thatconsider the following medicines could compete with WAYLIVRAas competitors and IONIS-APOCIII-LRx in FCS:potential future competitors to WAINUA and TEGSEDI for ATTRv-PN and/or ATTR-CM:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
Onpattro (Patisiran) | Received CRL in the U.S. for ATTR-CM Approved in US, EU, Japan and select other markets for ATTRv-PN | Intravenous infusion | ||||||
Vyndaqel/Vyndamax (Tafamidis and tafamidis meglumine) | Pfizer | A small molecule medicine to stabilize TTR protein | Approved in EU, Japan and select other markets for ATTRv-PN, ATTR-CM; indications vary by region | Oral | ||||
Amvuttra (Vutrisiran) | Subcutaneous | |||||||
| Oral | ||||||||
| NTLA-2001 | Intellia/ Regeneron | CRISPR therapeutic candidate designed to reduce circulating TTR protein levels | Phase 3 ATTR-CM | Intravenous Infusion | ||||
| ALXN2220 | AstraZeneca | A monoclonal IgG1 which acts by targeting and depleting TTR protein | Phase 3 ATTR-CM | Intravenous Infusion | ||||
| NNC6019-0001 | Novo Nordisk | A monoclonal antibody to deplete amyloid via antibody-mediated phagocytosis | Phase 2 ATTR-CM | Intravenous Infusion |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
We believe that the following medicines could compete with tominersenWAYLIVRA and olezarsen in Huntington’s Disease:FCS and SHTG:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
ARO-APOC3 (Plozasiran) | ||||||||
| Pegozafermin | ||||||||
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
We believe that the following medicines could potentially compete with tofersen:donidalorsen as a prophylactic treatment for patients with HAE:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
Takhzyro (lanadelumab-flyo) | Subcutaneous Injection | |||||||
Cinryze (C1 esterase inhibitor) | Takeda | A human plasma protein that mediates inflammation and coagulation | Approved for HAE patients six years and older | Intravenous Infusion | ||||
Orladeyo (berotralstat) | BioCryst | Oral | ||||||
| Oral | ||||||||
(C1 esterase inhibitor) | C1 esterase inhibitor | Approved for HAE patients 6 years and older | Subcutaneous Injection | |||||
| Garadacimab | CSL Behring | An anti-factor XIIa monoclonal antibody | Under regulatory review in the U.S. and EU | Subcutaneous Injection | ||||
| Deucrictibant | Pharvaris | An oral B2-receptor antagonist | Phase 2 | Oral | ||||
| STAR-0215 | Astria | A | Subcutaneous Injection | |||||
| NTLA-2002 | Intellia | CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene | Phase 1/2 | Intravenous Infusion |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
Zilganersen
We believe there are no medicines in clinical development for AxD.
Ulefnersen
We believe there are no medicines in clinical development for FUS-ALS.
Pelacarsen
We believe that the following medicines could compete with pelacarsen in CVD in patients with elevated LP(a):
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
| Olpasiran | Amgen/ Arrowhead | RNAi therapeutic designed to lower Lp(a) | Phase 3 | Subcutaneous Injection | ||||
| Zerlasiran | Silence | RNAi therapeutic designed to lower Lp(a) | Phase 2 | Subcutaneous Injection | ||||
| Lepodisiran | Lilly | RNAi therapeutic designed to lower Lp(a) | Phase 2 | Subcutaneous Injection | ||||
| Muvalaplin | Lilly | Small molecule therapy to lower Lp(a) | Phase 2 | Oral |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
Bepirovirsen
We believe that the following medicines could compete with bepirovirsen in HBV:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
Elebsiran (VIR-2218) | Vir Biotech / Alnylam | RNAi therapeutic to reduce HBV viral antigens | Phase 2 | Subcutaneous Injection | ||||
Imdusiran (AB-729) | Arbutus Biopharma | RNAi therapeutic to reduce HBV viral antigens | Phase 2 | Subcutaneous Injection | ||||
| Xalnesiran | Roche | RNAi therapeutic to reduce HBV viral antigens | Phase 2 | Subcutaneous Injection |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
IONIS-FB-LRx
We believe that the following medicines could compete with IONIS-FB-LRx in IgAN:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
| Tarpeyo (budesonide) | Calliditas | A corticosteroid indicated to reduce proteinuria in adults with primary IgAN | Approved for IgAN | Oral | ||||
Filspari (Sparsentan) | Travere | An endothelin & angiotensin II receptor antagonist to reduce proteinuria in adults with primary IgAN | Approved for IgAN | Oral | ||||
| Atrasentan | Novartis (Chinook) | An endothelin A receptor antagonist | Phase 3 (IgAN) | Oral | ||||
| Iptacopan | Novartis (Chinook) | A factor B inhibitor of the alternative complement pathway | Phase 3 (IgAN) | Oral | ||||
| Zigakibart | Novartis (Chinook) | An anti-APRIL monoclonal antibody | Phase 3 (IgAN) | Subcutaneous Injection | ||||
| Sibeprenlimab | Otsuka (Visterra) | A humanized IgG2 monoclonal antibody that inhibits APRIL | Phase 3 (IgAN) | Intravenous Infusion | ||||
| Atacicept | Vera | A recombinant fusion protein a dual inhibitor of BLyS and APRIL | Phase 3 (IgAN) | Subcutaneous Injection | ||||
| Ravulizumab | Alexion (AstraZeneca) | A humanized monoclonal antibody to complement factor 5 | Phase 2 (IgAN) | Subcutaneous Injection | ||||
| Vemircopan | Alexion (AstraZeneca) | A complement factor D inhibitor | Phase 2 (IgAN) | Oral | ||||
| Felzartamab | Hi-Bio | A monoclonal antibody directed against CD38 | Phase 2 (IgAN) | Intravenous Infusion |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
We believe that the following medicines could compete with IONIS-FB-LRx in GA:
| Medicine | Company | Medicine Description (1) | Phase (1) | Route of Administration (1) | ||||
| Ivervay (avacincaptad pegol) | Iveric Bio | A complement C5 inhibitor approved for GA secondary to AMD | Approved (GA) | Intravitreal | ||||
| Syfovre (pegcetacoplan) | Apellis | A complement C5 inhibitor approved for GA secondary to AMD | Approved (GA) | Intravitreal | ||||
| Tinlarebant | Belite Bio | A small molecule RBP4 antagonist | Phase 3 (GA) | Oral | ||||
| Danicopan | Alexion | A factor D inhibitor | Phase 2 (GA) | Oral | ||||
| PPY988 (GT005) | Novartis | A gene therapy with encoding for human complement factor I | Phase 2 (GA) | Intraocular | ||||
| AVD-104 | Aviceda | A glycomimetic nanoparticle | Phase 2 (GA) | Intravitreal | ||||
| ANX007 | Annexon Bio | A fragment antigen-binding (fab) antibody | Phase 2 (GA) | Intravitreal |
| (1) | Taken from public documents including respective company press releases, company presentations, and scientific presentations. |
Corporate Responsibility and Environmental, Social and Governance Initiatives
We believe operating responsibly and sustainably creates long-term value for our company and our stakeholders. We recognize the importance of Corporate Responsibility, or CR, and Environmental, Social and Governance, or ESG, initiatives as it relates to our business strategy and risk assessment. In 2023, we continued to evolve our CR program by building on our foundation and further defining our strategic direction. This includes completing our first CR materiality assessment, updating our CR framework to better focus on our ESG priorities and developing goals to drive and measure our performance.
We began reporting on CR metrics in 2021 and have continued to expand disclosure since then. In 2023, we established three strategic CR pillars that we believe are most important to our business:
Ionis Corporate Responsibility Strategic Pillars
Innovate to improve the lives of people with serious diseases | Empowering our employees and communities | Operating responsibly and sustainably |
| We innovate across the business and work tirelessly to discover, develop and deliver important new medicines for people with serious diseases. | We are committed to fostering an inclusive culture that drives excellence, embraces diversity, and supports our communities. | We operate with integrity to help create a better, more sustainable future for all through environmental stewardship and responsible business practices and stakeholder interactions. |
•Innovation and R&D •Access and Affordability •Patient Advocacy and Engagement | •Workplace Culture, Talent Attraction and Development •Diversity, Equity and Inclusion •Social Impact and Community Engagement | •Environmental Sustainability •Governance and Integrity •Data Privacy and Cybersecurity |
Our CR initiatives are driven by our Chief Executive Officer and executive-level CR Steering Committee, or CR Committee. The CR Committee consists of senior leaders in key functions across the company, including legal, finance, investor relations, human resources, research and development, manufacturing, commercial, compliance and corporate affairs. In 2023, we expanded our CR Committee to include a broader cross-section of senior leaders to ensure we continue to develop the right programs and policies.
The CR Committee is part of our governance framework, which defines responsibilities and ensures we have the right systems and controls to oversee ethical and sustainable operations across our business. Our Board of Directors oversees our overall CR strategy and management of material ESG risks and opportunities and receives updates related to corporate governance and corporate responsibility from the CR Committee at least once annually. In 2023, the Nominating, Governance and Review Committee assumed responsibility for CR and ESG-related matters.
We look to our stakeholders and third-party frameworks such as the Sustainability Accounting Standards Board Health Care – Biotechnology and Pharmaceuticals Standard and the Task Force on Climate-Related Financial Disclosures to inform our approach and our disclosures.
We will share more details on our updated CR framework, goals and ESG initiatives in our 2023 CR Report, which will be published in April 2024 and available on our website. Nothing in the report or on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.
Employees &and Human Capital
As of February 18, 2021,15, 2024, we employed 757927 people, the vast majority of whom reside in the United States.U.S. A significant number of our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies. Our average employee turnover rate in 20202023 was 11.57 percent, excluding reductions related to the Akcea Acquisition, while the turnover for life sciences/sciences and medical device companies over this period was 2123 percent according to a survey published by Radford – an Aon Hewitt Company. Given the uniqueness and complexity of our technology, it is critical to retain the knowledge and experience of outstanding long service employees. The experience and seniority of our employees is as critical to our future success as it has been to the success we have enjoyed to date.
Collective bargaining agreements do not cover any of our employees, and management considers relations with our employees to be good. We believe that the future will be defined by outstanding people and we are committed to recruiting, developing, motivating, and rewarding them.
We encourage you to visit our website for more detailed information regarding our Human Capital programs and initiatives. Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.
Benefits
| ● | Comprehensive medical, dental and vision insurance; |
| ● | 401(k) matching; |
| ● | Stock options, RSUs and an Employee Stock Purchase Plan, or |
| ● | Vacation, holiday, sick time and paid time off for volunteering; |
| ● | Wellness |
| ● | Flexible spending accounts for health and dependent day care needs; |
| ● | Family care benefits; |
| ● | Life, AD&D insurance and long-term disability insurance coverage options; and |
| ● | Employee Assistance Program, or |
We recognize achievements with salary increases, stockequity awards, promotions, and bonus opportunities.
Pay Equity
We are committed to paying our employees fairly, regardless of their gender, ethnicity, race, age or other personal characteristics. To ensure we are achieving our commitment, we benchmark and evaluate pay based on market data and consider factors such as an employee’s role and experience, an employee’s performance and internal equity. We also regularly review our compensation practices, both in terms of our overall workforce and individual employees, to ensure our pay is fair and equitable.
Diversity, Equity and Inclusion
At Ionis, we encourage diversity in our workforce. Prejudicial barriers to human potential and productivity are foreign to our values. We recognize that in order for the full potential of our workforce to be realized, we must cultivate an inclusive culture where all employees feel empowered to contribute fully in an environment that values different perspectives, leading to better ideas and increased innovation. We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors.
Training and Development
We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills to be successful.successful at Ionis. All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: “Working the Ionis Way.”
We empower our employees to build rewarding careers at Ionis, driven by a culture of yeshaving a bias to act that encourages personal and professional employee growth. Ionis offers robust training opportunities with course offerings and events available to every employee regardless of level or function. In addition, employees also have access to Ionis’ learning and development library whichthat houses important information on career growth and planning. By supporting our employees, we know that each professional development milestone enables our continued success.
Information about our Executive Officers
The following sets forth certain information regarding our executive officers as of February 18, 2021:15, 2024:
| Name | Age | Position | ||
| Brett P. Monia, Ph.D. | Chief Executive Officer | |||
| Joseph T. Baroldi | 46 | Executive Vice President, Chief Business Officer | ||
| Brian Birchler | 58 | Executive Vice President, Corporate and Development Operations | ||
| C. Frank Bennett, Ph.D. | Executive Vice President, Chief Scientific Officer | |||
| Onaiza Cadoret-Manier | Executive Vice President, Chief | |||
| Richard S. Geary, Ph.D. | Executive Vice President, Chief Development Officer | |||
| Elizabeth L. Hougen | Executive Vice President, Finance and Chief Financial Officer | |||
| Patrick R. O’Neil, Esq. | ||||
| Eugene Schneider, M.D. | Executive Vice President, Chief Clinical Development and Operations Officer | |||
| Eric E. Swayze, Ph.D. | Executive Vice President, Research |
BRETT P. MONIA, Ph.D.
Chief Executive Officer
Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr. Monia served as Chief Operating Officer. From January 2012 to January 2018, Dr. Monia served as Senior Vice President. From February 2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 to February 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000 he held various positions within our Molecular Pharmacology department.
JOSEPH T. BAROLDI, M.A., M.B.A., M.S.
Executive Vice President, Chief Business Officer
Mr. Baroldi has served as Ionis’ Executive Vice President, Chief Business Officer since January 2022. Prior to Ionis, Mr. Baroldi was the chief operating officer at Avidity Biosciences, a biotechnology company focused on oligonucleotide-based therapies. Prior to Avidity, Mr. Baroldi was Vice President, Business Development at Ionis, where he held several roles of increasing responsibility from 2009 to 2020. Mr. Baroldi has also held positions in strategic planning and scientific research for Gen-Probe Inc.
BRIAN BIRCHLER
Executive Vice President, Corporate and Development Operations
Mr. Birchler has served as Ionis’ Executive Vice President, Corporate and Development Operations since March 2022. From January 2008 to March 2022, Mr. Birchler served as our Senior Vice President, Drug Development Operations. From January 2005 to January 2008 he served as our Vice President, Drug Development Operations and from January 2003 to January 2005, as our Vice President, Development Chemistry and Operations. Mr. Birchler joined Ionis in 1995 as Senior Scientist/Senior Research Associate. Prior to joining Ionis, Mr. Birchler was employed by CIBA Vision Corp. and Burroughs Wellcome Pharmaceuticals in various engineering, development and commercial positions.
C. FRANK BENNETT, Ph.D.
Executive Vice President, Chief Scientific Officer
Dr. Bennett has served as Ionis’ Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr. Bennett was promoted to Chief Scientific Officer. From January 2006 to December 2019, Dr. Bennett served as Senior Vice President, Antisense Research. From June 1995 to January 2006, Dr. Bennett served as our Vice President, Research. From March 1993 to June 1995, he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular and Cellular Biology department. Prior to joining Ionis in 1989, Dr. Bennett was employed by SmithKline and French Laboratories in various research positions. He is a member of the Board of Directors for Flamingo Therapeutics and an external member of the Scientific Advisory Board of Experimental Therapeutics Center in Singapore and the Hereditary Disease Foundation.
ONAIZA CADORET-MANIER
Executive Vice President, Chief Corporate DevelopmentGlobal Product Strategy and CommercialOperations Officer
Ms. Cadoret-Manier has served as Ionis’ Executive Vice President, Chief Product Strategy and Operations Officer since February 2022. From April 2020 to February 2022, Ms. Cadoret-Manier served as our Executive Vice President, Chief Corporate Development and Commercial Officersince April 2020.. Ms. Cadoret-Manier joined Ionis as Chief Corporate Development and Commercial Officer in January 2020. Prior to joining Ionis, from 2018 to 2019 Ms. Cadoret-Manier was the chief commercial officer for Grail Biosciences, an early detection genomics company. Prior to Grail, Ms. Cadoret-Manier was vice president of the Respiratory Franchise at Genentech where she worked from 2011 to 2018. Ms. Cadoret-Manier also has held multiple senior management positions overseeing corporate strategy, alliances, and marketing and sales for numerous disease areas for Genentech, Pfizer and Amylin Pharmaceuticals.
RICHARD S. GEARY, Ph.D.
Executive Vice President, Chief Development Officer
Dr. Geary has served as Ionis’ Executive Vice President, Chief Development Officer since January 2021. From April 2020 to December 2020, Dr. Geary served as our Executive Vice President, Development and from August 2008 to March 2020, was our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group Leader for the bioanalytical and preclinical pharmacokinetics group in the Applied Chemistry Department at Southwest Research Institute.
ELIZABETH L. HOUGEN
Executive Vice President, Finance and Chief Financial Officer
Ms. Hougen has served as Ionis’ Executive Vice President and Chief Financial Officer since April 2020. From January 2013 to March 2020, Ms. Hougen served as our Senior Vice President, Finance and Chief Financial Officer. From January 2007 to December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 2007, she served as our Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance and Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.
PATRICK R. O’NEIL, Esq.
Mr. O’Neil has served as Ionis’ Executive Vice President,Chief Legal Officer and General Counsel.Counsel since September 2021. Mr. O’Neil also serves as our Corporate Secretary. From March 2020 to September 2021, Mr. O’Neil served as our Executive Vice President, Legal & General Counsel and Chief Compliance Officer and Corporate Secretary.Officer. From January 2013 to March 2020, Mr. O’Neil served as our Senior Vice President, Legal and General Counsel. From September 2010 to January 2013, Mr. O’Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. O’Neil was an associate at Cooley LLP.
EUGENE SCHNEIDER, M.D.
Executive Vice President, Chief Clinical Development and Operations Officer
Dr. Schneider was promoted tohas served as Ionis’ Executive Vice President and Chief Clinical Development and Operations Officer of Ionis insince September 2023. From January 2021.2021 to September 2023, Dr. Schneider served as our Executive Vice President and Chief Clinical Development Officer. From August 2018 to December 2020, Dr. Schneider served as our Senior Vice President, Head of Clinical Development. From April 2015 to July 2018, Dr. Schneider was our Vice President, Clinical Development, Severe and Rare Diseases. Dr. Schneider joined Ionis in December 2013 as Executive Director, Clinical Development. Dr. Schneider has two decades of experience in clinical development primarily in the rare diseases space. Prior to joining Ionis, Dr. Schneider was senior medical director at both Synageva BioPharma and Biovail Technologies Ltd.
ERIC E. SWAYZE, Ph.D.
Executive Vice President, Research
Dr. Swayze has served as Ionis’ Executive Vice President, Research since April 2020 and is responsible for leading preclinical antisense drug discovery and antisense technology research. In January 2020, Dr. Swayze was promoted to Senior Vice President of Research. Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology.
Investing in our securities involves a high degree of risk. You should carefully consider carefully the following information about the risks described below, together with the other information contained in this report and in our other public filings in evaluating our business. If any of the following risks actually occur, our business could be materially harmed, and our financial condition and results of operations could be materially and adversely affected. As a result, the trading price of our securities could decline, and you might lose all or part of your investment.
Risks Related to the Commercialization of our Medicines
We have limited experience as a company in commercializing medicines and we maywill have to continue to invest significant resources to develop theseour capabilities. If we are unable to establish effective marketing, sales, market access, distribution, and distribution capabilitiesrelated functions, or enter into agreements with third parties to market, sell and distributecommercialize our medicines, we may not be able to generate revenue from our medicines.
We currently rely on third parties for the commercialization of our marketed medicines, have limited experience as a company in commercializing medicines and will have to continue to invest significant financial and management resources to develop the marketing, sale and distribution of pharmaceutical products and thereinfrastructure required to successfully commercialize our medicines. There are significant risks involved in building and managing a sales organization, including our ability to hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team. We will also need to continue to scale-up existing internal support functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs. Any failure to effectively managebuild or maintain the infrastructure required to successfully commercialize our internalmedicines, including our sales, marketing, market access, distribution, and distributionrelated capabilities, wouldor scale-up our existing support functions, could adversely impact the commercialization ofrevenue we generate from our medicines. WeIn addition, if we choose to rely on third parties to assist us in commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers to assist us in sales, marketing and distribution functions on acceptable financial terms, or at all. Even ifIf we are ablecontinue to engage third parties to market, sell and distributeassist us in the commercialization of our medicines, our product revenues and profitability may be lower if we rely on such third parties for these functions than if we were to perform them on our own. In addition, we likely will have little control overcommercialized such third parties, and any of them may fail to devote the necessary resources and attention to market, sell and distribute our medicines effectively. If we are not successful in commercializing our medicines, either on our own or through arrangements with one or more third parties, we may not be able to generate revenue from our medicines.
ourselves.If the market does not accept our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines and our medicines in development, we are not likely to generate substantial revenues or become consistently profitable.
Even if our medicines are authorized for marketing, including SPINRAZA, TEGSEDI and WAYLIVRA, our success will depend upon the medical community, patients and third-party payers accepting our medicines as medically useful, cost-effective, safe and convenient. Even when the FDA or foreign regulatory authorities authorize our or our partners’ medicines for commercialization, doctors may not prescribe our medicines to treat patients. WeFurthermore, we and our partners may not successfully commercialize additional medicines.
Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, then we may not be able to sell our medicines in that market. Similarly, cost control initiatives by governments or third-party payers could decrease the price received for our medicines or increase patient coinsurance to a level that makes our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines and our medicines in development, economically unviable. If the pricing of any of our medicines decreases for any reason, it will reduce our revenue for such medicine. For example, Biogen has in the past disclosed that SPINRAZA revenue decreased in part due to lower pricing in the U.S. and certain rest-of-world markets.
The degree of market acceptance for our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines and our medicines in development, depends upon a number of factors, including the:
| ● | receipt and scope of marketing authorizations; |
| ● | establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing products; |
| ● | cost and effectiveness of our medicines compared to other available therapies; |
| ● | patient convenience of the dosing regimen for our medicines; and |
| ● | reimbursement policies of government and third-party payers. |
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept or use any of the medicines that we or our partners may develop.
For example, TEGSEDI requires periodic blood and urine monitoring and is available in the U.S. only through a risk evaluation and mitigation strategy, or REMS program. In addition, the product label for TEGSEDI in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis, requires periodic blood and urine monitoring, and TEGSEDI is only available through a Risk Evaluation and Mitigation Strategy, or REMS, program. glomerulonephritis. Our main competitionexternal competitors in the U.S. market for TEGSEDI isare patisiran and vutrisiran, both marketed by Alnylam Pharmaceuticals, Inc. AlthoughNeither patisiran requires intravenous administration and pre-treatment with steroids, it does not havenor vutrisiran has a boxed warning or REMS. nor does either require use of a REMS program. Additionally, the product label for WAYLIVRA in the European Union, or EU, requires regular blood monitoring. In each case, these label requirements couldhave negatively affectaffected our ability to attract and retain patients for these medicines. We believe that the enhanced monitoring we have implemented to support early detection and management of these issues can help manage these safety issues so that patients can continue treatment. Since implementation of the enhanced monitoring, serious platelet events have been infrequent. While we believe we can better maintain patients on TEGSEDI and WAYLIVRA through our patient-centric commercial approach where we plan to have greater involvement with physicians and patients, if we cannot effectively maintain patients on TEGSEDI or WAYLIVRA, including due to limitations or restrictions on our ability to conduct periodic blood and urine monitoring of our patients as a result of the current COVID-19 Pandemic, we may not be able to generate substantial revenue from TEGSEDI or WAYLIVRA sales.
If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines and our medicines in development, our revenue will be limited.
In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and reimbursement from third-party payers. The majority of patients in the U.S. who would fit within our target patient populations for our medicines have their healthcare supported by a combination of Medicare coverage, other government health programs such as Medicaid, managed care providers, private health insurers and other organizations. Coverage decisions may depend upon clinical and economic standards that disfavor new medicines when more established or lower cost therapeutic alternatives are already available or subsequently become available. Assuming coverage is approved, the resulting reimbursement payment rates might not be enough to make our medicines affordable. Accordingly, SPINRAZA, TEGSEDIEven if favorable coverage status and WAYLIVRA for FCSadequate reimbursement rates are attained, less favorable coverage policies and reimbursement rates may be implemented in the EU and, if approved, WAYLIVRA in the U.S. or Canada and for additional indications,future. Accordingly, our commercial medicines and our medicines in development will face competition from other therapies and medicines for limited financial resources. WeFurthermore, we or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of management time and financial and other resources. Third-partyIn addition, third-party payers may never consider our future products as cost-effective. Adequatecost-effective and adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development.
Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs. In addition, in the U.S., no uniform policy of coverage and reimbursement for medicines exists among third-party payers. Therefore, coverage and reimbursement for medicines can differ significantly from payer to payer. For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the Affordable Care Act,ACA, was passed in March 2010, and substantially changed the way healthcare is financed by both governmental and private insurers and continues to significantly impact the U.S. pharmaceutical industry. There remainhave been judicial and Congressional challenges to certain aspects of the Affordable Care Act,ACA, as well as efforts to repeal or replace certain aspects of the Affordable Care Act. On December 18, 2019, the U.S. Court of Appeals for the 5th Circuit upheld the District Court ruling that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the Affordable Care Act are invalid as well. However, in March 2020, before the District Court could rule on the remaining provisions of the Affordable Care Act, the U.S. Supreme Court agreed to review the case. In November 2020, the U.S. Supreme Court heard oral arguments and is expected to rule on the case in its current session, which began in October 2020. Although the U.S. Supreme Court has not yet ruled on the constitutionality of the Affordable Care Act, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the Affordable Care Act marketplace.ACA. It is unclear how the Supreme Court ruling, other suchfuture litigation and healthcare reform measures will impact the Affordable Care ActACA and our business.
Further, we believe that future coverage, reimbursement and reimbursementpricing will likely be subject to increased restrictions both in the U.S. and in international markets. For example, inIn the U.S., recent health reform measures have resulted in reductions in Medicare and other healthcare funding, and there have been several recent U.S. Congressional inquiries, legislation and legislationexecutive orders designed to, among other things, reform government program reimbursement methodologies for medicines and bring more transparency to drug pricing. Such restrictions may include legislative proposals seeking to reduce drug prices, (e.g., by placing limits on pharmaceutical price increases and tying Medicare Part B drug prices to international drug prices), increase competition (e.g.,(including by allowingenhancing support for personal importation of drugs from Canada)generic and biosimilar drugs), lower out-of-pocket drug costs for patients, (e.g.,curtail spread pricing practices by cappingpharmacy benefit managers, and foster scientific innovation to promote better health care and improved health. In addition, the Inflation Reduction Act of 2022, or the IRA, includes key actions aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price cap on such drugs. Specifically, in an effort to curb Medicare patients’ out-of-pocket costs for prescription drugs, the Part D beneficiaryredesign legislation under the IRA requires, among other things, (1) a cap on out-of-pocket pharmacy expenses)drug spending under Part D, (2) drug manufacturers to pay a rebate to the federal government if prices for drugs covered under Part D and Part B increase patient accessfaster than the rate of inflation, and (3) drug manufacturers to lower-cost genericcontribute to the catastrophic coverage phase for Part D drugs as discounts through a manufacturer discount program. The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. These provisions take effect progressively starting in fiscal year 2023. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges. In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and biosimilar drugs. In November 2020,improve quality of care. It is unclear whether the U.S. Departmentmodels will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether or how these selected models or similar policy initiatives will impact prescription drug pricing in the future.
Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payers. Our future product sales may be subject to additional discounts from list price in the form of rebates and discounts provided to covered entities under the Public Health Service Act 340B drug pricing program. Changes to the 340B program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and Human Services issued a final rule modifying the anti-kickback law safe harbors for plans, pharmacies, and pharmaceutical benefit managers. rebate liability.
At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program, or SIP, proposal to import certain drugs from Canada for specific state healthcare programs. It is unclear how this program will be implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada. Other states have also submitted SIP proposals that are pending review by the FDA. Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs. Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, and third-party payers, whether foreign or domestic, or governmental or commercial, may allocate their resources to address the current COVID-19 Pandemic or experience delays or disruptions in their ability to devote resources to coverage and reimbursement matters related to our products or medicines as a result of the COVID-19 Pandemic, which would negatively affect the potential commercial success of our products, our revenue and our profits.
If we or our partners fail to compete effectively, our medicines, including our commercial medicines and our medicines in development, will not generate significant revenues.
Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major pharmaceutical companies and specialized biopharmaceutical firms. In addition, other companies are engaged in developing RNA-targeted technology. Our competitors may succeed in developing medicines that are:
| ● | priced lower than our medicines; |
| ● | reimbursed more favorably by government and other third-party payers than our medicines; |
| ● | safer than our medicines; |
| ● | more effective than our medicines; or |
| ● | more convenient to use than our medicines. |
These competitive developments could make our medicines, including our commercial medicines and our medicines in development, obsolete or non-competitive.
Certain of our partners are pursuing other technologies or developing other medicines either on their own or in collaboration with others, including our competitors, to treat some of the same diseases our own collaborative programs target. Competition may negatively impact a partner’s focus on and commitment to our medicines and, as a result, could delay or otherwise negatively affect the commercialization of our medicines, including our commercial medicines and our medicines in development.
Many of our competitors have substantially greater financial, technical and human resources than we do. In addition, many of these competitors have significantly greater experience than we do in conducting preclinical testing and human clinical studies of new pharmaceutical products, in obtaining FDA and other regulatory authorizations of such products and in commercializing such products. Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do or more successfully commercialize their products.
There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain geographic markets of products against targets that are also targets of products in our development pipeline. For example:
| ● | Onasemnogene abeparvovec and risdiplam compete with SPINRAZA; |
| ● | Taldefgrobep alfa, Evrysdi + GYM329 and NMD670 could compete with SPINRAZA; |
| ● | Patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with TEGSEDI and WAINUA; |
| ● | Acoramidis, NTLA-2001 and NNC6019-0001 could compete with TEGSEDI and WAINUA; |
| ● | ARO-APOC3 and pegozafermin could compete with WAYLIVRA and olezarsen; |
| ● | Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous, garadacimab, deucrictibant, NTLA-2002 and STAR-0215 could compete with donidalorsen; |
| ● | Olpasiran, zerlasiran, lepodisiran and muvalaplin could compete with pelacarsen; |
| ● | NI-005/AP-101 could compete with QALSODY; |
| ● | VIR-2218 + PEG-IFN-α, VIR-3434 ± VIR-2218 ± PEG-IFN-α, VIR-2218 + BRII-179, NI-204VIR-2218 + GS-9688 + nivolumab, AB-729, imdusiran + Peg-IFNa-2α + NA, xalnesiran + RG6084 + NA, xalnesiran + NA, xalnesiran + pegIFN + NA, xalnesiran + RO7049389 + NA, xalnesiran + ruzotolimod + NA, RO7049389 + ruzotolimod + NA could complete with bepirovirsen; and |
| ● | Budesonide, sparsentan, atrasentan, iptacopan, zigakibart, sibeprenlimab, atacicept, ravulizumab, vemircopan, felzartamab, povetacicept, avacincaptad pegol, pegcetacoplan, tinlarebant, danicopan, GT005, AVD-104 and ANX007 could compete with IONIS-FB-LRx. |
SPINRAZA injection for intrathecal use is an antisense medicine indicated for the treatment of SMA patients of all ages approved in over 50 countries. Specifically, SPINRAZA faces competition from onasemnogene abeparvovec, a gene therapy product that was approved in the U.S. in May 2019 and in the EU in May 2020 for the treatment of SMA, as well as risdiplam, an oral product for the treatment of SMA that was approved in the U.S. in August 2020 and in the EU in March 2021. Biogen has in the past disclosed that SPINRAZA revenue decreased due to a reduction in demand as a result of increased competition and that future sales of SPINRAZA may be adversely affected by competing products.
Additionally, companies that are developing medicines that target the same patient populations as our medicines in development may compete with us to enroll participants in the clinical trials for such medicines, which could make it more difficult for us to complete enrollment for these clinical trials.
Our medicines could be subject to regulatory limitations following approval.
Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the manufacture, marketing and distribution of medicines. Promotional communications regarding prescription medicines must be consistent with the information in the product’s approved labeling. We or our partners may not obtain the labeling claims necessary or desirable to successfully commercialize our medicines, including our commercial medicines and our medicines in development.
The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine through the product label and on advertising, promotional and distribution activities. For example:
| ● | in the U.S., TEGSEDI’s label contains a boxed warning for thrombocytopenia and glomerulonephritis; |
| ● | TEGSEDI requires periodic blood and urine monitoring; and |
| ● | in the U.S., TEGSEDI is available only through a REMS program. |
Prescription medicines may be promoted only for the approved indication(s) in accordance with the approved label. The FDA and other regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of post-approval clinical studies or patient monitoring, which could be time consuming and expensive. For example, in connection with the conditional marketing approval for WAYLIVRA in the EU, we are required to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. If the results of such post-marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authorities may withdraw marketing authorization or may condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill.
If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur subsequent to regulatory approval, or if we, our CMOs or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to conduct additional clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines.
We depend on our collaborations with Biogen for the development and commercialization of SPINRAZA and QALSODY.
We have entered into separate collaborative arrangements with Biogen to develop and commercialize SPINRAZA and QALSODY. We entered into these collaborations primarily to:
| ● | fund our development activities for SPINRAZA and QALSODY; |
| ● | seek and obtain regulatory approvals for SPINRAZA and QALSODY; and |
| ● | successfully commercialize SPINRAZA and QALSODY. |
We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA and QALSODY, generate additional clinical data for SPINRAZA and QALSODY, manufacture SPINRAZA and QALSODY, and successfully commercialize SPINRAZA and QALSODY. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaborations. If Biogen fails to further develop SPINRAZA or QALSODY, obtain additional regulatory approvals for SPINRAZA or QALSODY, manufacture SPINRAZA or QALSODY, or successfully commercialize SPINRAZA or QALSODY, or if Biogen’s efforts in any of these respects are ineffective, revenues for SPINRAZA or QALSODY would be negatively affected.
In addition, our collaborations with Biogen may not continue for various reasons. Biogen can terminate our collaborations at any time. If Biogen stops developing or commercializing SPINRAZA or QALSODY, we would have to seek or spend additional funding, and SPINRAZA’s or QALSODY’s commercialization may be harmed.
We depend on our collaboration with AstraZeneca for the joint development and commercialization of WAINUA.
We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize WAINUA. Under the terms of the collaboration agreement, we and AstraZeneca will co-develop and co-commercialize WAINUA in the U.S. and AstraZeneca will have the sole right to commercialize WAINUA in all other countries. As a company we do not have experience with co-commercialization arrangements. We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for WAINUA is not successful for any reason, WAINUA may not meet our commercial objectives and our revenues for WAINUA may be limited.
In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for WAINUA in the U.S. by mutual agreement. If any subcommittee cannot reach unanimous agreement on any matter within its respective scope of authority, such matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize WAINUA.
If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.
To successfully commercialize any of our medicines, we would need to optimize and manage large-scale commercial manufacturing capabilities either on a standalone basis or through a third-party manufacturer. We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and drug product for WAYLIVRA. Any delays or disruption to our own or third-party commercial manufacturing capabilities, including any interruption to our supply chain as a result of the current COVID-19 Pandemic, could limit the commercial success of our medicines.
In addition, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine. There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these suppliers will need to increase their scale of production to meet our projected needs for commercial manufacturing. Further, we must continue to improve our manufacturing processes to allow us to reduce our drug costs. We or our partners may not be able to manufacture our medicines at a cost or in quantities necessary to make commercially successful products.
We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and WAINUA and drug product for WAYLIVRA. Any delays or disruption to our own or third-party commercial manufacturing capabilities could limit the commercial success of our medicines.
Risks Related to the Development and Regulatory Approval of our Medicines
If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines, we or our partners cannot sell them in the applicable markets.
We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for commercialization. In addition, it is possible that SPINRAZA, TEGSEDI and WAYLIVRAour commercial medicines may not be approved in additional markets or for additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies to demonstrate the safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners must conduct these studies in compliance with FDA regulations and with comparable regulations in other countries.
We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for our medicines. It is possible that regulatory agenciesauthorities will not approve our medicines for marketing or SPINRAZA, TEGSEDI or WAYLIVRAour commercial medicines in additional markets or for additional indications. If the FDA or another regulatory agencyauthority believes that we or our partners have not sufficiently demonstrated the safety or efficacy of any of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines or our medicines in development, the agencyauthority will not approve the specific medicine or will require additional studies, which cancould be time consuming and expensive and which will delay or harm commercialization of the medicine. For example, in August 2018 we received a complete response letter from the FDA regarding the new drug application for WAYLIVRA in which the FDA determined that the safety concerns identified with WAYLIVRA in our clinical development program outweighed the expected benefits of triglyceride lowering in patients with FCS. We also received a Notice of Non-Compliance Withdrawal Letter, or Non-W, from Health Canada for WAYLIVRA in November 2018. We are engaged with the FDA and plan to work with Health Canada to confirm a path forward for WAYLIVRA.
The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including:
| ● | such authorities may disagree with the design or implementation of our clinical studies; |
| ● | we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication; |
| ● | such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the standard of care is potentially different from the U.S.; |
| ● | we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval; |
| ● | such authorities may disagree with the interpretation of data from preclinical or clinical studies; |
| ● | such authorities may find deficiencies in |
| ● | the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner rendering our clinical data insufficient for approval. |
Failure to receive marketing authorization for our medicines in development, or failure to receive additional marketing authorizations for SPINRAZA, TEGSEDI or WAYLIVRA,our commercial medicines, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.
If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to abandon one or more of our drug development programs.
Drug discovery and drug development hashave inherent risks and the historical failure rate for drugs is high. Antisense medicines are a relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human use in the intended indication,indication(s), we may need to abandon one or more of our drug development programs.
Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in late-stage clinical studies.
Successful results in preclinical or initial human clinical studies, including the Phase 2 results for some of our medicines in development, may not predict the results of subsequent clinical studies. If any of our medicines in Phase 3 clinical studies includingdo not show sufficient efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
In the past, we have invested in clinical studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies or have been discontinued for other reasons. For example, in October 2021, Biogen reported that QALSODY did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring QALSODY were seen across multiple secondary and exploratory measures of disease activity and clinical function. In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen tofersen, pelacarsen, IONIS-TTR-LRx and IONIS-APOCIII-LRx. in patients with manifest Huntington’s disease based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results could occur in clinical studies for our other medicines.
There are a number of factors that could cause a clinical study to fail or be delayed, including:
| ● | the clinical study may produce negative or inconclusive results; |
| ● | regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements; |
| ● | we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of efficacy in the trial; |
| ● | we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; |
| ● | enrollment in our clinical studies may be slower than we anticipate; |
| ● | we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not identify, recruit |
| ● | the institutional review board for a prospective site might withhold or delay its approval for the study; |
| ● | people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the clinical study process or personal issues; |
| ● | a clinical study site may deviate from the protocol for the study; |
| ● | the cost of our clinical studies may be greater than we anticipate; |
| ● | our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and |
| ● | the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed. |
Moreover, our commercial medicines are chemically similar to each other. As a result, a safety observation we encounter with one of our medicines could have, or be perceived by a regulatory authority to have, an ongoing OLE extension study of WAYLIVRA in patients with FCSimpact on a different medicine we are developing. This could cause the FDA or other regulators to ask questions or take actions that could harm or delay our ability to develop and an OLE study of TEGSEDI in patients with hATTR, and an early access program,commercialize our medicines or EAP, for WAYLIVRA. Adverse events or results from these studies or the EAPs could negatively impactincrease our pending or future marketing approval applications for WAYLIVRA and TEGSEDI in patients with FCS or hATTR amyloidosis or the commercial opportunity for WAYLIVRA or TEGSEDI.
costs. Any failure or delay in theour clinical studies including the studies of tominersen, tofersen, pelacarsen, IONIS-TTR-LRx and IONIS-APOCIII-LRx, could reduce the commercial potential or viability of our medicines.
We depend on third parties to conduct our clinical studies for our medicines and any failure of those parties to fulfill their obligations could adversely affect our development and commercialization plans.
We depend on independent clinical investigators, contract research organizations and other third-party service providers to conduct our clinical studies for our medicines and expect to continue to do so in the future. For example, we use clinical research organizations, such as Pharmaceutical Research Associates, Inc., Icon Clinical Research Limited, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc., PPD and MedpaceThermo Fisher Scientific Inc. for the clinical studies for our medicines, including tominersen, tofersen, pelacarsen, IONIS-TTR-LRxWAINUA for the treatment of ATTR-CM, donidalorsen, olezarsen, ulefnersen and IONIS-APOCIII-LRx.zilganersen. We rely heavily on these parties for successful execution of our clinical studies, but do not control many aspects of their activities. For example, the investigators are not our employees. However,employees, but we are responsible for ensuring that these third partiessuch investigators conduct each of our clinical studies in accordance with the general investigational plan and approved protocols for the study. Third parties may not complete activities on schedule or may not conduct our clinical studies in accordance with regulatory requirements or our stated protocols. The failureFor example, some of our key vendors have in the past experienced labor shortages, which impacted their ability to perform services for us for certain of our clinical trials. Subsequent failures of these third parties to carry out their obligations,, including as a result of delays or disruption caused by the current COVID-19 Pandemic that may affect the third party’s ability to conduct the clinical studies for our medicines, or a termination of our relationship with thesesuch third parties, could delay or prevent the development, marketing authorization and commercialization of our medicinesmedicines.
In addition, while we do not have any clinical trial sites in Ukraine or Gaza, we do have a limited number of clinical trial sites in Russia and Israel that may be materially impacted by the ongoing wars between Russia and Ukraine and military conflicts in Israel and the surrounding areas, as well as related political or economic responses and counter-responses by various global actors, or collectively, conflicts in Eastern Europe and the Middle East, and could result in difficulties enrolling or completing our clinical trials in such areas on schedule. Furthermore, the U.S. and its European allies have imposed significant sanctions against Russia, including regional embargoes, full blocking sanctions, and other restrictions targeting major Russian financial institutions. The U.S. government has also indicated it will consider imposing additional marketing authorizations for TEGSEDIsanctions and WAYLIVRA.other similar measures in the future. Our ability to conduct clinical trials in Russia may become restricted under applicable sanctions laws, which would require us to identify alternative trial sites, and could increase our costs and delay the clinical development of certain of our medicines.
Since corporate partnering is a significant part of our strategy to fund the advancement and commercialization of our development programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional partners, we may have to delay or stop progress on our drug development programs.
To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add key development resources. We plan to continue to rely on additional collaborative arrangements to develop and commercialize manysome of our unpartnered medicines. However, we may not be able to negotiate favorable collaborative arrangements for these drug programs. If we cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer.
Our corporate partners are developing and/orand funding many of the medicines in our development pipeline. For example, we are relying on:
| ● |
| ● | Novartis for development and funding of pelacarsen; |
| ● |
| ● | Roche for development and funding of IONIS-FB-LRx. |
If any of these pharmaceutical companies stops developing and/orand funding these medicines, our business could suffer and we may not have, or be willing to dedicate, the resources available to develop these medicines on our own. Our collaborators can terminate their relationships with us under certain circumstances, many of which are outside of our control. For example, as part of a reprioritization of its pipelinein 2022, Pfizer and strategic review of its rare disease business, GSK declined its optionBayer decided to license TEGSEDIdiscontinue the clinical development programs for vupanorsen and IONIS-FB-LRx.fesomersen, respectively.
Even with funding from corporate partners, if our partners do not effectively perform their obligations under our agreements with them, it would delay or stop the progress of our drug development and commercial programs.
In addition to receiving funding, we enter into collaborative arrangements with third parties to:
| ● | conduct clinical studies; |
| ● | seek and obtain marketing |
| ● | manufacture |
Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development programs, such as our collaborations with AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, PfizerOtsuka and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we first anticipated.
For example, a collaborator such as AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, PfizerOtsuka or Roche, could determine that it is in its financial interest to:
| ● | pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us; |
| ● | pursue higher-priority programs or change the focus of its own development programs; or |
| ● | choose to devote fewer resources to our medicines than it does |
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise negatively affect the commercialization of our medicines, including QALSODY, SPINRAZA, tominersen, pelacarsenWAINUA, bepirovirsen, donidalorsen, IONIS-FB-LRx and tofersen.pelacarsen.
Risks Associated with our Businesses as a Whole
Risks related to our financial results
If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.
Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our drug programs will require significant additional research, development, manufacturing, preclinical and clinical testing, marketing authorization,authorizations, preclinical activities and commitment of significant additional resources prior to their successful commercialization. TheseIn addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the expansion of our manufacturing capabilities. All of these activities will require significant cash. As of December 31, 2020,2023, we had cash, cash equivalents and short-term investments equal to $1.9$2.3 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA,our commercial medicines, or to license certain medicines and proprietary technologies, we will need additional funding in the future. Our future capital requirements will depend on many factors such as the following:as:
| ● | successful commercialization of |
| ● | the profile and launch timing of our medicines |
| ● | changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements; |
| ● | continued scientific progress in our research, drug discovery and development programs; |
| ● | the size of our programs and progress with preclinical and clinical studies; |
| ● | the time and costs involved in obtaining marketing authorizations; |
| ● | competing technological and market developments, including the introduction by others of new therapies that address our |
| ● | our manufacturing requirements and capacity to fulfill such requirements. |
If we need additional funds, we may need to raise them through public or private financing. Additional financing may not be available at all or on acceptable terms.terms or at all. If we raise additional funds by issuing equity securities, the shares of existing stockholders will be diluted and the price, as well as the price of our other securities, may decline. If adequate funds are not available or not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs.programs, or commercial operations. Alternatively, we may obtain funds through arrangements with collaborative partners or others, which could require us to give up rights to certain of our technologies or medicines.
We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future.
Because drug discovery and development require substantial lead-time and money prior to commercialization, our expenses have generally exceeded our revenue since we were founded in January 1989. As of December 31, 2023, we had an accumulated deficit of approximately $1.8 billion and stockholders’ equity of approximately $0.4 billion. Most of our income has historically come from collaborative arrangements, including commercial revenue from royalties and R&D revenue, with additional income from research grants and the sale or licensing of our patents, as well as interest income. We will now and continuing into the foreseeable future need to invest significant financial resources to develop capabilities to commercialize medicines on our own and expect that our income in the future will be driven primarily by commercial sales. If we do not earn substantial revenue from commercial sales, we may incur additional operating losses in the future, which could restrict our ability to successfully develop additional medicines or sustain future profitability.
We may not be entitled to obtain additional milestone payments under our royalty monetization agreement with Royalty Pharma.
In January 2023, we entered into a Royalty Purchase Agreement with Royalty Pharma Investments. In addition to the $500 million we received at closing, this agreement makes available to us up to an additional $625 million in milestone payments. However, these additional milestone payments are subject to satisfaction of certain conditions related to the regulatory approval or commercial sales of pelacarsen, in certain cases by specific deadlines. Should we not satisfy such conditions by the applicable deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments to us could be substantially less than the maximum amounts available thereunder.
Risks related to our intellectual property
If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us.
Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual property rights to proprietary products and services. However, we may not receive issued patents on any of our pending patent applications in the U.S. or in other countries and we may not be able to obtain, maintain or enforce our patents and other intellectual property rights, any of which could impact our ability to compete effectively. In addition, the scope of any of our issued patents may not be sufficiently broad to provide us with a competitive advantage. Furthermore, other parties may successfully challenge, invalidate or circumvent our issued patents or patents licensed to us so that our patent rights do not create an effective competitive barrier or revenue source.
We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in foreign countries will consider the claims in our patents and applications covering SPINRAZA, TEGSEDI, WAYLIVRA,our commercial medicines, or any of our medicines in development, as patentable. Method-of-use patents protect the use of a product for the specified method. This type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method. Moreover, even if competitors do not actively promote their product for our targeted indications, physicians may prescribe these products off-label. Although off-label prescriptions may infringe or contribute to the infringement of method-of-use patents, the practice is common and such infringement is difficult to prevent, includingeven through legal action.
If we or any licensor partner loses or cannot obtain patent protection for SPINRAZA, TEGSEDI, WAYLIVRA,our commercial medicines or any of our other medicines in development, it could have a material adverse impact on our business.
Intellectual property litigation could be expensive and prevent us from pursuing our programs.
From time to time, we have to defend our intellectual property rights. If we are involved in an intellectual property dispute, we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities. Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
If a third-partythird party claims that our medicines or technology infringe its patents or other intellectual property rights, we may have to discontinue an important product or product line, alter our products and processes, pay license fees or cease certain activities. We may not be able to obtain a license to needed intellectual property on favorable terms, if at all. There are many patents issued or applied for in the biotechnology industry, and we may not be aware of patents or patent applications held by others that relate to our business. This is especially true since patent applications in the U.S. are filed confidentially for the first 18 months. Moreover, the validity and breadth of biotechnology patents involve complex legal and factual questions for which important legal issues remain.
Risks related to product liability
We are exposed to potential product liability claims, and insurance against these claims may not be available to us at a reasonable rate in the future or at all.
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing and sale of therapeutic products, including potential product liability claims related to our commercial medicines and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage. However, this insurance coverage may not be adequate to cover claims against us, or be available to us at an acceptable cost, if at all. Regardless of their merit or eventual outcome, product liability claims may result in decreased demand for our medicines, injury to our reputation, withdrawal of clinical study volunteers and loss of revenues. Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material.
Risks related to our business strategy and personnel
The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our business and reduce our likelihood of success.
We are dependent on the principal members of our management and scientific staff.staff, and as we move towards commercializing medicines on our own, we will become increasingly dependent on the principal members of our commercial team. We do not have employment agreements with any of our executive officersemployees that would prevent them from leaving us. The loss of our management, and key scientific or commercial employees might slow the achievement of important research and development or commercial goals. It is also critical to our success that we recruit and retain qualified scientific personnel to perform research and development work.work and that we recruit and retain qualified marketing, sales, market access, distribution, and related personnel to commercialize our medicines. We may not be able to attract and retain skilled and experienced scientific personnel on acceptable terms because of intense competition for experienced scientistspersonnel among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies or in commercializing our medicines may make it more challenging to recruit and retain qualified scientific personnel. Similarly,personnel.
Risks related to pandemics, climate change and other events
Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, wars, civil or political unrest, terrorism or other catastrophic events.
Our business could be adversely affected by health epidemics in regions where we or our partners are commercializing our medicines, have concentrations of clinical trial sites or other business operations, and could cause disruption in the operations of third-party manufacturers and contract research organizations upon whom we rely. For example, enrollment in some of our clinical trials was delayed due to the COVID-19 pandemic.
In recent years, extreme weather events and changing weather patterns have become more common. As a result, we are potentially exposed to varying natural disaster or extreme weather risks such as hurricanes, tornadoes, fires, droughts, floods, or other events that may result from the impact of climate change on the environment. The potential impacts of climate change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we currently manufacture most of our research and clinical supplies in a manufacturing facility located in Carlsbad, California. We manufacture the finished drug product for TEGSEDI, WAINUA and WAYLIVRA at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA and QALSODY. The facilities and the equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace.
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, wars, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed. Although we possess property damage and business interruption insurance coverage, this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a shutdown of the U.S. government, including the FDA.
Risks related to cybersecurity, social media and artificial intelligence
We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.
We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to operate our business. The multitude and complexity of our computer systems may make them vulnerable to service interruption or destruction, disruption of data integrity, malicious intrusion, or random attacks. Likewise, data privacy or security incidents or breaches by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized persons or to the public. Cyber-attacks are increasing in their frequency, sophistication and intensity, particularly as companies (including us) moved to more remote work structures during and following the COVID-19 pandemic. In addition, the number and frequency of cybersecurity events globally may be heightened during times of geopolitical tension or instability between countries, including, for example, the ongoing conflicts in Eastern Europe and the Middle East.
Cyber-attacks could include the deployment of harmful malware, denial-of-service, social engineering and other means to affect service reliability and threaten data confidentiality, integrity and availability. Our business partners face similar risks and any security breach of their systems could adversely affect our security posture. A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, delay progress on the development of our medicines, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue. Moreover, the prevalent use of mobile devices that access confidential information increases the risk of data security breaches, which could lead to the loss of confidential information, trade secrets or other intellectual property. While we have invested, and continue to invest, in the protection of our data and information technology infrastructure, our efforts may not prevent service interruptions or identify breaches in our systems that could adversely affect our business and operations and result in the loss of critical or sensitive information, which could result in financial, legal, business or reputational harm to us.
The increasing use of social media platforms and artificial intelligence based software presents new risks and challenges.
Social media is increasingly being used to communicate about our medicines and the diseases our therapies are designed to treat. Social media practices in the biopharmaceutical industry continue to evolve and regulations relating to such use are not always clear and create uncertainty and risk of noncompliance with regulations applicable to our business. There is also a risk of inappropriate disclosure of sensitive information or negative or inaccurate posts or comments about us on social media. We may also encounter criticism on social media regarding our company, management, or medicines. Our reputation could be damaged by negative publicity or if adverse information concerning us is posted on social media platforms or similar mediums, which we may not be able to reverse. If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face restrictive regulatory actions or incur other harm to our business.
Additionally, the use of artificial intelligence, or AI, based software is increasingly being used in the biopharmaceutical industry. Use of AI based software may lead to the release of confidential proprietary information, which may impact our ability to realize the benefit of our intellectual property.
Risks related to our securities and the global credit markets
If we do not progress in our programs as anticipated, the price of our securities could decrease.
For planning purposes, we estimate and may disclose the timing of a variety of clinical, regulatory and other milestones, such as when we anticipate a certain medicine will enter clinical trials, when we anticipate completing a clinical study, or when we anticipate filing an application for, or obtaining, marketing authorization, or when we or our partners plan to commercially launch a medicine. We base our estimates on present facts and a variety of assumptions, many of which are outside of our control. If we do not achieve milestones in accordance with our or our investors’ or securities analysts’ expectations, including milestones related to our commercial medicines and medicines in development, the price of our securities could decrease.
If the price of our securities continues to be highly volatile, this could make it harder to liquidate your investment and could increase your risk of suffering a loss.
The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and is likely to continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of our securities. During the 12 months preceding December 31, 2023, the closing market price of our common stock ranged from $52.27 to $32.69 per share. Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.
Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. For example, recent events such as the COVID-19 pandemic, the ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank have caused disruptions of global financial markets and resulted in increased volatility in the trading price of our common stock. In addition, industry factors may materially harm the market price of our common stock. Nasdaq, and the market for biotechnology companies in particular, have historically experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of investor confidence in the market for biotechnology or pharmaceutical stocks or the stocks of other companies that investors perceive to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could depress our stock price regardless of our business, prospects, financial conditions or results of operations.
Provisions in our certificate of incorporation, bylaws, convertible notes documents, call spread hedge transaction documents and Delaware law may prevent stockholders from receiving a premium for their shares.
Our certificate of incorporation provides for classified terms for the members of our board of directors. Our certificate also includes a provision that requires at least 66 2/3 percent of our voting stockholders to approve a merger or certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where certain directors approve the transaction or certain minimum price criteria and other procedural requirements are met.
Our certificate of incorporation also requires that any action required or permitted to be taken by our stockholders must be taken at a duly called annual or special meeting of stockholders and may not be taken by written consent. In addition, only our board of directors, chairperson of the board or chief executive officer can call special meetings of our stockholders. We have in the past, and may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis. In addition, our board of directors has the authority to fix the rights and preferences of, and issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without action by our stockholders.
The provisions of our convertible senior notes could make it more difficult or more expensive for a third party to acquire us. Upon the occurrence of certain transactions constituting a fundamental change, holders of the notes will have the right, at their option, to require us to repurchase all of their notes or a portion of their notes, which may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over the then-current market prices.
In 2023, we completed a $575 million offering of 1.75% Notes and used $488.2 million of the net proceeds from the issuance of the 1.75% Notes to repurchase $504.4 million of our 0.125% Notes. In 2021, we completed a $632.5 million offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million. In 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. Additionally, in connection with the pricing of our 0% Notes and 0.125% Notes, we entered into call spread transactions in which we purchased note hedges and sold warrants. Terminating or unwinding the call spread transactions could require us to make substantial payments to the counterparties under those agreements or may increase our stock price. The costs or any increase in stock price that may arise from terminating or unwinding such agreements could make an acquisition of our company significantly more expensive to the purchaser.
These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then-current market prices, and may limit the ability of our stockholders to approve transactions that they think may be in their best interests.
Future sales of our common stock in the public market could adversely affect the trading price of our securities.
Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could occur, could adversely affect trading prices of our securities. For example, as of December 31, 2023, we may issue approximately 28.2 million shares of our common stock upon conversion of our 1.75% Notes, 0% Notes and 0.125% Notes. In connection with the issuance of the 0% Notes and 0.125% Notes, we entered into certain call spread transactions covering 10.9 million shares and 6.6 million shares, respectively, that we expect will offset the dilution to holders of common stock upon any conversion of those notes. In addition, of the shares reserved, 6.1 million shares are reserved for issuance upon conversion of 0.125% Notes that we have repurchased and are currently held by us in treasury (and thus would not be dilutive). As a result, to the extent we elect to convert the 0.125% Notes held by us in treasury, we expect we would receive up to 6.1 million shares upon settlement of related convertible note hedges (without any additional dilution caused by the conversion of the 0.125% Notes held in treasury). However, the anti-dilutive effect of the convertible note hedges is offset by certain warrant transactions we entered into in connection with the issuance of the 0% Notes and the 0.125% Notes. The addition of any of these shares into the public market may have an adverse effect on the price of our securities.
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and 0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock. The call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the converted 0% Notes or 0.125% Notes, as the case may be. However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants.
Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial condition or stock price.
The global credit and financial markets have experienced extreme volatility and disruptions recently, including as a result of the COVID-19 pandemic, ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank. These disruptions can result in severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. There can be no assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur. If the current equity and credit markets deteriorate, it may make any necessary debt or equity financing more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our operations, growth plans, financial performance or stock price. In addition, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover any or all of our losses and may not continue to be available to us on acceptable terms, or at all.
A variety of risks associated with operating our business and marketing our medicines internationally could adversely affect our business. In addition to our U.S. operations, we are commercializing TEGSEDI in the EU, Canada, Latin America and certain Caribbean countries, and WAYLIVRA in the EU, Latin America and certain Caribbean countries. We face risks associated with our international operations, including possible unfavorable regulatory, pricing and reimbursement, political, tax and labor conditions, which could harm our business. Because we have international operations, we are subject to numerous risks associated with international business activities, including:
| ● | compliance with differing or unexpected regulatory requirements for our medicines and foreign employees; |
| ● | complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems; |
| ● | difficulties in staffing and managing foreign operations; |
| ● | in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners; |
| ● | foreign government taxes, regulations and permit requirements; |
| ● | U.S. and foreign government tariffs, trade and export restrictions, price and exchange controls and other regulatory requirements; |
| ● | anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions; |
| ● | economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, in particular foreign countries or globally; |
| ● | fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing business in another country; |
| ● | compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad; |
| ● | workforce uncertainty in countries where labor unrest is more common than in the U.S.; and |
| ● | changes in diplomatic and trade relationships. |
Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the United Kingdom’s Bribery Act 2010. In many other countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is no certainty that all employees and third-party business partners (including our contract research organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions. Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition.
Risks related to compliance with laws
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry, including federal and state anti-kickback laws, false claims laws, transparency laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. Penalties for violations of applicable healthcare laws and regulations may include significant civil, criminal and administrative penalties, damages, disgorgement, fines, imprisonment, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and additional reporting requirements and oversight if we enter into a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws. In addition, violations may also result in reputational harm, diminished profits and future earnings.
Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with laws regulating the protection of the environment and health and human safety, our business could be adversely affected.
Our research, development and manufacturing activities involve the use of potentially harmful biological materials as well as materials, chemicals and various radioactive compounds that could be hazardous to human health and safety or the environment. We store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California pending ultimate use and disposal. We cannot completely eliminate the risk of contamination, which could cause:
| ● | interruption of our research, development and manufacturing efforts; |
| ● | injury to our employees and others; |
| ● | environmental damage resulting in costly clean up; and |
| ● | liabilities under federal, state and local laws and regulations governing health and human safety, as well as the use, storage, handling and disposal of these materials and resultant waste products. |
In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although we carry insurance for pollution liability in amounts and types that we consider commercially reasonable, the coverage or coverage limits of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would be adversely affected.
Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our costs and the risk of noncompliance.
Each year we are required to evaluate our internal control systems to allow management to report on, and our Independent Registered Public Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a result, we continue to incur additional expenses and divert our management’s time to comply with these regulations. In addition, if we cannot recruitcontinue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation by regulatory authorities, such as the SEC, the Public Company Accounting Oversight Board, or PCAOB, or The Nasdaq Global Select Market. Any such action could adversely affect our financial results and retain qualified marketing, salesthe market price of our common stock.
The SEC and distribution personnel,other regulators have continued to adopt new rules and regulations and make additional changes to existing regulations that require our abilitycompliance. In July 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted, and in August 2022, the SEC adopted additional rules and regulations under the Dodd-Frank Act related to effectively implement“say on pay” and proxy access. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to additional compliance costs and impact the manner in which we operate our new commercial strategy following the Akcea Acquisition will be adversely affected.business.
Risks related to taxes
Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.
Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses, or NOLs, carried over from a prior taxable year. Under that provision,the Code, we can carryforwardcarry forward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits.
Under the Tax Cut and Jobs Act of 2017, or the Tax Act, as modified by the Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act,current U.S. federal net operating losses incurredincome tax law, U.S. federal NOLs generated in 2018 and in futuretaxable years beginning after December 31, 2017 may be carried forward indefinitely, but the deductibility of such U.S. federal net operating lossesNOLs is limited to 80 percent of taxable income beginning in 2021.income. It is uncertain if and to what extent various states will conform to thecurrent U.S. federal Tax Act or the CARES Act. The CARES Act also reinstated the net operating loss carryback provisions whereby net operating losses incurred in calendarincome tax years 2018, 2019law, and 2020 may be carried back to offset taxable income of the five tax years preceding the year of the loss.
In addition, under Sections 382 and 383 of the Code, and corresponding provisions of state law, if a corporation undergoes an “ownership change,” which is generally defined as a greater than 50 percentpercentage-point cumulative change, by value, in its equity ownership over a three-year period, the corporation’s ability to use its pre-change net operating lossNOL carryforwards and other pre-change tax attributes to offset its post-change income or taxes may be limited. We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of which may be outside of our control. If an ownership change occurs and our ability to use our net operating lossNOL carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively increasing our future tax obligations. As a result of our merger with Akcea Therapeutics, Inc. in 2020, or the Akcea Acquisition,Merger, we will beare subject to the Separate Return Limitation Year,separate return limitation year, or SRLY, Rules.rules. Under the SRLY rules, our utilization of Akcea’s pre-acquisition net operating losspre-merger NOL and tax credit carryforwards will beis limited to the amount of income that Akcea contributes to our consolidated taxable income. The Akcea pre-acquisitionpre-merger tax attributes cannot be used to offset any of the income that Ionis contributes to our consolidated taxable income.
Our future taxable income could be impacted by changes in tax laws, regulations and treaties.
A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could materially affect us.
We could be subject to additional tax liabilities.
We are subject to U.S. federal, state, local and foreign income taxes, sales taxes in the U.S. and foreign income taxes,, withholding taxes and transaction taxes in foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination is uncertain. In addition, our tax obligations and effective tax rates could be adversely affected by changes in the relevant tax, accounting and other laws, regulations, principles and interpretations, including those relating to income tax nexus, by recognizing tax losses or lower than anticipated earnings in jurisdictions where we have lower statutory rates and higher than anticipated earnings in jurisdictions where we have higher statutory rates, by changes in foreign currency exchange rates, or by changes in the valuation of our deferred tax assets and liabilities. We may be audited in various jurisdictions, and such jurisdictions may assess additional taxes, sales taxes and value-added taxes against us. Although we believe our tax estimates are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our operating results or cash flows in the period for which a determination is made.made.
We have implemented and maintain various information security processes designed to detect, respond to, recover, and protect our technology ecosystem from cybersecurity threats. These processes are designed to identify, assess, and manage material risks that may result from cybersecurity threats and apply to our critical technologies inclusive of global financial marketsnetworks, third party hosted services, communications systems, hardware, software, and has resultedcritical data, including intellectual property and confidential information that is proprietary, strategic, or competitive in increased volatility in the trading price of our common stock. Additionally, broad market and industry factors may also materially harm the market price of our common stock irrespective of our operating performance. The stock market in general, and NASDAQ and the market for biotechnology companies in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of investor confidence in the market for biotechnology or pharmaceutical stocks or the stocks of other companies which investors perceive to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could depress our stock price regardless of our business, prospects, financial conditions or results of operations.nature.
Our certificate of incorporation provides for classified terms for the members ofInformation Technology department, led by our board of directors. Our certificate also includes a provision that requires at least 66 2/3 percent ofSenior Vice President, Information Technology, helps to detect, respond to, and manage cybersecurity threats and risks by monitoring and evaluating our voting stockholders to approve a merger orthreat environment using various manual and automated tools in certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where certain directors approve the transaction or certain minimum price criteriaenvironments and systems and other procedural requirements are met.methods including, for example:
| ● | analyzing reports of certain threats and actors; |
| ● | conducting scans of the threat environment; |
| ● | evaluating our and our industry’s risk profile; |
| ● | evaluating certain threats reported to us; |
| ● | conducting internal and external audits; |
| ● | conducting threat assessments for certain internal and external threats; and |
| ● | conducting vulnerability assessments to identify vulnerabilities. |
Depending on the environment and system, we have implemented and maintain various technical, physical, and organizational measures, processes, standards, and policies designed to manage and mitigate material risks from cybersecurity threats to our critical technologies, including, for example:
| ● | incident response plan; |
| ● | disaster recovery/business continuity plans; |
| ● | risk assessments; |
| ● | encryption of certain data; |
| ● | network security and access controls for certain systems; |
| ● | physical security; |
| ● | asset management, tracking and disposal; |
| ● | systems monitoring; and |
| ● | employee training. |
Our certificateassessment and management of incorporation also requires that any action required or permitted to be taken by our stockholders must be taken atmaterial risks from cybersecurity threats are integrated into the Company’s overall risk management processes. For example, cybersecurity risk is assessed as a duly called annual or special meetingcomponent of stockholders and may not be taken by written consent.the Company’s enterprise risk management program. In addition, onlywe have developed a process whereby our board of directors, chairmansenior management will evaluate material risks from cybersecurity threats against our overall business objectives and will report certain cybersecurity incidents to the Audit Committee of the board or chief executive officer can call special meetingsBoard of Directors, which evaluates our stockholders. overall enterprise risk.
We have in the past,use third-party service providers to perform various functions throughout our business, such as application providers and may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third partyhosting companies. We use third-party service providers to acquire our company on a hostile basis. In addition, our board of directors has the authority to fix the rights and preferences of, and issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without action by our stockholders.
For a description of the notes by purchasingrisks from cybersecurity threats that may materially affect the Company and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative instruments, thathow they may wish to usedo so, see our risk factors under Part 1. Item 1A. Risk Factors in connection with such hedging, which may have a negative effectthis Annual Report on Form 10-K, including the conversion value of those notes and an adverse impact on the trading price of our common stock. The call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the converted 0.125% Notes, as the case may be. However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants.
risk factor titled “We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.risks.”
Our research, developmentBoard of Directors addresses the Company’s cybersecurity risk management as part of its general oversight function. The Audit Committee of the Board of Directors is responsible for overseeing the Company’s cybersecurity risk management processes, including oversight and manufacturing activities involvemitigation of risks from cybersecurity threats.
Our cybersecurity risk assessment and management processes are implemented and maintained by our Senior Vice President, Information Technology, who is an information technology professional with healthcare and digital certifications and has over 25 years of relevant experience, and other employees in our Information Technology department who are certified security professionals and have relevant experience.
Our Senior Vice President, Information Technology is responsible for hiring appropriate personnel, helping to integrate cybersecurity risk considerations into the useCompany’s overall risk management strategy, communicating key priorities to relevant personnel, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-related reports.
Our cybersecurity incident response plan is designed to escalate cybersecurity incidents, depending on the circumstances, to our senior management team and Audit Committee of potentially harmful biological materials as well as materials, chemicalsthe Board of Directors. As part of such process, the Audit Committee of the Board of Directors receives regular reports from our Senior Vice President, Information Technology concerning the Company’s significant cybersecurity threats and various radioactive compounds that could be hazardous to human health and safety or the environment. We store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California pending ultimate use and disposal. We cannot completely eliminate the risk of contamination, which could cause:
Item 2. Properties
As of February 18, 2021,15, 2024, the following are the primary facilities in which we operate:
| Property Description | Location | Square Footage | Owned or Leased | Initial Lease Term End Date | Lease Extension Options | Location | Square Footage | Owned or Leased | Initial Lease Term End Date | Lease Extension Options | ||||||||||
| Laboratory and office space facility | Carlsbad, CA | 176,000 | Owned | Carlsbad, CA | 176,300 | Leased | 2037 | Two, five-year options to extend | ||||||||||||
| Office and meeting space facility | Carlsbad, CA | 74,000 | Owned | Carlsbad, CA | 74,000 | Leased | 2037 | Two, five-year options to extend | ||||||||||||
| Office space facility | Boston, MA | 30,175 | Leased | 2028 | One, five-year option to extend | |||||||||||||||
| Manufacturing facility | Carlsbad, CA | 26,800 | Owned | Carlsbad, CA | 26,800 | Owned | ||||||||||||||
| Manufacturing support facility | Carlsbad, CA | 25,800 | Leased | 2026 | One, five-year option to extend | Carlsbad, CA | 25,800 | Leased | 2026 | One, five-year option to extend | ||||||||||
| Office and storage space facility | Carlsbad, CA | 18,700 | Leased | 2023 | One, five-year option to extend | |||||||||||||||
| Office space facility | Boston, MA | 14,300 | Leased | 2029 | One, five-year option to extend | |||||||||||||||
| Office space facility | Carlsbad, CA | 5,800 | Leased | 2027 | None | |||||||||||||||
| Warehouse facility | Carlsbad, CA | 4,200 | Leased | 2028 | None | |||||||||||||||
| Office space facility | Carlsbad, CA | 5,800 | Leased | 2023 | One, five-year option to extend | Dublin, Ireland | 3,900 | Leased | 2025 | None | ||||||||||
| 357,275 | 331,100 | |||||||||||||||||||
For details of legal proceedings, seerefer to Part IV, Item 15, Note 9,11, Legal Proceedings, in the Notes to the Consolidated Financial Statements.
Not applicable.
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
Market Information and Dividends
Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol “IONS.” As of February 18, 2021,15, 2024, there were approximately 506476 stockholders of record of our common stock. Because many of our shares are held by brokers and other institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented by these record holders.
We have never paid dividends and do not anticipate paying any dividends in the foreseeable future.
Performance Graph (1)
Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 20152018 in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index. The total return assumes reinvestment of dividends.
* $100 invested on December 31, 20152018 in stock or index, including reinvestment of dividends. Fiscal year ending December 31.
COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN
Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index,
and the Nasdaq Biotechnology Index
| Dec-15 | Dec-16 | Dec-17 | Dec-18 | Dec-19 | Dec-20 | Dec-18 | Dec-19 | Dec-20 | Dec-21 | Dec-22 | Dec-23 | |||||||||||||||||||||||||||||||||||||
| Ionis Pharmaceuticals, Inc. | $ | 100.00 | $ | 77.23 | $ | 81.22 | $ | 87.29 | $ | 97.55 | $ | 91.30 | $ | 100.00 | $ | 111.75 | $ | 104.59 | $ | 56.29 | $ | 69.87 | $ | 93.58 | ||||||||||||||||||||||||
| Nasdaq Composite Index | $ | 100.00 | $ | 108.87 | $ | 141.13 | $ | 137.12 | $ | 187.44 | $ | 271.64 | $ | 100.00 | $ | 136.69 | $ | 198.10 | $ | 242.03 | $ | 163.28 | $ | 236.17 | ||||||||||||||||||||||||
| Nasdaq Biotechnology Index | $ | 100.00 | $ | 78.65 | $ | 95.67 | $ | 87.19 | $ | 109.08 | $ | 137.90 | $ | 100.00 | $ | 125.11 | $ | 158.17 | $ | 158.20 | $ | 142.19 | $ | 148.72 | ||||||||||||||||||||||||
| (1) | This section is not “soliciting material,” is not deemed “filed” with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing. |
This financial review presents our operating results for each of the two years in the period ended December 31, 2020,2023, and our financial condition atas of December 31, 2020.2023. Refer to our 20192022 Form 10-K for our results of operations for 20192022 compared to 2018.2021. Except for the historical information contained herein, the following discussion contains forward-looking statements that are subject to known and unknown risks, uncertainties and other factors that may cause our actual results to differ materially from those expressed or implied by such forward-looking statements. We discuss such risks, uncertainties and other factors throughout this report and specifically under Item 1A of Part I of this report, “Risk Factors.”Risk Factors. In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements as indexed on page F-1.included in Item 8 of Part II of this report.
Overview
As noted in our Business Overview in Part I of this report, for more than 30 years, three decades, we have beeninvented medicines that we believe bring better futures to people with serious diseases. Today, as a leaderpioneer in RNA-targeted therapy and believe our medicines, are pioneering new markets, changing standards of care and transforming the lives of people with devastating diseases.we continue to drive innovation in RNA therapies. We currently have threefive marketed medicines: SPINRAZA, QALSODY, WAINUA, TEGSEDI and WAYLIVRA. We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and other areas of high patient need. We currently have nine medicines in Phase 3 development and a late-stage pipeline primarily focused on two core franchises: neurologymultiple additional medicines in early and cardiometabolic. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision of becoming one of the most successful biotechnology companies. Formid-stage development. Refer to Part I, Item 1, Business, for further details on our business refer to the Business section of Part I of this report.and key developments in our medicines.
Below we have included our results of operations for 2023 compared to 2022. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021. The following table provides selected summary information from our consolidated statements of operations for 2023 and 2022 (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Total revenue | $ | 787.6 | $ | 587.4 | ||||
| Total operating expenses | $ | 1,141.4 | $ | 997.6 | ||||
| Loss from operations | $ | (353.7 | ) | $ | (410.2 | ) | ||
| Net loss | $ | (366.3 | ) | $ | (269.7 | ) | ||
| Cash, cash equivalents and short-term investments | $ | 2,331.2 | $ | 1,986.9 | ||||
Revenue
Total revenue for 2023 was $787.6 million compared to $587.4 million in 2022 and was comprised of the following (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Revenue: | ||||||||
| Commercial revenue: | ||||||||
| SPINRAZA royalties | $ | 240.4 | $ | 242.3 | ||||
| Other commercial revenue: | ||||||||
| TEGSEDI and WAYLIVRA revenue, net | 34.9 | 30.1 | ||||||
| Licensing and other royalty revenue | 33.3 | 31.0 | ||||||
| Total other commercial revenue | 68.2 | 61.1 | ||||||
| Total commercial revenue | 308.6 | 303.4 | ||||||
| R&D revenue: | ||||||||
| Amortization from upfront payments | 125.3 | 68.6 | ||||||
| Milestone payments | 100.5 | 74.0 | ||||||
| License fees | 116.8 | 37.0 | ||||||
| Other services | 10.0 | 27.6 | ||||||
| Collaborative agreement revenue | 352.6 | 207.2 | ||||||
| WAINUA joint development revenue | 126.4 | 76.8 | ||||||
| Total R&D revenue | 479.0 | 284.0 | ||||||
| Total revenue | $ | 787.6 | $ | 587.4 | ||||
Commercial revenues in 2023 were relatively consistent compared to 2022. Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which were relatively consistent compared to 2022. Our commercial revenue in 2023 also included royalties from QALSODY U.S. product sales.
Our R&D revenue increased in 2023 compared to 2022 primarily due to continued success with our pipeline and technology. As a result, we earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from our new collaborations with Otsuka, Roche and Novartis.
WAINUA (Eplontersen) Collaboration with AstraZeneca
Our financial results for the years ended December 31, 2023 and 2022 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR. Under the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading and conducting the Phase 3 development program, we are recognizing as R&D revenue the 55 percent of cost-share funding AstraZeneca is responsible for, 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 medical affairs and commercial costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, general and administrative, or SG&A, expenses, respectively. We expect our medical affairs and commercialization expenses to increase as WAINUA advances toward the market under our collaboration with AstraZeneca.
The following is a summary of our financial resultstable sets forth information on revenue and expenses under this collaboration (in millions):
| Year Ended December 31, | ||||||||
| 2020 | 2019 | |||||||
| Total revenue | $ | 729.3 | $ | 1,122.6 | ||||
| Total operating expenses | $ | 901.3 | $ | 756.7 | ||||
| Income (loss) from operations | $ | (172.1 | ) | $ | 365.9 | |||
| Net income (loss) | $ | (486.8 | ) | $ | 303.3 | |||
| Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders | $ | (451.3 | ) | $ | 294.1 | |||
| Cash, cash equivalents and short-term investments | $ | 1,892.4 | $ | 2,499.5 | ||||
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| WAINUA joint development revenue | $ | 126.4 | $ | 76.8 | ||||
| Research and development expenses related to Phase 3 development expenses for WAINUA | 150.8 | 147.1 | ||||||
| Medical affairs expenses for WAINUA | 4.1 | 2.0 | ||||||
| Commercialization expenses for WAINUA | 15.6 | 2.6 | ||||||
Our WAINUA joint development revenue in 2023 includes a $50 million milestone payment from AstraZeneca that we earned when the FDA approved WAINUA for ATTRv-PN in the U.S.
Operating Expenses
The following table sets forth information on operating expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Operating expenses, excluding non-cash compensation expense related to equity awards | $ | 1,035.7 | $ | 897.3 | ||||
| Non-cash compensation expense related to equity awards | 105.7 | 100.3 | ||||||
| Total operating expenses | $ | 1,141.4 | $ | 997.6 | ||||
Our operating expenses, for 2020excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2019 principally2022, primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee we paid to Vect-Horus. Our R&D expenses increased as we advanced our pipeline, which included an increase in the costs associated with our clinical studies as most of our Phase 3 studies were either fully enrolled or approaching full enrollment at the end of 2023. Our SG&A expenses increased due to expenses related to our launch preparation activities for WAINUA, olezarsen and donidalorsen.
To analyze and compare our results of operations to other similar companies, we believe it is important to exclude non-cash compensation expense related to equity awards from our operating expenses. We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations. Further, we internally evaluate the performance of our operations excluding it.
Cost of Sales
Our cost of sales is comprised of costs related to our commercial revenue, which consisted of manufacturing costs, including certain fixed costs, transportation and freight, indirect overhead costs associated with the manufacturing and distribution of TEGSEDI and WAYLIVRA and certain associated period costs.
The following table sets forth information on cost of sales (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Cost of sales, excluding non-cash compensation expense related to equity awards | $ | 8.7 | $ | 13.4 | ||||
| Non-cash compensation expense related to equity awards | 0.4 | 0.7 | ||||||
| Total cost of sales | $ | 9.1 | $ | 14.1 | ||||
Research, Development and Patent Expenses
Our research, development and patent expenses consist of expenses for drug discovery, drug development, medical affairs, manufacturing and development chemistry and R&D support expenses.
The following table sets forth information on research, development and patent expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Research, development and patent expenses, excluding non-cash compensation expense related to equity awards | $ | 821.7 | $ | 759.4 | ||||
| Non-cash compensation expense related to equity awards | 77.9 | 73.7 | ||||||
| Total research, development and patent expenses | $ | 899.6 | $ | 833.1 | ||||
Drug Discovery
We use our proprietary technologies to generate information about the function of genes and to determine the value of genes as drug discovery targets. We use this information to direct our own drug discovery research, and that of our partners. Drug discovery is also the function that is responsible for advancing our core technology. This function is also responsible for making investments in complementary technologies to expand the reach of our technologies.
The following table sets forth information on drug discovery expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Drug discovery expenses, excluding non-cash compensation expense related to equity awards | $ | 125.6 | $ | 181.3 | ||||
| Non-cash compensation expense related to equity awards | 16.2 | 16.2 | ||||||
| Total drug discovery expenses | $ | 141.8 | $ | 197.5 | ||||
Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022. In 2022, we recognized $80 million for licensing Metagenomi’s gene editing technologies.
Drug Development
The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase 3 development for which we have incurred significant costs (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| WAINUA | $ | 115.5 | $ | 103.9 | ||||
| TEGSEDI and WAYLIVRA | 8.1 | 10.6 | ||||||
| Olezarsen | 138.3 | 68.1 | ||||||
| Donidalorsen | 24.9 | 14.1 | ||||||
| Zilganersen | 8.4 | 5.6 | ||||||
| Ulefnersen | 10.8 | 8.4 | ||||||
| Other development projects | 101.0 | 123.5 | ||||||
| Development overhead expenses | 123.3 | 92.0 | ||||||
| Total drug development, excluding non-cash compensation expense related to equity awards | 530.3 | 426.2 | ||||||
| Non-cash compensation expense related to equity awards | 34.5 | 31.5 | ||||||
| Total drug development expenses | $ | 564.8 | $ | 457.7 | ||||
Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to our investments in theadvancing late-stage pipeline and full or nearly full enrollment of many of our Phase 3 program for IONIS-TTR-LRx and our wholly owned pipeline. Additionally, we incurred approximately $90 million in costs related to the Akcea Acquisition and restructured European operations. The costs primarily consisted of severance and retention costs of $29 million and stock-based compensation expensestudies.
We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the accelerationvarious indications we may be studying. Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in certain indications in order to focus our resources on more promising drug candidates or indications. Our Phase 1 and Phase 2 programs are clinical research programs that fuel our Phase 3 pipeline. When our medicines are in Phase 1 or Phase 2 clinical trials, they are in a dynamic state in which we may adjust the development strategy for each medicine. Although we may characterize a medicine as “in Phase 1” or “in Phase 2,” it does not mean that we are conducting a single, well-defined study with dedicated resources. Instead, we allocate our internal resources on a shared basis across numerous medicines based on each medicine’s particular needs at that time. This means we are constantly shifting resources among medicines. Therefore, what we spend on each medicine during a particular period is usually a function of Akcea equity awardswhat is required to keep the medicines progressing in clinical development, not what medicines we think are most important. For example, the number of $59 million.people required to start a new study is large, the number of people required to keep a study going is modest and the number of people required to finish a study is large. However, such fluctuations are not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each medicine. Because we always have numerous medicines in preclinical and varying stages of clinical research, the fluctuations in expenses from medicine to medicine, in large part, offset one another. If we partner a medicine, it may affect the size of a trial, its timing, its total cost and the timing of the related costs.
Medical Affairs
Our net lossmedical affairs function is responsible for 2020 included income taxfunding and coordinating investigator-sponsored trials, communicating scientific and clinical information to healthcare providers, medical professionals and patients, and managing publications.
The following table sets forth information on medical affairs expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Medical affairs expenses, excluding non-cash compensation expense related to equity awards | $ | 19.5 | $ | 15.9 | ||||
| Non-cash compensation expense related to equity awards | 3.4 | 2.0 | ||||||
| Total medical affairs expenses | $ | 22.9 | $ | 17.9 | ||||
Medical affairs expenses, excluding non-cash compensation expense of $317 millionrelated to equity awards, increased in 2023 compared to $44 million2022 as we continued advancing our late-stage pipeline.
Manufacturing and Development Chemistry
Expenditures in 2019.our manufacturing and development chemistry function consist primarily of personnel costs, specialized chemicals for oligonucleotide manufacturing, validation batches to support regulatory approvals, laboratory supplies and outside services. Our manufacturing and development chemistry function is responsible for providing drug supplies to drug development and our collaboration partners. Our manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice requirements.
The following table sets forth information on manufacturing and development chemistry expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards | $ | 65.3 | $ | 76.2 | ||||
| Non-cash compensation expense related to equity awards | 8.8 | 9.9 | ||||||
| Total manufacturing and development chemistry expenses | $ | 74.1 | $ | 86.1 | ||||
Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022. In 2022, we manufactured higher quantities of API to support launch preparation activities for WAINUA, olezarsen and donidalorsen. Refer to the section titled, Manufacturing, in Part I, Item 1, Business, for further details on the activities and types of costs we incur in our manufacturing process.
R&D Support
In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for buildings and equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, information technology costs, procurement costs and waste disposal costs. We call these costs R&D support expenses.
The following table sets forth information on R&D support expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Personnel costs | $ | 27.2 | $ | 21.2 | ||||
| Occupancy | 28.7 | 19.2 | ||||||
| Consulting | 4.8 | 0.8 | ||||||
| Patent expenses | 4.3 | 4.7 | ||||||
| Insurance | 3.6 | 3.8 | ||||||
| Computer software and licenses | 2.7 | 1.9 | ||||||
| Other | 9.7 | 8.2 | ||||||
| Total R&D support expenses, excluding non-cash compensation expense related to equity awards | 81.0 | 59.8 | ||||||
| Non-cash compensation expense related to equity awards | 15.0 | 14.1 | ||||||
| Total R&D support expenses | $ | 96.0 | $ | 73.9 | ||||
R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022. The increase was primarily due to a non-cash tax expense of $313 million related to an increaseincreased occupancy, personnel and consulting costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in the valuation allowance we recorded against our federal net deferred tax assets.Carlsbad, California. As a result, of the Akcea Acquisition, Ionis and Akcea will file their federal taxes on a consolidated basis beginning in the fourth quarter of 2020. 2022, our occupancy costs increased because we began incurring rent expense for these facilities.
Selling, General and Administrative Expenses
SG&A expenses include personnel and outside costs associated with the pre-commercialization and commercialization activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations and finance. Additionally, we include in SG&A expenses such costs as rent, repair and maintenance of buildings and equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe under our in-licensing agreements related to SPINRAZA and QALSODY.
The following table sets forth information on SG&A expenses (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards | $ | 205.1 | $ | 124.4 | ||||
| Non-cash compensation expense related to equity awards | 27.5 | 25.9 | ||||||
| Total selling, general and administrative expenses | $ | 232.6 | $ | 150.3 | ||||
SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to increased expenses related to our go-to-market activities for WAINUA, olezarsen and donidalorsen. In addition, we recorded a one-time expense of $20 million when we terminated a build-to-suit lease agreement in August 2023. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details on the lease termination.
Investment Income
Investment income for 2023 was $89.0 million compared to $25.3 million for 2022. The increase in investment income was primarily due to an increase in interest rates associated with our investments in debt securities and an increase in our cash available for investment during 2023 compared to 2022. Our cash balance increased due to the $500.0 million upfront payment we received in January 2023 from our royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, net proceeds we received from the debt offering in June 2023 and payments from partners. These increases were partially offset by the repurchase of $504.4 million in principal of our 0.125% Notes during 2023.
Interest Expense
The following table sets forth information on interest expense (in millions):
| Year Ended December 31, | ||||||||
| 2023 | 2022 | |||||||
| Convertible senior notes: | ||||||||
| Non-cash amortization of debt issuance costs | $ | 5.9 | $ | 5.3 | ||||
| Interest expense payable in cash | 6.4 | 0.7 | ||||||
| Interest on mortgage for primary R&D and manufacturing facilities | 0.4 | 2.1 | ||||||
| Total interest expense | $ | 12.7 | $ | 8.1 | ||||
In 2023, we completed a $575.0 million offering of our 1.75% Notes and repurchased $504.4 million in principal of our 0.125% Notes. As a result, beginning in the second quarter of 2023, our interest expense related to our convertible notes increased because we began incurring interest expense for our 1.75% Notes.
Interest Expense Related to Sale of Future Royalties
We recorded $68.8 million of interest expense related to the sale of future royalties in 2023 as a result of the Royalty Pharma transaction, in which we sold a minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details.
Loss on Investments
We recorded a $1.9 million and $7.3 million loss on investments for 2023 and 2022, respectively. The period-over-period fluctuation in our loss on investments was primarily driven by changes in the fair value of our investments in publicly traded and privately held biotechnology companies.
Gain on Sale of Real Estate
In 2022, we closed a purchase and sale agreement with a real estate investor in which we sold and leased back the facilities at our headquarters location in Carlsbad, California for a total purchase price of $263.4 million and recorded a gain of $150.1 million in 2022, resulting in income tax expense of $8.8 million. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, for further details on this transaction.
Other Income (Expense)
In 2023, we completed a $575.0 million offering of our 1.75% Notes and used $488.2 million of the net proceeds to repurchase $504.4 million in principal of our 0.125% Notes. As a result of these repurchases, we recorded a $13.4 million gain on early retirement of debt in 2023, which reflects the difference between the amounts we paid to repurchase portions of our 0.125% Notes and the net carrying balance of the liability at the time that we repurchased the debt. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details regarding our convertible debt.
Income Tax Expense (Benefit)
We recorded an income tax expense of $32.3 million for 2023 compared to $11.7 million for 2022.
The primary drivers of our income tax expense despite our full year pretax loss relate to the requirement for taxpayers to amortize research and development expenditures over five years pursuant to Internal Revenue Code, or IRC, Section 174 beginning in 2022 under the Tax Cuts and Jobs Act of 2017, or TCJA, and the impact of the royalty purchase agreement with Royalty Pharma, which we reflected as a taxable sale which required us to include the proceeds from the sale, net of currently deductible issuance costs, as taxable income in 2023. The resulting tax liability is partially offset by the utilization of our R&D tax credits.
The increase in income tax expense for 2023 compared to 2022 relates primarily to the impact of the Royalty Pharma transaction.
We continue to maintain a full valuation allowance againston all of Ionis’ federal net deferred tax assets in the fourth quarter of 2020, due largely to Akcea’s history of losses, and the expected impact of this on Ionis’ consolidated federal taxable income. We now maintain a valuation allowance against all our consolidated federal and state net deferred tax assets. See
Net Loss and Net Loss per Share
We generated a net loss of $366.3 million for 2023 compared to $269.7 million for 2022. Our net loss increased for 2023 compared to 2022 primarily due to factors discussed in the sections above. Basic and diluted net loss per share for 2023 were $2.56 compared to $1.90 for 2022.
Liquidity and Capital Resources
We have financed our operations primarily from research and development collaborative agreements. We also financed our operations from commercial revenue from SPINRAZA and QALSODY royalties and TEGSEDI and WAYLIVRA commercial revenue. In addition, we expect to receive commercial revenue from WAINUA royalties beginning in 2024. From our inception through December 31, 2023, we have earned approximately $7.2 billion in revenue. We have also financed our operations through the sale of our equity securities, the issuance of long-term debt and the sale of future royalties. From the time we were founded through December 31, 2023, we have raised net proceeds of approximately $2.1 billion from the sale of our equity securities. Additionally, from our inception through December 31, 2023, we have borrowed approximately $2.7 billion under long-term debt arrangements and received proceeds of $0.5 billion from the sale of future royalties to finance a portion of our operations.
Our cash, cash equivalents and short-term investments, working capital and long-term obligations increased from 2022 to 2023. As discussed above, in 2023, we repurchased $504.4 million in principal of our 0.125% Notes. In the third quarter of 2023, we closed a real estate transaction and received $32.4 million. In the second quarter of 2023, we issued $575.0 million of 1.75% Notes (due in June 2028). In the first quarter of 2023, we received an upfront payment of $500.0 million when we entered into a royalty purchase agreement with Royalty Pharma and recorded a corresponding long-term liability related to the sale of future royalties.
The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of December 31, 2023. The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt in Part IV, Item 15, Note 5, 7, Income Taxes,Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements.
| Contractual Obligations | Payments Due by Period (in millions) | |||||||||||
| (selected balances described below) | Total | Less than 1 year | More than 1 year | |||||||||
| 1.75% Notes (principal and interest payable) | $ | 620.3 | $ | 10.1 | $ | 610.2 | ||||||
| 0% Notes (principal payable) | 632.5 | — | 632.5 | |||||||||
| 0.125% Notes (principal and interest payable) | 44.6 | 44.6 | — | |||||||||
| Building mortgage payments (principal and interest payable) | 10.2 | 0.5 | 9.7 | |||||||||
| Operating leases | 279.5 | 20.4 | 259.1 | |||||||||
| Other obligations (principal and interest payable) | 0.8 | 0.1 | 0.7 | |||||||||
| Total | $ | 1,587.9 | $ | 75.7 | $ | 1,512.2 | ||||||
Our contractual obligations consist primarily of our convertible debt. In addition, we also have a facility mortgage, facility leases, equipment financing arrangements and other obligations. We believe our cash, cash equivalents and short-term investments, as well as plans for cash in the future, will be sufficient to fund our planned operations and these obligations. We have not entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).
Convertible Debt and Call Spread
Refer to our Convertible Debt and Call Spread accounting policies in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, and Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for the significant terms of each convertible debt instrument.
Operating Facilities
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further discussiondetails on our valuation allowance assessment.operating facilities.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details on our operating leases.
Royalty Revenue Monetization
In January 2023, we entered into a royalty purchase agreement with 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. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details on this agreement.
Other Obligations
In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2023 for the purchase of services, capital equipment and materials as part of our normal course of business.
We may enter into additional collaborations with partners which could provide for additional revenue to us and we may incur additional cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use our cash, cash equivalents and short-term investments at December 31, 2020,to finance our activities. However, we believemay also pursue other financing alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, securing lines of credit or executing royalty monetization agreements. Whether we haveuse our existing capital resources or choose to obtain financing will depend on various factors, including the future success of our business, the prevailing interest rate environment and the condition of financial resources to execute on our strategic priorities for 2021 and beyond.markets generally.
Critical Accounting Estimates
We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the United States.U.S. As such, we make certain estimates, judgments and assumptions that we believe are reasonable, based upon the information available to us. These judgments involve making estimates about the effect of matters that are inherently uncertain and may significantly impact our quarterly or annual results of operations and financial condition. Each quarter, our senior management reviews the development, selection and disclosure of such estimates with the audit committee of our board of directors. In the following paragraphs, we describe the specific risks associated with these critical accounting estimates and we caution that future events rarely develop exactly as one may expect, and that best estimates may require adjustment. Our significant accounting policies are outlined in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements.
The following are our significant accounting estimates, which we believe are the most critical to aid in fully understanding and evaluating our reported financial results:
| ● | Assessing the propriety of revenue recognition and associated deferred revenue; |
| ● | Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities; and |
| ● |
The following are descriptions of our critical accounting estimates.
Revenue Recognition
We earn revenue from several sources. The judgements and estimates we make vary between each source of our revenue. 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 Accounting Standards Codification, or ASC, Topic 808, Collaborative Arrangements, or ASC 808. 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 are therefore 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.
The following is a summary of the critical accounting estimates we make with respect to each of our significant revenue sources.