Ionis Pharmaceuticals, Inc. is a pioneer in RNA-targeted medicines with a deep understanding of disease biology and an industry-leading drug discovery technology.
With the company’s commercial launch of TRYNGOLZA (olezarsen) in the United States, or U.S., following its approval by the U.S. Food and Drug Administration, or FDA, the company began a new chapter as a fully integrated commercial-stage biotechnology company. The company has six marketed medicines to treat serious diseases: TRYNGOLZA,...
Ionis Pharmaceuticals, Inc. is a pioneer in RNA-targeted medicines with a deep understanding of disease biology and an industry-leading drug discovery technology.
With the company’s commercial launch of TRYNGOLZA (olezarsen) in the United States, or U.S., following its approval by the U.S. Food and Drug Administration, or FDA, the company began a new chapter as a fully integrated commercial-stage biotechnology company. The company has six marketed medicines to treat serious diseases: TRYNGOLZA, WAINUA (eplontersen), SPINRAZA (nusinersen), QALSODY (tofersen), TEGSEDI (inotersen), and WAYLIVRA (volanesorsen).
Marketed Medicines
TRYNGOLZA is approved in the U.S. as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. TRYNGOLZA is the first-ever FDA-approved treatment that significantly and substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in acute pancreatitis, or AP, events when used with an appropriate diet (less than or equal to 20 grams of fat per day). TRYNGOLZA is the first medicine the company is commercializing independently in the U.S.
WAINUA is approved in numerous countries, including the U.S. and the United Kingdom, or the U.K., for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTRv-PN, in adults. WAINUA is the only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector. The company and AstraZeneca are co-developing WAINUA globally and co-commercializing WAINUA in the U.S. AstraZeneca has exclusive rights to commercialize WAINUA outside of the U.S.
SPINRAZA provides the treatment of pediatric and adult patients with spinal muscular atrophy, or SMA. The company's partner, Biogen, is responsible for commercializing SPINRAZA worldwide.
QALSODY is approved in the U.S., European Union, or EU, China, and Japan for the treatment of Amyotrophic Lateral Sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-ALS. QALSODY received accelerated approval from the FDA and marketing authorization under exceptional circumstances from the European Medicines Agency, or EMA. QALSODY was the first treatment approved to target a genetic cause of ALS. The company's partner, Biogen, is responsible for commercializing QALSODY worldwide.
TEGSEDI is approved in the EU, Canada, and Brazil for the treatment of ATTRv-PN in adults. The company sells TEGSEDI in Europe through its distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. The company and Sobi terminated their agreement for TEGSEDI in North America, after which the company discontinued TEGSEDI in North America. In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with the company.
WAYLIVRA is approved in the EU and Brazil 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. The company sells WAYLIVRA in Europe through its distribution agreement with Sobi. In Latin America, PTC is commercializing WAYLIVRA in Brazil for two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through its exclusive license agreement with the company.
In addition to its marketed medicines, the company is also positioned to deliver multiple products to the market independently in the next three years. Donidalorsen for the treatment of hereditary angioedema, or HAE, is under regulatory review in the U.S., positioning the company for its second independent commercial launch in 2025. The company also has a rich innovative late- and mid-stage pipeline across its focus areas of neurology, cardiology, and select areas of high patient needs. The company has nine medicines in Phase 3 development and multiple additional medicines in early and mid-stage development. The company delivered eight positive data readouts in the last year from its late- and mid-stage pipeline, including positive data for TRYNGOLZA, donidalorsen, and ION582, the company's medicine for people with Angelman syndrome, or AS. The company further advanced its next-generation technologies for RNA-targeted medicines, including advancing its first program using its mesyl phosphoramidate, or MsPA, backbone into clinical development.
Marketed Medicines – Bringing Value to Patients
TRYNGOLZA (apoC-III) – TRYNGOLZA (olezarsen), injection is an APOC-III-directed antisense medicine indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. TRYNGOLZA lowers the body’s production of apolipoprotein C-III, or apoC-III, a protein produced in the liver that is a key regulator of triglyceride metabolism. TRYNGOLZA was approved by the FDA in December 2024 and is the first-ever FDA-approved treatment that significantly and substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in AP events when used with an appropriate diet (less than or equal to 20 grams of fat per day). TRYNGOLZA is under regulatory review in the EU.
The company is also developing olezarsen to treat severe hypertriglyceridemia, or sHTG.
FDA approval was based on positive data from the placebo-controlled Phase 3 Balance study in adult patients with genetically identified FCS and fasting triglyceride levels =880 mg/dL. In the Balance study, TRYNGOLZA demonstrated a statistically significant reduction in triglyceride levels. TRYNGOLZA also demonstrated a substantial, clinically meaningful reduction in AP events. In addition, TRYNGOLZA demonstrated a favorable safety and tolerability profile in the Balance study.
TRYNGOLZA was reviewed by the FDA under Priority Review and had previously been granted Fast Track, Orphan Drug, and Breakthrough Therapy designations for the treatment of FCS.
WAINUA (TTR) – WAINUA (eplontersen) injection is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTRv-PN, in adults. WAINUA causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. WAINUA was approved in the U.S. in December 2023 and was recommended for approval by the CHMP in the EU in October 2024. WAINUA is also approved in other markets, including the UK and Canada, with additional regulatory reviews underway. The company and AstraZeneca are co-commercializing WAINUA in the U.S., and AstraZeneca has exclusive rest-of-world commercialization rights.
FDA approval was based on the interim analysis of the open-label Phase 3 NEURO-TTRansform study in patients with ATTRv-PN. The study compared WAINUA to the historical placebo arm from the TEGSEDI (inotersen) NEURO-TTR Phase 3 study. In the interim analysis, WAINUA demonstrated a statistically significant and clinically meaningful change from baseline for the co-primary endpoints of serum TTR concentration and Neuropathy Impairment Score +7, or mNIS+7. Additionally, WAINUA demonstrated a favorable safety and tolerability profile in the NEURO-TTRansform study.
The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR.
SPINRAZA (SMN) – 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 targets the root cause of SMA by increasing the production of functional survival motor neuron, or SMN, protein. SPINRAZA provides the treatment of patients with SMA. The company's partner, Biogen, is responsible for commercializing SPINRAZA worldwide.
The approval of SPINRAZA was based on efficacy and safety 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 OLE study for patients with SMA who participated in prior SPINRAZA studies. Additionally, Biogen conducted 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, which showed that early and sustained treatment with SPINRAZA helped participants to maintain and/or make progressive gains in motor function, with most children achieving motor milestones within age-appropriate timelines and no major motor milestones were lost. SPINRAZA demonstrated a favorable safety and tolerability profile in the studies.
Biogen continues to expand the body of evidence supporting SPINRAZA’s durable efficacy and established safety profile to address the remaining needs of SMA patients of all ages through additional studies. These include the Phase 2/3 DEVOTE study, which evaluated a higher dose of SPINRAZA compared to the approved dose, the Phase 4 RESPOND study, evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to the gene therapy, onasemnogene abeparvovec, and the Phase 3b ASCEND study 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. The positive data generated from the DEVOTE study were the basis of the recent U.S. and EU regulatory submissions that were accepted for review for higher dose nusinersen.
QALSODY (SOD1) – QALSODY (tofersen) injection for intrathecal use is an antisense medicine indicated for the treatment of Amyotrophic Lateral Sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-ALS. QALSODY inhibits the production of SOD1. QALSODY was granted accelerated approval in April 2023 based on reduction in plasma neurofilament light chain, or NfL, observed in patients treated with QALSODY. In May 2024, QALSODY was also approved in the EU under exceptional circumstances. Additionally, QALSODY was recently approved in China and Japan. The company's partner, Biogen, is responsible for commercializing QALSODY worldwide.
Biogen is also evaluating tofersen for the treatment of presymptomatic individuals who have a SOD1 genetic mutation.
The QALSODY regulatory submissions included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 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 open-label extension, or OLE, study. The 12-month integrated data show that earlier initiation of QALSODY, compared to delayed initiation, slowed declines in clinical function, respiratory function, muscle strength, and quality of life and build on the 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). Additionally, QALSODY demonstrated a favorable safety and tolerability profile in the VALOR study.
The FDA and EMA granted QALSODY Orphan Drug designation for the treatment of ALS.
TEGSEDI (TTR) – TEGSEDI (inotersen) injection is a transthyretin-directed antisense oligonucleotide medicine indicated for the treatment of ATTRv-PN in adults. TEGSEDI prevents the production of TTR protein, reducing the amount of amyloid buildup that damages organs and tissues. The company sells TEGSEDI in Europe through its distribution agreement with Sobi. In Latin America, PTC Therapeutics is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with the company.
The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with ATTRv-PN.
WAYLIVRA (apoC-III) – WAYLIVRA (volanesorsen) injection is an antisense oligonucleotide 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 apoC-III, a protein that is a key regulator of triglyceride levels. WAYLIVRA received conditional marketing authorization in May 2019, from the European Commission, or EC. The company sells WAYLIVRA in Europe through its distribution agreement with Sobi. In Latin America, WAYLIVRA is approved for two indications, FCS and FPL. PTC is commercializing WAYLIVRA in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with the company.
WAYLIVRA’s conditional marketing authorization in the EU for FCS and approval in Brazil for FCS were based on efficacy and safety data from the Phase 3 APPROACH study and supported by results from the Phase 3 COMPASS study. WAYLIVRA’s approval in Brazil for FPL was based on efficacy and safety data from the Phase 3 BROADEN study in patients with FPL.
Late-Stage Pipeline of Ionis-Owned Investigational Medicines
As a pioneer in RNA-targeted therapeutics, the company continues to drive innovation with a leading pipeline in neurology, cardiology, and select diseases of high unmet need.
The company is commercializing TRYNGOLZA (olezarsen) for the treatment of FCS in the U.S.
The company granted Otsuka exclusive rights to commercialize donidalorsen in Europe and the Asia-Pacific regions.
The company granted Theratechnologies exclusive rights to commercialize olezarsen and donidalorsen in Canada.
Olezarsen (apoC-III) – Olezarsen is an investigational RNA-targeted medicine that the company is evaluating for people with sHTG. Olezarsen is designed to lower the body’s production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. sHTG is a disease categorized by triglyceride levels of 500 mg/dL and above. It develops due to primary (genetic) and secondary causes, including diet and lifestyle, other medical conditions, and certain medications. People living with sHTG are at high risk of pancreatitis (a painful inflammation of the pancreas) and damage to the pancreas. As such, reducing the risk of pancreatitis is a critically important reason to treat sHTG. People with sHTG are also at risk of heart, brain, and blood vessel damage.
The company is conducting a broad development program for olezarsen that includes three fully enrolled Phase 3 studies supporting development for the treatment of sHTG: CORE, CORE2, and ESSENCE. Data from the ESSENCE study is expected in mid-2025, and data from the CORE and CORE2 studies are expected in the second half of 2025.
The company advanced olezarsen into Phase 3 development based on the positive results from a Phase 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established cardiovascular disease, or CVD. In the Phase 2 study, olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels. Olezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III. Olezarsen demonstrated a favorable safety and tolerability profile in the Phase 2 study supportive of continued development.
Donidalorsen (PKK) – Donidalorsen is an investigational RNA-targeted medicine the company designed to target the production of prekallikrein, or PKK, which plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. By reducing the production of PKK, donidalorsen could be an effective prophylactic approach to preventing HAE attacks. HAE is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face, and/or throat. Donidalorsen is under review in the U.S., and the FDA has set an action date of August 21, 2025, under the Prescription Drug User Fee Act, or PDUFA. Donidalorsen is also under regulatory review in the EU. Otsuka has exclusive rights to commercialize donidalorsen in Europe and Asia, and Theratechnologies has exclusive rights to commercialize donidalorsen in Canada.
The company’s regulatory submissions are based on the positive data from the placebo-controlled Phase 3 OASIS-HAE study, the Phase 3 OASISplus study, and the Phase 2 OLE study in patients with HAE. The OASIS-HAE study met its primary endpoint with a statistically significant reduction in the rate of HAE attacks and demonstrated clinically significant improvement in quality of life as measured by the Angioedema Quality of Life Questionnaire, or AE-QoL, in patients treated every four weeks and patients treated every eight weeks. The OASISplus study includes an OLE cohort and a prospective cohort to assess patients switching from available long-term prophylactic treatments to donidalorsen. Positive results from a February 2024 data cut from the ongoing OLE cohort showed that HAE attack rates continued to improve over time, and extended treatment resulted in further improved quality of life measures and high levels of disease control. In the OASISplus switch cohort, patients followed a pre-defined specific protocol to transition from their prior therapy to donidalorsen. Results showed that patients were able to switch to donidalorsen from prior prophylactic treatment without an increase in breakthrough attacks. Donidalorsen treatment also led to a further improvement in mean monthly HAE attack rates and continued improvements in measures of quality of life.
The FDA and EMA granted Orphan Drug designation to donidalorsen.
Zilganersen (GFAP) – Zilganersen (formerly ION373) is an investigational RNA-targeted medicine the company designed to inhibit the production of glial fibrillary acidic protein, or GFAP, that accumulates because of disease-causing variants in the GFAP gene. The company is developing zilganersen as a potential treatment for people with genetically confirmed Alexander disease, or AxD. AxD is an ultra-rare, progressive, and ultimately fatal type of leukodystrophy, which is a group of genetic disorders that affect the brain’s white matter. AxD can present throughout life as loss of independence and lack of ability to control muscles for swallowing, airway protection, and purposeful movements. The impact of AxD can vary depending on factors, such as age of onset. Diagnosing AxD is based on a combination of clinical presentation, brain magnetic resonance imaging, or MRI, findings, and genetic testing. There are no medicines approved for people with AxD, and treatments focus on managing their symptoms.
The company is conducting a single clinical study of zilganersen in patients with AxD designed to assess the efficacy, safety, and tolerability of zilganersen. In September 2023, the company advanced zilganersen into the Phase 3 portion of the study.
The FDA and EMA granted Orphan Drug designation to zilganersen. Additionally, the FDA granted Fast Track and Rare Pediatric designations to zilganersen.
ION582 (UBE3A) (BIIB121) – ION582 is an investigational RNA-targeted medicine the company designed to inhibit the expression of the UBE3A antisense transcript, or UBE3A-ATS, and increase production of UBE3A protein, for the potential treatment of AS.
The company is conducting the ongoing open-label Phase 1/2 study, HALOS, of ION582 in patients with AS designed to assess the safety, tolerability, and activity of multiple ascending doses of ION582 administered intrathecally. In 2024, the company presented positive results from the completed multiple ascending dose, or MAD, portion of the study in people with AS demonstrating consistent and encouraging clinical improvement on measures assessing all functional domains, including communication, cognition, and motor function. ION582 showed favorable safety and tolerability at all dose levels in the study.
Based on the positive results from the HALOS study and alignment with the FDA, the company plans to advance ION582 into Phase 3 development in the first half of 2025.
The FDA and EMA granted Orphan Drug designation to ION582. Additionally, the FDA granted Fast Track and Rare Pediatric designations to ION582.
Late-Stage Pipeline of Partnered Investigational Medicines
In addition to its Ionis-owned investigational medicines, the company also has numerous potentially transformational partnered medicines in clinical development.
Eplontersen (TTR) – Eplontersen is an investigational RNA-targeted medicine designed to degrade mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. Eplontersen is being evaluated in patients with hereditary or wild-type transthyretin-mediated amyloid cardiomyopathy, or ATTR-CM. ATTR-CM is a progressive and fatal disease caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death within two to six years from disease onset. The company and AstraZeneca are co-developing eplontersen globally and co-commercializing eplontersen in the U.S. AstraZeneca has exclusive rest-of-world commercialization rights.
The company is conducting the ongoing placebo-controlled CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR-CM. The company designed the study to evaluate the efficacy, safety, and tolerability of eplontersen in patients with ATTR-CM.
The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR. The FDA also granted Fast Track designation to eplontersen for ATTR-CM.
Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen is an investigational RNA-targeted medicine the company 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. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing CVD 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.
Novartis is conducting the placebo-controlled Phase 3 cardiovascular outcome study of pelacarsen, Lp(a)HORIZON, to assess the efficacy, safety, and tolerability of pelacarsen in patients with elevated Lp(a) levels and established or at risk for CVD.
In November 2018, at the American Heart Association annual meeting, the company reported results of the Phase 2 study of pelacarsen in patients with hyperlipoproteinemia(a). In the Phase 2 study, the company observed statistically significant and dose-dependent reductions from baseline in Lp(a) levels. Additionally, pelacarsen demonstrated a favorable safety and tolerability profile in the study.
The FDA and Center for Drug Evaluation of China National Medical Products Administration granted pelacarsen Fast Track designation and Breakthrough Therapy, respectively, for the treatment of patients with elevated Lp(a) and established CVD.
Bepirovirsen (HBV) (GSK3228836) – Bepirovirsen is an investigational RNA-targeted medicine the company designed to inhibit the production of viral proteins associated with hepatitis B virus, or HBV. These include proteins associated with infection and replication, including the hepatitis B surface antigen, or HBsAg, which is present in both acute and chronic infections and is associated with a poor prognosis in people with chronic HBV infection. 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, affecting more than 250 million people and resulting in more than 1 million deaths annually. 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. The company's partner, GSK, is responsible for ongoing development and commercialization of bepirovirsen worldwide.
GSK is conducting the placebo-controlled Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV designed to assess the efficacy, safety, and tolerability of bepirovirsen.
In June 2022, GSK presented positive results from the Phase 2b B-Clear study of bepirovirsen in patients with chronic HBV 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 the end of bepirovirsen treatment in people with chronic HBV infection. 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. In October 2023, GSK reported positive data from the B-Together Phase 2b study of bepirovirsen in patients with chronic HBV infection following sequential treatment with pegylated interferon. Bepirovirsen demonstrated a favorable safety and tolerability profile in these studies.
The FDA and Japanese Ministry of Health, Labour and Welfare, or MHLW, granted bepirovirsen Fast Track designation and SENKU (formerly known as SAKIGAKE) designation, respectively, for the treatment of patients with chronic HBV infection.
Sefaxersen (IgAN) (RO7434656) – Sefaxersen (formerly IONIS-FB-LRx) is an investigational RNA-targeted medicine the company designed to reduce the production of complement factor B, or FB, and to lower activation of 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 immunoglobulin A nephropathy, or IgAN. 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 kidney failure. Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage. The company's partner, Roche, is responsible for ongoing development and commercialization of sefaxersen worldwide.
In April 2023, Roche initiated a placebo-controlled Phase 3 study of sefaxersen, called IMAGINATION, in patients with IgAN designed to assess the efficacy, safety, and tolerability of sefaxersen.
The company reported positive results from a Phase 2 open-label study of sefaxersen in patients with IgAN, demonstrating robust and sustained reductions in complement FB and other key measures of the alternative complement pathway. Sefaxersen treatment also resulted in sustained reductions in proteinuria, with patients maintaining kidney function during six months of treatment. Sefaxersen demonstrated a favorable safety and tolerability profile in the study.
Ulefnersen (FUS) – Ulefnersen is an investigational RNA-targeted medicine the company designed to reduce the production of the fused in sarcoma, or FUS, protein to treat people with Amyotrophic Lateral Sclerosis, or ALS, caused by mutations in the FUS gene. Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss. FUS-ALS is a rare, fatal, neurodegenerative disorder characterized by muscle weakness, loss of movement, and difficulty breathing and swallowing, resulting in a severely declining quality of life and eventually death. Treatment options are extremely limited, with no medicines that significantly slow disease progression. The company's partner, Otsuka, is responsible for global regulatory and commercialization activities, and costs for ulefnersen.
In April 2021, the company initiated a Phase 3 study of ulefnersen in patients with FUS-ALS designed to assess the efficacy, safety, and tolerability of ulefnersen.
The FDA and EMA granted Orphan Drug designation to ulefnersen.
Collaborative Arrangements
The company has established alliances with a number of pharmaceutical companies. Its partners include the following companies, among others: AstraZeneca, Biogen, GSK, Novartis, Otsuka, and Roche.
AstraZeneca
WAINUA (Eplontersen) Collaboration
In 2021, the company entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. The FDA and Health Canada approved eplontersen with the brand name WAINUA for ATTRv-PN, while the Medicines and Healthcare products Regulatory Agency, or MHRA, approved WAINUA for ATTRv-PN in the UK as WAINZUA. Under the agreement, the company is jointly developing WAINUA with AstraZeneca worldwide for ATTRv-PN and ATTR cardiomyopathy, or ATTR-CM. The company is jointly commercializing WAINUA with AstraZeneca in the U.S. The company granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S.
The collaboration includes territory-specific development, commercial, and medical affairs cost-sharing provisions. AstraZeneca is responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the vast 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.
In January 2024, the company and AstraZeneca launched WAINUA in the U.S. for the treatment of adults with ATTRv-PN.
Cardiovascular, Renal, and Metabolic Collaboration
The company also has a collaboration with AstraZeneca focused on discovering and developing treatments for cardiovascular, renal, and metabolic diseases, which it formed in 2015. Under this collaboration, AstraZeneca has licensed multiple medicines from the company. AstraZeneca is responsible for global development, regulatory and commercialization activities, and costs for each of the medicines it has licensed from the company.
Over the term of the collaboration, the company is eligible to receive an upfront payment, license fees, development milestone payments, regulatory milestone payments, and sales milestone payments. In addition, the company is eligible to receive tiered royalties up to 10 percent on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement.
Biogen
Marketed Medicines
SPINRAZA
In 2012, the company entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA. The company is receiving tiered royalties ranging from 11 percent to 15 percent on sales of SPINRAZA. Under the agreement, Biogen is responsible for global development, regulatory, and commercialization activities and costs for SPINRAZA.
The company has exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. The company pays Cold Spring Harbor Laboratory and the University of Massachusetts a low single-digit royalty on net sales of SPINRAZA.
QALSODY
In 2018, Biogen exercised its option to license QALSODY from the company. The company is receiving tiered royalties ranging from 11 percent to 15 percent on net sales of QALSODY. Under the agreement, Biogen is responsible for global development, regulatory, and commercialization activities and costs for QALSODY. Biogen is also evaluating QALSODY as a potential treatment for presymptomatic SOD1-ALS patients in the ongoing ATLAS study.
New Antisense Medicines for the Treatment of SMA
In 2017, the company entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. In 2021, Biogen exercised its option to license ION306. Biogen is solely responsible for the costs and expenses related to the development, manufacturing, and potential future commercialization of ION306 following the option exercise.
Neurology Collaborations
The company has multiple collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders, including its 2018 and 2012 neurology collaborations. Under these collaborations, Biogen gained exclusive rights to the use of the company's antisense technology to develop therapies for certain neurological diseases and the option to license certain medicines resulting from these collaborations. The company is advancing multiple programs under this collaboration.
GSK
In 2010, the company entered into a collaboration with GSK using its antisense drug discovery platform to discover and develop new medicines against targets for serious and rare diseases, including infectious diseases. Under this collaboration, GSK is developing bepirovirsen for the treatment of chronic HBV infection. In 2019, following positive Phase 2 results, GSK licensed the company's HBV program. GSK is responsible for all global development, regulatory, and commercialization activities and costs for the HBV program.
Novartis
Pelacarsen Collaboration
In 2017, the company initiated a collaboration with Novartis to develop and commercialize pelacarsen for patients with elevated Lp(a) and CVD. Novartis is responsible for conducting and funding development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in 2019.
New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease
In 2023, the company entered into a collaboration and license agreement with Novartis for the discovery, development, and commercialization of a novel medicine for patients with Lp(a)-driven cardiovascular disease, or CVD. Novartis is solely responsible for the development, manufacturing, and potential commercialization of the next-generation Lp(a) medicine.
Roche
Sefaxersen for Complement-Mediated Diseases
In 2018, the company entered into an agreement with Roche to develop sefaxersen for the treatment of complement-mediated diseases, including IgAN, and geographic atrophy, or GA. In April 2023, Roche initiated a Phase 3 study of sefaxersen in patients with IgAN.
After positive data from a Phase 2 clinical study in patients with IgAN, Roche licensed sefaxersen in 2022. As a result, Roche is responsible for global development, regulatory, and commercialization activities, and costs for sefaxersen.
In July 2024, Roche discontinued development of sefaxersen for the treatment of GA, the advanced stage of dry age-related macular degeneration, following the completion of the Phase 2 study, which showed a favorable safety profile and target engagement, but insufficient efficacy to advance into Phase 3 development.
Huntington’s Disease
In 2013, the company entered into an agreement with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments for Huntington’s disease, or HD, based on its antisense technology. Under the agreement, the company discovered and developed tominersen, an investigational antisense medicine targeting HTT protein. The company developed tominersen through completion of its Phase 1/2 clinical study in people with early-stage HD. In 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. As a result, Roche is responsible for all global development, regulatory, and commercialization activities and costs for tominersen.
RNA-Targeting Medicines for Alzheimer’s Disease and Huntington’s Disease
In September 2023, the company entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-targeting investigational medicines for the treatment of Alzheimer’s disease, or AD, and HD. Under the agreement, the company is responsible for advancing the two programs through preclinical studies, and Roche is responsible for clinical development, manufacturing, and commercialization of the medicines.
Commercialization Partnerships
Otsuka
In December 2023, the company entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe. In the second quarter of 2024, the company expanded the agreement to include commercialization rights for donidalorsen in the Asia-Pacific region. The company is responsible for the ongoing development of donidalorsen.
In November 2024, the company entered into an agreement with Otsuka to commercialize ulefnersen worldwide. The company is responsible for the ongoing development of ulefnersen.
PTC Therapeutics
In August 2018, the company 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, the company is eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In December 2021 and September 2023, the company started receiving royalties from PTC for TEGSEDI and WAYLIVRA sales, respectively.
Swedish Orphan Biovitrum AB (Sobi)
The company began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution agreements with Sobi. Under the agreements, the company is responsible for supplying finished goods inventory to Sobi, and Sobi is responsible for selling each medicine to the end customer. In October 2023, the company’s agreement for TEGSEDI in North America was terminated, and the company discontinued TEGSEDI in North America in 2024.
Theratechnologies
In December 2024, the company entered into an agreement with Theratechnologies, Inc. to commercialize donidalorsen and olezarsen in Canada. The company is responsible for the ongoing development of donidalorsen and olezarsen.
Technology Enhancement Collaborations
Bicycle Therapeutics
In 2020, the company entered into a collaboration agreement with Bicycle Therapeutics, or Bicycle, and obtained an option to license its peptide technology that the company expects can expand its LICA platform to target both skeletal and cardiac muscle, and potentially deliver medicines across the blood-brain barrier. In 2021, the company exercised its option to license Bicycle’s technology. The company’s payment to Bicycle for licensing its technology included an equity investment in Bicycle.
Metagenomi
In 2022, the company 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.
Vect-Horus
In December 2023, the company entered into a license agreement with Vect-Horus to provide it with a worldwide, exclusive license for a specified number of targets using Vect-Horus’ platform technology ‘VECTrans’ for systemic delivery of RNA-targeted therapeutics.
Other Agreements
Alnylam Pharmaceuticals, Inc.
Under the terms of the company’s agreement with Alnylam, the company co-exclusively (with itself) licensed to Alnylam its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, the company is eligible to earn a technology access fee, participate in fees from Alnylam’s partnering programs, and earn future milestone and royalty payments from Alnylam. The company retained exclusive rights to its 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 non-exclusively licensed to the company 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.
Marketed Products
TRYNGOLZA/Olezarsen and ApoC-III
The company’s TRYNGOLZA (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 company has some key issued patents protecting olezarsen in the U.S. and Europe.
Trademark
The name ‘TRYNGOLZA’ is protected by trademarks throughout the world.
WAINUA/WAINZUA/Eplontersen and Transthyretin
Patents
WAINUA/WAINZUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect WAINUA/WAINZUA in other foreign jurisdictions are being pursued.
Trademarks
The names ‘WAINUA’ and ‘WAINZUA’ are protected by trademarks owned by the company’s commercial partner AstraZeneca.
SPINRAZA and Survival Motor Neuron 2
Patents
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 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, 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 dosing and therapeutic methods of using such compounds and compositions. With Biogen’s license of SPINRAZA, the company assigned its interest in these patents to Biogen.
Trademarks
The name ‘SPINRAZA’ is protected throughout the world by trademarks owned by the company’s commercial partner Biogen.
QALSODY and SOD-1
Patents
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, the company assigned its interest in these patents to Biogen.
Trademarks
The name ‘QALSODY’ is protected throughout the world by trademarks owned by the company’s commercial partner Biogen.
TEGSEDI and Transthyretin
Patents
TEGSEDI (inotersen) is protected from generic competition in the U.S. and Europe until at least 2031.
Trademarks
The name ‘TEGSEDI’ is protected by trademark throughout the world.
WAYLIVRA and ApoC-III
Patents
WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034. The company has 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. The company has also obtained issued patents claiming the specific sequence and chemical composition of WAYLIVRA in the U.S. and Europe.
Trademark
The name ‘WAYLIVRA’ is protected by trademark in Europe.
Late-Stage Ionis-Owned Programs
Donidalorsen and PKK
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.
Zilganersen and GFAP
Zilganersen is protected from generic competition in the U.S. until at least 2041. A patent application designed to protect zilganersen from generic competition is being pursued in Europe; a patent issuing from that application would have a term until at least 2041.
ION582 and UBE3A
ION582 is protected from generic competition in the U.S. until at least 2040. A patent application designed to protect ION582 from generic competition is being pursued in Europe; a patent issuing from that application would have a term until at least 2040.
Late-Stage Partnered Programs
Bepirovirsen and Hepatitis B Virus
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 is being pursued. With GSK’s license of bepirovirsen, the company assigned its interest in these patents to GSK.
Pelacarsen and Apo(a)
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 is being pursued.
Sefaxersen and Factor B
Sefaxersen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent protection designed to protect sefaxersen in other foreign jurisdictions is being pursued.
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.
Platform IP
In addition to the IP that provides exclusivity for specific products, the company also pursues IP that provides exclusivity for its core technology in the field of oligonucleotides and RNA-targeting therapeutics more generally. The company’s core technology patents include claims to chemically modified oligonucleotides, as well as designs utilizing these chemical modifications.
Chemically Modified Nucleosides and Oligonucleotides
The most broadly applicable of the company's patents are those that claim modified nucleosides and oligonucleotides comprising the modified nucleosides that the company incorporates into its medicines to increase their therapeutic efficacy.
Ligand-Conjugated Antisense (LICA) Technology
The company also has patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties. The company designed its GalNAc LICA medicines to provide an increase in potency for targets in the liver. The company has successfully obtained issued patent claims covering its LICA technology conjugated to any modified oligonucleotide, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides.
Manufacturing
The company also owns patents claiming methods of manufacturing and purifying oligonucleotides and related compounds. These patents claim methods for improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification.
Government Regulation
In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, the company is 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 federal, state, and local regulations.
The company’s 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 it conducts business.
The company’s manufacturing facility and its CMOs are subject to periodic inspection by the FDA and other foreign equivalents to ensure that they are operating in compliance with cGMP requirements.
The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including the company, 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.
History
The company was founded in 1989. It was incorporated in California in 1989 and changed its state of incorporation to Delaware in 1991. The company was formerly known as Isis Pharmaceuticals, Inc. and changed its name to Ionis Pharmaceuticals, Inc. in 2015.
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