Ionis Innovation

The Ionis antisense pipeline

Our antisense technology platform has served as a springboard for drug discovery and realized hope for patients with unmet needs. Our broad, diverse pipeline has more than 40 potential first-in-class and/or best-in-class medicines designed to treat a broad range of diseases.

The result of 30 years of perfecting and advancing RNA targeted drug discovery and development, our proprietary platform now provides a fast and efficient path from identification of potential causes of human diseases to the discovery of potentially life-saving medicines.

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Therapeutic Areas

Phase

Therapeutic area

Phase

Neurological

Ulefnersen

(FUS)

Amyotrophic Lateral Sclerosis

Ionis-Owned

Ulefnersen, formerly known as ION363, is an investigational antisense medicine designed to reduce the production of the fused in sarcoma (FUS) protein to treat people with amyotrophic lateral sclerosis (ALS) caused by mutations in the FUS gene. Ulefnersen is also known as Jacifusen (not an official USAN name) in honor of Jaci Hermstad, the first patient treated with the drug under an expanded access program. Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients.

About FUS-ALS

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. Current treatment options are extremely limited, with no medicines that significantly slow disease progression. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Tofersen

(SOD1)

Amyotrophic Lateral Sclerosis

Biogen

Tofersen is an investigational antisense medicine designed to inhibit the production of superoxide dismutase 1 (SOD1), which is a well understood genetic cause of amyotrophic lateral sclerosis (ALS).

Tofersen is currently being studied in the Phase 3, randomized, placebo-controlled ATLAS study to evaluate whether tofersen can delay clinical onset when initiated in presymptomatic individuals with ALS and a SOD1 genetic mutation. More details about ATLAS(NCT04856982) can be found at clinicaltrials.gov.

About SOD1-ALS

SOD1-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. SOD1-ALS is diagnosed in approximately 2% of all ALS cases, impacting about 330 people in the United States. Approximately 5-10% of people with ALS are thought to have a genetic form of the disease; however, they may not have a known family history of the disease.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Zilganersen

(GFAP)

Alexander Disease

Ionis-Owned

Zilganersen, formerly known as ION373, is an investigational antisense medicine targeting glial fibrillary acidic protein (GFAP) mRNA designed to inhibit the production of GFAP. Zilganersen is being developed as a potential therapy for Alexander disease (AxD).

About Alexander Disease

AxD is a rare, progressive and fatal neurological disease that affects the myelin sheath which protects nerve fibers. AxD is caused by a gain-of-function mutation in the GFAP gene and is characterized by progressive deterioration, including loss of skills and independence, generally leading to death in childhood or early adulthood. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION717*

(PRNP)

Prion Disease

Ionis-Owned

ION717 is an investigational antisense medicine designed to inhibit the production of prion protein (PrP) for the potential treatment of prion disease.

About 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*This investigational antisense medicine is in a Phase 1/2a study.

IONIS-MAPT_Rx

(TAU)

Alzheimer's Disease

Biogen

IONIS-MAPT_Rx, also known as BIIB080, is an investigational antisense medicine designed to selectively inhibit production of the microtubule-associated protein tau (MAPT), or tau protein in the brain. IONIS-MAPT_Rx is being developed to treat people with Alzheimer’s disease (AD) and potentially other neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain, such as certain forms of frontotemporal degeneration and progressive supranuclear palsy.

About Alzheimer’s Disease

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 the disease.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION859*

(LRRK2)

Parkinson's Disease

Biogen

ION859 (formerly IONIS-BIIB7_Rx), also known as BIIB094, is an investigational antisense medicine designed to inhibit the production of the leucine-rich repeat kinase 2 (LRRK2) protein as a potential therapy for Parkinson’s disease (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.

About Parkinson’s Disease

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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*This investigational antisense medicine is in a Phase 1 study. It is listed here in Phase 2 because the medicine is being tested in patients and not healthy volunteers.

ION464*

(SNCA)

Multiple System Atrophy & Parkinson's Disease

Biogen

ION464, also known as BIIB101, is an investigational antisense medicine designed to inhibit the production of the alpha-synuclein protein as a potential therapy for Parkinson’s disease (PD), multiple system atrophy (MSA) and related synucleinopathies.

About Multiple System Atrophy and Parkinson’s Disease

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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*This investigational antisense medicine is in a Phase 1 study. It is listed here in Phase 2 because the medicine is being tested in patients and not healthy volunteers.

ION541*

(ATXN2)

Amyotrophic Lateral Sclerosis

Biogen

ION541, also known as BIIB105, is an investigational antisense medicine designed to reduce the production of the ataxin-2 (ATXN2) protein for the potential treatment of amyotrophic lateral sclerosis (ALS). The reduction of ATXN2 has been shown to decrease aggregation of TDP-43, a toxic RNA binding protein found in most patients with ALS, including the approximately 90 percent of the ALS population with no known family history of ALS.

About Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder characterized by progressive degeneration of motor neurons resulting in a declining quality of life due to muscle weakness, loss of movement and difficulty in breathing and swallowing. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*This investigational antisense medicine is in a Phase 1/2 study.

ION582*

(UBE3A-ATS)

Angelman Syndrome

Biogen

ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A transcript (UBE3A-ATS) for the potential treatment of Angelman syndrome (AS).

About Angelman Syndrome

AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by intellectual disability, balance issues, motor impairment, and debilitating seizures. Some patients are unable to walk or speak. Some symptoms can be managed with existing drugs; however, there are no approved disease modifying therapies.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*This investigational antisense medicine is in a Phase 1/2a study.

Tominersen

(HTT)

Huntington’s Disease

Roche

Tominersen, formerly known as IONIS-HTT_Rx and RG6042, is an investigational antisense medicine designed to target the underlying cause of Huntington’s disease (HD) by reducing the production of all forms of the huntingtin protein (HTT), including its mutated variant (mHTT).

About Huntington’s Disease

HD is an inherited genetic brain disorder that results in the progressive loss of both mental faculties and physical control. It is caused by the expansion of the cytosine-adenine-guanine (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 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION306

(SMN2)

Spinal Muscular Atrophy

Biogen

ION306, also known as BIIB115, is an investigational antisense medicine in development for spinal muscular atrophy (SMA). This program has the potential to help address additional unmet needs of patients as well as be administered with long interval dosing. ION306 is designed to target the root cause of SMA by increasing the production of functional SMN protein.

About Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a rare, genetic, neuromuscular disease that affects individuals of all ages. It is characterized by a loss of motor neurons in the spinal cord and lower brain stem, resulting in progressive muscle atrophy and weakness. SMA is caused by a deficiency in the production of survival motor neuron (SMN) protein due to a damaged or missing SMN1 gene, with a spectrum of disease severity. Some individuals with SMA may never sit; some sit but never walk; and some walk but may lose that ability over time. In the absence of treatment, children with the most severe form of SMA would usually not be expected to reach their second birthday.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Cardiovascular

Eplontersen

(TTR)

Transthyretin Amyloid Cardiomyopathy

AstraZeneca**

Eplontersen, formerly known as IONIS-TTR-L_Rx and AKCEA-TTR-L_Rx, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of TTR protein. We are developing eplontersen as a monthly self-administered subcutaneous injection to treat all types of ATTR.

About ATTR

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 tract, eyes, kidneys, central nervous system, thyroid and bone marrow. The progressive accumulation of TTR amyloid deposits in these tissues and organs leads to organ failure and eventually death.

ATTR-CM is 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 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 ATTR-CM worldwide.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

^*^* Ionis is jointly developing and commercializing eplontersen.

Olezarsen

(ApoC-III)

FCS

Ionis-Owned

Olezarsen, formerly known as IONIS-APOCIII-L_Rx and AKCEA-APOCIII-L_Rx, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of apoC-III for patients who are at risk of disease due to elevated triglyceride levels.

About FCS

ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood. People with severely elevated triglycerides, such as people with FCS, are at high risk for acute pancreatitis and an increased risk of cardiovascular disease, or CVD. It is estimated that FCS affects one to two individuals per million worldwide and more than three million patients have severe hypertriglyceridemia in the U.S.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Olezarsen

(ApoC-III)

Severe Hypertriglyceridemia

Ionis-Owned

About Severe Hypertriglyceridemia

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Pelacarsen

(Apo(a))

CVD

Novartis

Pelacarsen, also known as IONIS-APO(a)-L_Rx, AKCEA-APO(a)-L_Rx, and TQJ230, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of apolipoprotein(a), or apo(a), in the liver to offer a direct approach for reducing Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD.

About Lp(a)

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. We believe antisense technology is well suited to address hyperlipoproteinemia(a) because it specifically targets the RNA that codes for all forms of the Apo(a) molecule. It is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a).

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Fesomersen

(Factor XI)

Thrombotic Disorders

Ionis-Owned

Fesomersen, formerly known as IONIS-FXI-L_Rxis an investigational ligand-conjugated antisense (LICA) medicine 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.

About Thrombotic Disorders

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, fesomersen has the potential to 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION904

(Angiotensinogen)

Treatment-Resistant Hypertension

Ionis-Owned

ION904 is an investigational next-generation ligand-conjugated antisense (LICA) medicine designed to inhibit the production of angiotensinogen to decrease blood pressure in people with uncontrolled hypertension.

About Treatment-Resistant Hypertension

Treatment-resistant hypertension (TRH) is defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. People with TRH have been found to have a three-fold higher chance of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Specialty Rare

Donidalorsen

(PKK)

Hereditary Angioedema

Ionis-Owned

Donidalorsen, formerly known as IONIS-PKK-L_Rx, is an investigational ligand-conjugated antisense (LICA) medicine designed to target the prekallikrein (PKK) pathway.

About Hereditary Angioedema

Hereditary angioedema (HAE) is a rare genetic disease that is characterized by severe and 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Sapablursen

(TMPRSS6 )

Polycythemia Vera

Ionis-Owned

Sapablursen, formerly known as IONIS-TMPRSS6-L_Rx, is an investigational ligand-conjugated antisense (LICA) medicine 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 (PV).

About Polycythemia Vera

Polycythemia Vera (PV) is a rare, non-genetic and potentially fatal disease caused 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 due to hepcidin overexpression. There are no approved disease-modifying treatments for PV.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

Other Medicines

Bepirovirsen

(Hepatitis B Virus)

Hepatitis B Virus Infection

GSK

Bepirovirsen, formerly known as IONIS-HBV_Rx and GSK3228836, is an investigational antisense medicine designed to inhibit the production of viral proteins associated with hepatitis B virus (HBV). These include proteins associated with infection and replication, including the hepatitis B surface antigen (HBsAg), which is present in both acute and chronic infections and is associated with a poor prognosis in people with chronic HBV infection.

About Hepatitis B Virus Infection

Hepatitis 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 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

IONIS-FB-L_Rx

(Complement Factor B)

IgA Nephropathy

Roche

IONIS-FB-L_Rx, also known as RG6299, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of complement factor B (FB), and the alternative complement pathway.

About IgA Nephropathy
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, or IgA, 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.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

IONIS-FB-L_Rx

(Complement Factor B)

Geographic Atrophy/AMD

Roche

IONIS-FB-L_Rx, also known as RG6299, is a ligand-conjugated (LICA) investigational antisense medicine designed to inhibit the production of complement factor B (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 geographic atrophy (GA), secondary to age-related macular degeneration (AMD).

About Age-related Macular Degeneration

Age-related Macular Degeneration (AMD) is the leading cause of central vision loss in developed countries. GA is an advanced form of AMD.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION224

(DGAT2)

Metabolic Dysfunction-Associated Steatohepatitis

Ionis-Owned

ION224 is an investigational ligand-conjugated antisense (LICA) medicine designed to reduce the production of diacylglycerol acyltransferase 2 (DGAT2) to treat patients with metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). 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. The Phase 2 trial demonstrated clinical evidence that the reduction of hepatic fat after DGAT2 inhibition correlates with MASH histological endpoints.

About Metabolic Dysfunction-Associated Steatohepatitis (MASH)

MASH is the more severe form of metabolic dysfunction-associated fatty liver disease (MASLD). It is related to the epidemic of obesity, pre-diabetes and diabetes. Unlike liver disease caused by alcohol consumption, MASH is the result of an accumulation of fat in the liver, which can lead to inflammation, cirrhosis and liver-related death.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION839

(PNPLA3)

Metabolic Dysfunction-Associated Steatohepatitis

AstraZeneca

ION839 (formerly IONIS-AZ6-2.5-L_Rx), also known as AZD2693, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of patatin-like phospholipase domain-containing 3 (PNPLA3) protein. PNPLA3 is a protein that is found on the surface of intracellular lipid droplets. Studies have shown that a common genetic mutation of PNPLA3 is strongly associated with an increased risk for metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), an accumulation of fat in the liver that causes liver damage. The mutant PNPLA3 protein is resistant to degradation, causing it to accumulate on the surface of lipid droplets, which disrupts the normal process for degrading lipid droplets, leading to increased liver fat accumulation, the underlying pathology of MASH. In a mouse model of MASH that results from the expression of mutant PNPLA3, intervention with an antisense drug targeting PNPLA3 reduced hepatic mutant protein expression. This inhibition of mutant protein expression reduced liver fat accumulation, inflammation, and fibrosis, all hallmarks of MASH pathology in the mutant mouse model.

About Metabolic Dysfunction-Associated Steatohepatitis (MASH)
MASH is the more severe form of metabolic dysfunction-associated fatty liver disease (MASLD). It is related to the epidemic of obesity, pre-diabetes and diabetes. Unlike liver disease caused by alcohol consumption, MASH is the result of an accumulation of fat in the liver, which can lead to inflammation, cirrhosis and liver-related death.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION455

(HSD17B13)

Metabolic Dysfunction-Associated Steatohepatitis

AstraZeneca

ION455, also known as AZD7503, is an investigational ligand-conjugated antisense (LICA) medicine designed to inhibit the production of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) protein as a potential treatment for non-alcoholic steatohepatitis.

About Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.

ION532

(APOL1)

Chronic Kidney Disease

AstraZeneca

ION532 (formerly IONIS-AZ5-2.5_Rx ), also known as AZD2373, is an investigational medicine designed to reduce the production of apolipoprotein L1 (APOL1) for the treatment of APOL1-associated chronic kidney disease (CKD). Genetic studies have shown that two risk alleles (termed G1 and G2) are highly associated with nondiabetic CKD and increased rate of progression towards kidney failure, providing an exciting opportunity for personalized medicine in CKD. These two variants are more frequently found in individuals of West-African ancestry. Reduction of APOL1 with ION532 in a preclinical mouse model of APOL1-related kidney disease demonstrated significantly reduced proteinuria, a hallmark of CKD. ION532 is being developed for the treatment of APOL1-associated nephropathies.

About Chronic Kidney Disease

CKD is a worldwide public health problem, affecting about 10% of the population. Within United States, over 37 million adults have CKD and millions of others are at increased risk. CKD may be caused by diabetes, high blood pressure and other disorders. Without treatment, CKD may progress and eventually lead to kidney failure, which requires dialysis or a kidney transplant to maintain life.

Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.