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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 first-in-class and/or best-in-class medicines designed to treat a broad range of diseases including cancer and cardiovascular, neurological, infectious and pulmonary 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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AKCEA-APO(a)-LRx
(Apo(a))
CVD
Akcea/ Novartis

Generation 2+ LICA antisense drug

AKCEA-APO(a)-LRx, also known as TQJ230, is a Generation 2+ LICA antisense drug designed to reduce apolipoprotein(a) in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a), a very atherogenic and thrombogenic form of LDL. Elevated Lp(a) is recognized as an independent, genetic cause of coronary artery disease, heart attack, stroke and peripheral arterial disease. Currently, there is no effective drug therapy to specifically and robustly lower elevated levels of Lp(a). Lp(a) levels are determined at birth and, therefore, lifestyle modification, including diet and exercise, do not impact Lp(a) levels. Even patients who can control their LDL-C remain at high-risk of cardiovascular events if they have high levels of Lp(a).

AKCEA-APO(a)-LRx is being developed for patients who are at significant risk of CVD because of their elevated Lp(a). We believe AKCEA-APO(a)-LRx is the first and currently only drug in clinical development designed to selectively and robustly inhibit the production of Lp(a).

About Lp(a)

Lp(a) is a lipoprotein particle assembled in the liver that consists of an LDL-C-like particle and apolipoprotein(a). Lp(a) is considered a key driver for cardiovascular disease due to its association with an increased risk of coronary heart disease. There is evidence that elevated Lp(a) levels may contribute directly to heart attacks. Lp(a) levels in blood can vary greatly between individuals primarily due to genetic variations. Because elevated Lp(a) is a genetically determined condition that is not responsive to lifestyle changes, patients are unable to adequately control their Lp(a) levels through improved diet or increased physical activity. Moreover, current therapies are not able to reduce Lp(a) to recommended levels in patients who have high Lp(a). Although Lp(a) can be measured by a routine lipid blood panel, the lack of drugs to effectively lower Lp(a) has made treating patients with Lp(a)-driven cardiovascular disease difficult.

Select Publications
  1. Merki, E. et al. (2011) Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol. 57, 1611-1621.
  2. Nordestgaard, B.G. et al. (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 31, 2844-2853.
  3. Tsimikas, S. et al. (2012) Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease. J Am Coll Cardiol. 63, 716-721.

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

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AKCEA-TTR-LRx
(TTR)
ATTR
Akcea

Generation 2+ LICA antisense drug

AKCEA-TTR-LRx is is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of transthyretin, or TTR protein, to treat all types of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease. In patients with ATTR. Both the mutant and wild type (wt) TTR protein builds up as fibrils in tissues, such as the peripheral nerves, heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. The presence of TTR fibrils interferes with the normal functions of these tissues. As the TTR protein fibrils enlarge, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.

About TTR Amyloidosis (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.

Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromise their function and eventually leading to death within five to fifteen years of disease onset. There are an estimated 10,000 patients with polyneuropathy due to hATTR worldwide.

ATTR cardiomyopathy 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 3 to 5 years from disease onset. ATTR cardiomyopathy includes both the genetic and wild-type form of the disease. There are an estimated 240,000 patients with ATTR cardiomyopathy worldwide.

Often patients with the polyneuropathy form of TTR amyloidosis will also have TTR build up in the heart and also experience cardiomyopathy symptoms. Similarly, patients with the cardiomyopathy form of TTR amyloidosis may often have TTR build up in their peripheral nerves and can experience nerve damage and progressive difficulty with motor functions.

Select Publications
  1. Ackermann, E.J. et al.  (2012) Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 19, 43-44.
  2. Benson, M.D. et al.  (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve. 33, 609-618.
  3. Benson, M.D. et al.  (2011) Rate of Progression of Transthyretin Amyloidosis. Am J Cardiol.108, 285-289.

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

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Vupanorsen
(ANGPTL3)
CVD
Akcea/Pfizer

Generation 2+ LICA antisense drug

Vupanorsen, formerly known as AKCEA-ANGPTL3-LRx, is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce angiopoietin-like 3 protein, or ANGPTL3. Human genetic studies have shown that lower levels of ANGPTL3 are associated with lower plasma triglyceride (TG) and LDL-C and protection against certain cardiovascular diseases1-3. Studies in animals have demonstrated that targeted reduction of ANGPTL3 with antisense drugs results in substantially decreased TG and LDL-C4. A large number of patients with elevated risk of cardiovascular disease are not reaching recommended TG and LDL-C goals. Vupanorsen is being developed to reduce plasma levels of ANGPTL3 with the goal of lowering levels of plasma TG and LDL-C to potentially reduce the risk of future cardiovascular events.

About ANGPTL3 and Cardiovascular Disease
Angiopoietin-like-3, or ANGPTL3, is a well-established regulator of the blood lipids LDL-C and triglycerides. ANGTPL3 has also been identified as an important factor in cardiovascular disease (CVD). Studies have shown that people with a loss of function (LOF) mutations and/or decreased ANGPLT3 plasma levels have reduced risk for CVD. For example, genomic analysis of over 180,000 individuals with genetic variations that cause a LOF in ANGPTL3 demonstrated a 34% reduction in risk of coronary heart disease among carriers of ANGPTL3 LOF mutations1. In addition, circulating ANGPTL3 concentrations were found to be lower in healthy control subjects than in those who have had heart attacks. Additionally, individuals with complete ANGPTL3 deficiency showed no evidence of atherosclerosis relative to control subjects who had a mean total atherosclerotic plaque burden of about 39%. Thus, treatment to lower ANGPTL3 plasma levels could be an important advance in cardiovascular therapy for individuals at risk for ischemic heart disease who have elevated LDL-C and plasma triglycerides, which usually reflects elevated plasma remnant cholesterol.

Select Publications
  1. Stitziel, N.O. et al. (2017) ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 69(16):2054-2063.
  2. Shimizugawa, T. et al. (2002) ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 277(37):33742-33748.
  3. Musunuru, K. et al. (2010) Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 363(23):2220-2227.
  4. Graham, M.J. et al. (2017) Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 377(3):222-232.

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

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AKCEA-APOCIII-LRx
(ApoCIII)
CVD
Akcea

Generation 2+ LICA antisense drug

AKCEA-APOCIII-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to inhibit the production of apoC-III for patients who are at risk for cardiometabolic disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. People with elevated triglycerides are at increased risk for cardiovascular disease and for type 2 diabetes. People with severely elevated triglycerides, such as people with familial chylomicronemia syndrome (FCS), are at high risk for acute pancreatitis and other serious conditions. ApoC-III is also the target of WAYLIVRA, the first approved medicine for patients with FCS.

About ApoC-III and Triglycerides

ApoC-III is an important emerging target linking hypertriglyceridemia with cardiovascular disease (CVD). In several studies, apoC-III levels are an independent risk factor for CVD. Further, its presence on lipoproteins may increase their atherogenicity. A study in the New England Journal of Medicine reported that out of a sample of over 100,000 people, individuals with an apoC-III loss-of-function mutation had a reduced risk of clinical coronary heart disease. Each decrease of 1mg/dL in plasma levels of apoC-III was associated with a 4% decrease in the risk of incident coronary heart disease. Triglycerides may also play a role in cardiovascular risk. In two separate studies encompassing nearly 20,000 patients, as triglyceride levels increased, so did the risk of a cardiovascular event. In summary, apoC-III impacts triglyceride levels and may also increase inflammatory processes. This combination of effects makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled.

Select Publications
  1. Graham, M.J. et al.  (2013) Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 112, 1479-1490.
  2. Kathiresan et al.  (2014) Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. N Engl J Med. 371, 22-31.
  3. Jorgensen, A.B. et al.  (2014) Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 371, 32-41.
  4. Gaudet, D. (2015) JJ. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med.373(5):438-47.
  5. Alexander, V.J. (2019) N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 40(33):2785-279

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

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IONIS-FB-LRx
(Complement Factor B)
IgA Nephropathy
Roche

Generation 2+ LICA antisense drug
IONIS-FB-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of complement factor B (FB). Genetic association studies have shown that overaction of this cascade has been associated with the development of several complement-mediated diseases, including IgA nephropathy (IgAN). FB, a key regulatory protein, is produced predominately in the liver and circulates at high levels throughout the vascular system, including in the kidney.

About IgA Nephropathy (IgAN)
IgA Nephropathy (IgAN) is the most prevalent primary chronic glomerulonephritis worldwide and is an important cause of chronic kidney disease and renal failure. Also known as Berger’s disease, IgAN is characterized by immunodeposits with dominant or codominant IgA in the glomerular mesangium of the kidneys, resulting in inflammation and tissue damage. Although IgAN may occur at any age, it generally presents in the second or third decade of life. The clinical presentation, disease progression and histologic findings are highly variable among affected individuals. Current therapies are aimed at reduction in proteinuria with administration of angiotensin inhibitors and control of blood pressure. Sometimes immunosuppressive therapies are given; however, this practice is not universally accepted.

Select Publications
  1. Floege, J. et al. (2018) IgA nephropathy: new insights into the role of complement. Kid International. 94, 16-18.
  2. Yen, S.C. et al. (2017) New insights into the pathogenesis of IgA nephropathy. Pediatr Nephrol 33:763-777.
  3. Thompson, A. et al. (2019) Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. CJASN 14

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

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IONIS-AGT-LRx
(Angiotensinogen)
Treatment-Resistant Hypertension
Ionis-Owned

Generation 2+ LICA antisense drug

IONIS-AGT-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of angiotensinogen to decrease blood pressure in patients with treatment resistant hypertension (TRH). Despite availability of generic antihypertensive agents, TRH is a major contributor to cardiovascular and renal disease.

Inhibiting the renin-angiotensin-aldosterone system (RAAS) is a well-established method of treating hypertension and complications of hypertension. While angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely used, many patients with high blood pressure are not well controlled by these treatment options. Angiotensinogen, the target of IONIS-AGT-LRx, is upstream of ACE inhibitors and ARBs in the RAAS pathway. Therefore, reducing angiotensinogen levels has the potential to decrease blood pressure in patients whose blood pressure is not adequately controlled by currently available treatment options. Furthermore, inhibiting angiotensinogen, which is made in the liver, may maintain renal compensatory mechanisms, which could lead to fewer side effects compared to current standard of care.

About Treatment Resistant Hypertension (TRH)

Approximately 70 million adults in the United States have hypertension, half of which have uncontrolled hypertension. About 12-15 percent of patients with uncontrolled hypertension have resistant hypertension, defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. Current estimates approximate that there are up to three million patients with TRH in the U.S. Patients with TRH have been found to have 3-fold increased odds of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.

Select Publications
  1. Wu, C.H. et al. (2019) Antisense oligonucleotides targeting angiotensinogen: insights from animal studies. Biosci Rep. 2019 Jan 11;39(1).
  2. Ferrario, C.M. et al. (2017) Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res. 2017 Nov;125(Pt A):57-71.
  3. Mullick, A.E. et al. (2017) Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. Hypertension. 2017 Sep;70(3):566-576.
  4. Williams, B.  (2016) Drug discovery in renin-angiotensin system intervention: Past and future. Ther Adv Cardiovasc Dis;10:118-125.

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

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IONIS-FXI-LRx
(Factor XI)
Clotting Disorders
Bayer

Generation 2+ LICA antisense drug

IONIS-FXI-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of Factor XI, a clotting factor produced in the liver that is an important component of the coagulation pathway. High levels of Factor XI increase the risk of blood clot formation inside blood vessels (thrombosis), which can cause heart attacks and strokes. Alternatively, individuals deficient in Factor XI have a lower incidence of thrombosis-related events and little to no increase in bleeding risk. This makes Factor XI an attractive target for an antithrombotic drug because of the potential to separate antithrombotic activity from bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, these anticoagulants are associated with increased bleeding risk at therapeutic doses, which can lead to major, sometimes fatal bleeding events. In clinical studies evaluating the safety and efficacy of the non-LICA version of IONIS-FL-LRx (IONIS-FXIRx), dose-dependent inhibition of Factor XI activity was demonstrated, which was associated with significant reductions in clotting events and no increase in major bleeding events. These data coupled with data in humans with little to no Factor XI activity provide evidence that IONIS-FXIRx has the potential to be used broadly as an anti-thrombotic in different therapeutic settings for which additional safe and well tolerated anti-thrombotic drugs are needed, especially in patient populations that are at high risk for thrombosis and are also at high risk for bleeding.

About Thrombosis

Thrombosis is the aberrant formation of blood clots inside blood vessels. Blood clots can obstruct blood flow to prevent sufficient oxygen flow to tissues and organs. In addition, clot fragments can break off from the blood clot and travel downstream to occlude other parts of the circulation. Thrombosis is responsible for many heart attacks and strokes and is the leading cause of morbidity and mortality worldwide.

Current antithrombotic treatments include anticoagulants such as warfarin, Factor Xa inhibitors and thrombin inhibitors. Although these drugs are effective at lowering the risk of thrombosis, these drugs place patients at significant risk of serious bleeding because they target factors required for normal coagulation.

Factor XI is a clotting factor produced in the liver that is an important component in the intrinsic pathway of the coagulation process. Factor XI’s role in blood coagulation is in clot stabilization and expansion and not in clot initiation. People with high levels of Factor XI have increased risk of thrombosis while those with deficient Factor XI have a lower incidence of thromboembolic events and minimal risk of bleeding.

Selected Publications

  1. Buller, H.R. et al. (2014) Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. N Engl J Med. Epub ahead of print.
  2. Crosby, J.R. et al. (2013) Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol. 33, 1670-1678.
  3. Lowenberg, E.C. et al. (2010) Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost.8, 2349-2357.
  4. Younis, H.S. et al. (2012) Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood. 119, 2401-2408.
  5. Zhang, H. et al. (2010) Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood. 116, 4684-4692.

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

 

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IONIS-AZ4-2.5LRx
(Undisclosed)
CVD
AstraZeneca

Generation 2+ LICA antisense drug

IONIS-AZ4-2.5-LRx, also known as AZD8233, is a Generation 2.5 ligand-conjugated antisense (LICA) drug designed to inhibit an undisclosed target to treat cardiovascular disease.

 

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ION532
(Undisclosed)
Kidney Disease
AstraZeneca

Generation 2.5 antisense drug

ION532, formerly known as IONIS-AZ5-2.5Rx and AZD2373.

About Chronic Kidney Disease

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.

Select Publication

https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-Kidney-Disease-Fact-Sheet.pdf

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ION547
(Undisclosed)
Cardiometabolic Disease
Ionis-Owned

Generation 2.5 LICA antisense drug

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ION904
(Undisclosed)
Cardiometabolic Disease
Ionis-Owned

Generation 2.5 LICA antisense drug

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Metabolic

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-GHR-LRx
(GHr)
Acromegaly
Ionis-Owned

Generation 2+ LICA antisense drug

IONIS-GHR-LRx  is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of the growth hormone receptor (GHr) to decrease the circulating level of insulin-like growth factor-1 (IGF-1). IGF-1 is a hormone primarily produced in the liver that plays an important role in childhood growth and has anabolic effects in adults. Several different diseases result from abnormally low or high levels of IGF-1, or an inappropriate response to this hormone. When produced in excess, IGF-1 results in acromegaly, a chronic, slowly progressing and life-threatening disease.

About GHr and Acromegaly

Acromegaly is a chronic, slowly progressing and life-threatening disease most often caused by oversecretion of growth hormone (GH) by benign pituitary tumors. Elevated levels of GH can overstimulate growth hormone receptors (GHr) and induce excess production of insulin-like growth factor-1 (IGF-1). High levels of circulating GH and IGF-1 lead to this multisystem disease characterized by organ overgrowth and physical disfigurement, such as enlarged hands, feet, and facial features. Patients with acromegaly also experience multiple comorbidities, such as type 2 diabetes, hypertension, and respiratory complications, as well as premature mortality. Because IGF-1 mediates the majority of the growth-promoting action of GH, reducing GHr production could in turn decrease levels of IGF-1 and provide a potential treatment to patients with acromegaly. Current treatments to block IGF-1 include surgical removal of the pituitary gland, which is often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.

Select Publications
  1. Tachas, G. et al. (2006) A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice. J Endocrinol. 189, 147-154.

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

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AKCEA-APOCIII-LRx
(ApoCIII)
FCS
Akcea

Generation 2+ LICA antisense drug

AKCEA-APOCIII-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to inhibit the production of apoC-III, for patients who are at risk of disease due to elevated triglyceride levels. 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 familial chylomicronemia syndrome (FCS), are at high risk for acute pancreatitis and other serious conditions. ApoC-III is also the target of WAYLIVRA, the first approved medicine for patients with FCS.

About familial chylomicronemia syndrome (FCS)

FCS is a rare, genetic disease characterized by extremely elevated triglyceride levels that is estimated to affect 3,000 to 5,000 people worldwide. People with FCS are at high risk of unpredictable and potentially fatal acute pancreatitis. In addition to pancreatitis, FCS patients are at risk of chronic complications due to permanent organ damage, including chronic pancreatitis and pancreatogenic (type 3c) diabetes. They can experience daily symptoms including abdominal pain, generalized fatigue and impaired cognition that affect their ability to work. People with FCS also report major emotional and psychosocial effects including anxiety, social withdrawal, depression and brain fog. Additional information on FCS is available at www.fcsfocus.com, through the LPLD Alliance at http://www.lpldalliance.org and through The FCS Foundation at http://www.livingwithfcs.org. For a full list of organizations supporting the FCS community worldwide, please click here.

Select Publications
  1. Scherer, J. et al.  (2014) Issues in hypertriglyceridemic pancreatitis: an update. J. Clin Gastroenterol. 48, 195-203.
  2. Gaudet, D. et al. (2014) Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med. 371, 2200-2206.
  3. Witztum, J.L. et al. (2019) Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 381(6):531-542.
  4. Alexander, V.J. (2019) N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 40(33):2785-279

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

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IONIS-GCGRRx
(GCGR)
Diabetes
Suzhou-Ribo (China only)

Generation 2+ antisense drug

IONIS-GCGRRx is a Generation 2+ antisense drug designed to reduce the production of glucagon receptors, or GCGR, to treat patients with type 2 diabetes. GCGR is a receptor for the hormone glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action can lead to significant increase in blood glucose level. In addition, reducing GCGR produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and enhances insulin secretion.

About Type 2 Diabetes

Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated in type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more common type, the body does not make or use insulin well and therefore, blood glucose levels are not regulated properly.

Diabetes is an epidemic that continues to grow at an alarming rate. According to the latest Center for Disease Control statistics released, there are currently 29 million people in the U.S. that have diabetes, with type 2 diabetes constituting 90 to 95 percent of those cases. Moreover, an additional 86 million American adults, or one out of every three adults, are prediabetic. It is estimated that 15 to 30 percent of prediabetic people will develop full-fledged metabolic disorder within five years.

Select Publications
  1. Liang, Y. et al. (2004) Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes. 53, 410-417.
  2. van Dongen, M.G. et al.  (2014) First proof of pharmacology in humans of a novel glucagon receptor antisense drug. J Clin Pharmacol. Epub ahead of print.

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

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ION839
(PNPLA3)
NASH
AstraZeneca

Generation 2.5 LICA antisense drug

ION839, formerly known as IONIS-AZ6-2.5-LRx and AZD2693, is a generation 2.5 ligand-conjugated (LICA) antisense drug 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 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 NASH. In a mouse model of NASH 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 NASH pathology in the mutant mouse model.

ABOUT NASH
Non-alcoholic fatty liver disease (NAFLD) describes the full spectrum of liver disease progression from fatty liver to non-alcoholic steatohepatitis (NASH) to cirrhosis to hepatocellular carcinoma. While fatty liver is often asymptomatic, NASH, which is characterized by liver steatosis, inflammation, and scarring, can lead to increased risk of cardiovascular disease, need for liver transplantation, and early death. NASH epidemiology studies have estimated 13-32% of the global population has NAFLD, 1.5%-6.5% have NASH, and approximately 9% of NASH patients progress to advanced liver disease. There are currently no commercially available NASH medications.

Select Publications
  1. Trepo, E. et al. (2016) PNPLA3 Gene in Liver Diseases. J Hepatol. 65(2), 399-412
  2. BasuRay, S. et al. (2019) Accumulation of PNPLA3 on Lipid Droplets Is the Basis of Associated Hepatic Steatosis. PNAS. 116(19), 9521-9526
  3. Linden, D. et al. (2019) Pnpla3 Silencing With Antisense Oligonucleotides Ameliorates Nonalcoholic Steatohepatitis and Fibrosis in Pnpla3 I148M Knock-In Mice. Mol Metab. 22, 49-61
  4. Diehl. A.M. et al. (2017) Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med. 377(21), 2063-2072

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

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ION224
(DGAT2)
NASH
Ionis-Owned

Generation 2+ LICA antisense drug

ION224 is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, to treat patients with NASH, or nonalcoholic steatohepatitis. NASH is a common liver disease characterized by excessive triglycerides in the liver with concurrent inflammation and cellular damage. 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 animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis, lowered blood lipid levels and reversed diet-induced insulin resistance in animal models of obesity and fatty liver disease. [3,5]

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.

About NASH

NASH is a liver disease characterized by the presence of excessive liver fat (steatosis) that is accompanied by inflammation and cellular damage. NASH is considered a “silent” liver disease because in the early stages of the disease, patients generally feel well and are unaware they have the disease. However, as NASH progresses, scarring, or fibrosis, begins to accumulate in the liver. Ultimately, cirrhosis of the liver develops and the liver can no longer function normally. About 20 percent of NASH patients are reported to develop cirrhosis, and 30 to 40 percent of patients with NASH cirrhosis experience liver-related death. [4] Currently, liver transplantation is the only treatment for advanced cirrhosis and liver failure. Because of the high prevalence of NASH, it has recently become the third most common indication for liver transplantation in the US. [2] The exact cause of NASH is not well understood but the development of fatty liver diseases has been linked to obesity. As the number of people with obesity continues to rise globally, a parallel increase in the incidence of NASH has also been observed. Currently, it is estimated that 2 to 3 percent of the general population have NASH. [1] However, with the growing obesity epidemic, it is likely that the number of patients with NASH will also continue to rise.

Select Publications
  1. Bellentani, S. et al. (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 28,155-161.
  2. Byrne, C.D. et al. (2015) NAFLD: a multisystem disease. J Hepatol. 621, S47-64.
  3. Choi, C.S. et al. (2007) Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 282, 22678-22688.
  4. Takahashi, Y. et al.  (2015) Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 21, 3777-3785.
  5. Yu, X.X. et al. (2005) Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 42, 362-371.

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

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Neurological

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
Tofersen
(SOD1)
Amyotrophic Lateral Sclerosis
Biogen

Generation 2+ antisense drug

Tofersen (formerly IONIS-SOD1Rx), also known as BIIB067, is an antisense drug designed to reduce the production of superoxide dismutase 1 (SOD1), which is the best understood genetic cause of familial amyotrophic lateral sclerosis (ALS). ALS is a rare, fatal neurodegenerative disorder. Patients with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. A mutation in the SOD-1 gene results in an inherited form of ALS, referred to as SOD1-ALS. There is substantial evidence that mutations in the SOD1 gene are responsible for a toxic gain of function that can lead to rapid progressive loss of motor neurons in patients with SOD1-ALS. As a result, patients with SOD1-ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease.

About Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder. Patients with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. There is substantial evidence that mutations in the SOD1 gene are responsible for a toxic gain of function that can lead to progressive loss of motor neurons in patients with SOD1-ALS. As a result, patients with SOD1-ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. SOD1-ALS is the second most common familial form of ALS, accounting for up to 20 percent of familial ALS. Familial ALS represents approximately 15 to 20 percent of all cases of ALS. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Select Publications
  1. Miller, T.M. et al. (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12(5):435-42.

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

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Tominersen
(HTT)
Huntington’s Disease
Roche

Generation 2+ antisense drug

Tominersen, formerly known as IONIS-HTTRx and RG6042, is an antisense drug designed to reduce the production of the huntingtin (HTT) protein, which is the genetic cause of Huntington’s disease (HD). HD is caused by expansion of the CAG trinucleotide sequence in the HTT gene, which produces a toxic protein that progressively destroys neurons in the brain. As a result, HD patients experience progressive loss of mental faculties and physical control as their disease progresses.

The European Medicines Agency has granted orphan drug designation to tominersen for the treatment of patients with HD.

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 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.

Select Publications
  1. Kordasiewicz, H.B. et al. (2012) Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron. 74, 1031-1044.

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

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AKCEA-TTR-LRx
(TTR)
hATTR Polyneuropathy
Akcea

Generation 2+ LICA antisense drug

AKCEA-TTR-LRx is is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of transthyretin, or TTR protein, to treat all types of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease. In patients with ATTR. Both the mutant and wild type (wt) TTR protein builds up as fibrils in tissues, such as the peripheral nerves, heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. The presence of TTR fibrils interferes with the normal functions of these tissues. As the TTR protein fibrils enlarge, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.

About TTR Amyloidosis (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.

Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromise their function and eventually leading to death within five to fifteen years of disease onset. There are an estimated 10,000 patients with polyneuropathy due to hATTR worldwide.

ATTR cardiomyopathy 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 3 to 5 years from disease onset. ATTR cardiomyopathy includes both the genetic and wild-type form of the disease. There are an estimated 240,000 patients with ATTR cardiomyopathy worldwide.

Often patients with the polyneuropathy form of TTR amyloidosis will also have TTR build up in the heart and also experience cardiomyopathy symptoms. Similarly, patients with the cardiomyopathy form of TTR amyloidosis may often have TTR build up in their peripheral nerves and can experience nerve damage and progressive difficulty with motor functions.

Select Publications
  1. Ackermann, E.J. et al.  (2012) Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 19, 43-44.
  2. Benson, M.D. et al.  (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve. 33, 609-618.
  3. Benson, M.D. et al.  (2011) Rate of Progression of Transthyretin Amyloidosis. Am J Cardiol.108, 285-289.

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

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IONIS-C9Rx
(C9ORF72)
Amyotrophic Lateral Sclerosis
Biogen

Generation 2+ antisense drug

IONIS-C9Rx, also known as BIIB078, is a Generation 2+ antisense drug designed to reduce the production of the mutated chromosome 9 open reading frame 72 (C9ORF72) gene. A mutation in the C9ORF72 gene results in an inherited form of amyotrophic lateral sclerosis (ALS), referred to as C9ORF72-ALS, the leading known genetic cause of ALS worldwide. There is substantial evidence that this mutation is responsible for a toxic gain of function repeat expansion that can lead to rapid progressive loss of motor neurons in people with C9ORF72-ALS. C9ORF72-ALS is a fatal disease characterized by muscle weakness, loss of movement, difficulty in breathing and swallowing.

About Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder characterized by loss and dysfunction of neurons in motor pathways with a prevalence of approximately five cases per 100,000 persons in the U.S.1 People with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. A mutation in the C9ORF72 gene results in an inherited form of ALS, referred to as C9ORF72-ALS. Familial ALS represents approximately 15 to 20 percent of all cases of ALS and C9ORF72-related ALS accounts for up to 34 percent of all familial cases.2,3 It is currently the leading known genetic cause of ALS worldwide. People with C9ORF72-ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Select Publications
  1. Mehta, P. et al. (2018) "Prevalence of Amyotrophic Lateral Sclerosis — United States, 2014." MMWR Morb Mortal Wkly Rep 67, 216–218.
  2. McCampbell et al. "Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models." The Journal of Clinical Investigations, Advanced Online Publication, July 16, 2018.
  3. Van Blitterswijk, M. et al. (2012). How do C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding repeat expansion disorders? Current Opinion in Neurology, 25(6), 689–700.

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

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IONIS-MAPTRx
(TAU)
Alzheimer's Disease & Frontotemporal Degeneration
Biogen

Generation 2+ antisense drug

IONIS-MAPTRx, also known as BIIB080, is an antisense oligonucleotide (ASO) drug designed to selectively reduce production of the tau protein in the brain. Microtubule-associated protein tau (MAPT) or tau, is thought to be a contributor or cause of certain neurodegenerative diseases, known as tauopathies, that are characterized by the deposition of abnormal tau protein in neurons and glia in the brain. These disorders include Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP), and some forms of frontotemporal degeneration (FTD).

About Alzheimer’s Disease (AD)

It is estimated that in the U.S., 10% of people age 65 and older is living with dementia. Alzheimer’s disease (AD) is the most common form of dementia, accounting for an estimated 70% of cases. AD is a neurodegenerative disorder characterized by cognitive decline and behavioral disturbances that eventually result in a person’s inability to perform daily activities. AD relentlessly progresses to death over 5-20 years. Unlike amyloid deposits that appear diffusely throughout the brain for up to 20 years before the onset of AD, tau deposits are temporally and spatially closely-related to where brain atrophy occurs and cognitive deficits originate.

About Frontotemporal Degeneration

Frontotemporal degeneration (FTD) is a rare form of dementia resulting from neuronal damage in parts of the brain called the frontal and temporal lobes. As neurons die in these regions, these lobes atrophy. FTD typically occurs between the ages of 45 and 64 years old, with patients surviving approximately 9 years from diagnosis. In the early stages of the disease, patients experience substantial personality and social behavior changes, including apathy, loss of empathy, emotional bluntness, impulsiveness, poor judgment, communication impairment, among others. Death is typically the result of disease progression leading to pneumonia, failure to thrive, or cardiopulmonary failure.

Select Publications
  1. DeVos, S.L. et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Trans. Med. 9, 374.
  2. DeVos, S.L. et al. (2013) Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33:12887.

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

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ION859
(LRRK2)
Parkinson's Disease
Biogen

Generation 2+ antisense drug

ION859 (formerly IONIS-BIIB7Rx), also known as BIIB094, is an antisense oligonucleotide (ASO) targeting Leucine Rich Repeat Kinase 2 (LRRK2) messenger ribonucleic acid (mRNA). ION859 is designed to prevent the production of LRRK2 protein and is being developed as a potential therapy for Parkinson’s disease (PD). The most common genetic mutations in PD cases are found in the LRRK2 gene. Increased LRRK2 protein activity is hypothesized to be one of the key drivers of PD pathogenesis. It is hypothesized that reduction of LRRK2 mRNA and, subsequently, reduced synthesis of LRRK2 protein will ameliorate the toxic effects of gain-of-function mutations as well as the primary pathology in PD patients without the LRRK2 mutation.

About Parkinson’s Disease
Parkinson’s disease is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patient’s with Parkinson’s disease can experience tremors, loss of balance and coordination, stiffness, slowing of movement, changes in speech and in some cases cognitive decline. Parkinson’s disease is ultimately fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy. The exact cause is unknown, but it is believed to be a combination of genetics and environmental factors. There are known hereditary mutations that cause Parkinson’s disease, including dominantly inherited gain-of-function mutations in the LRRK2 gene.

Select Publications
  1. Cookson, M.R. (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature reviews Neuroscience 11, 791-797.
  2. Zhao, H.T. et al. (2017). LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson’s Disease Mouse Model. Molecular Therapy - Nucleic Acids 8, 508-519

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

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IONIS-DNM2-2.5Rx
(DNM2)
Centronuclear Myopathy
Dynacure

Generation 2.5 antisense drug

IONIS-DNM2-2.5Rx is an antisense drug designed to reduce the production of Dynamin 2 (DNM2) protein for the treatment of centronuclear myopathy (CNM). CNM is a group of rare congenital myopathies where cell nuclei are abnormally located in the center of the skeletal muscle cells. DNM2 reduction, either by genetic manipulation or antisense oligonucleotide treatment, improves muscle mass and muscle force in mouse models of main forms of CNM, and extends lifespan in the most severe form of CNM.

About Centronuclear Myopathy

CNM is a group of rare congenital myopathies where cell nuclei are abnormally located in the center of the skeletal muscle cells. Clinical features include muscle weakness, hypotonia and muscle atrophy, ranging from severe to mild. There are three main forms of CNM. X-linked CNM (XL-CNM, also known as myotubular myopathy) is a life-threatening form of CNM with a neonatal disease onset caused by mutations in myotubularin (MTM1); autosomal recessive CNM (AR-CNM) is a less severe form with a neonatal to childhood onset caused by mutations in amphiphysin 2 (BIN1); autosomal dominant CNM (AD-CNM) is a mild form of CNM with likely an adulthood onset due to mutations in dynamin 2 (DNM2). Estimated incidence of XL-CNM is 1 in 50,000 male live births. AR-CNM and AD-CNM may have similar incidence, but prevalence is higher due to longer survival.

Select Publications

Buono, S. et al. “Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy” Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11066-11071. Epub 2018 Oct 5.

Tasfaout, H. et al. “Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice” Nature Communications volume 8, Article number: 15661 (2017).

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

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ION464
(SNCA)
Multiple System Atrophy & Parkinson's Disease
Biogen

Generation 2+ antisense drug

ION464 (formerly IONIS-BIIB6Rx), also known as BIIB101, is an antisense drug  targeting alpha-synuclein (SNCA) messenger ribonucleic acid (mRNA). ION464 is designed to prevent the production of alpha-synuclein protein and is being developed as a potential therapy for Parkinson’s disease (PD), Multiple System Atrophy (MSA) and related synucleinopathies. Alpha-synuclein protein aberrantly accumulates in the brains of PD and MSA patients and is thought to be one of the key drivers of pathogenesis. It is hypothesized that reduction of SNCA mRNA and, subsequently, reduced synthesis of alpha-synuclein protein will ameliorate the toxic effects of gain-of-function mutations as well as the primary pathology in PD and MSA patients without SNCA mutations.

About Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patient’s 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 is no disease modifying therapy.  The exact cause is unknown, but it is believed to be a combination of genetics and environmental factors. There are known hereditary mutations that cause PD, including dominantly inherited mutations in the SNCA gene.

About Multiple System Atrophy

Multiple System Atrophy (MSA) is a rare, fatal, rapidly progressing neurodegenerative disease. Patients with MSA typically experience progressive motor dysfunction, with death often occurring less than 10 years after symptom onset. Symptoms in MSA can be similar to Parkinson’s disease, but can also include ataxia, autonomic changes and vision disturbances. Aberrant accumulation of alpha-synuclein in MSA is unique in that it is prominent not only in neurons, but also in glia cells, the supporting cells in the brain.

Clinical Trials Posting

https://clinicaltrials.gov/ct2/show/NCT04165486

Select Publications
  1. Cole T.A. et al. (2018) Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease. Mol Ther. 26(2):550-567.

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

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ION716
(PRNP)
Prion Diseases
Ionis-Owned

Generation 2+ antisense drug

ION716 is an antisense oligonucleotide (ASO) targeting prion protein (PrP) messenger ribonucleic acid (mRNA). ION716 is designed to inhibit the production of cellular PrP protein (PrPC) and is being developed as a potential therapy for Prion diseases. ASO-mediated reduction of PrPC has the potential to ameliorate, prevent, or even reverse Prion diseases.

About Prion Diseases

Prion disease is a fatal, incurable neurodegenerative disease that typically presents as a rapidly progressive dementia. Regardless of etiology – sporadic, genetic, or acquired, and regardless of clinical name – Creutzfeldt-Jakob disease, fatal familial insomina, or Gerstmann-Straussler-Scheinker syndrome, all prion diseases are caused by conformational change of PrP from its native fold to a self-propagating misfolded form (PrPSc), which is an abnormal, pathogenic agent that causes brain damage.

Select Publications
  1. Raymond et al. JCI Insights (2019), 5 (16), PMID: 31361599

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

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ION581
(UBE3A-ATS)
Angelman Syndrome
Biogen

Generation 2+ antisense drug

ION581 is an antisense oligonucleotide (ASO) that targets Ubiquitin Protein Ligase E3A-Antisense Transcript (UBE3A-ATS), which is a long non-coding ribonucleic acid (lncRNA). ION581 reduces the levels of UBE3A-ATS and is being developed as a potential therapy for Angelman Syndrome (AS). Angelman Syndrome is caused by maternal deficiency of the Ubiquitin Protein Ligase E3A (UBE3A). The paternal copy of the UBE3A gene is usually intact but is silenced by the UBE3A-ATS. It has been shown in iPSC neurons derived from AS patients and in an AS mouse model that ASO-mediated suppression of UBE3A-ATS results in UBE3A unsilencing and robust expression from the paternal allele. ASO-mediated up-regulation of UBE3A mRNA has the potential to restore the levels of UBE3A protein in neurons in patients with AS.

About Angelman syndrome

Angelman syndrome is a rare neurogenetic disorder caused by the loss of function of the maternally inherited UBE3A gene and affects approximately 1 in 15,000 individuals. Angelman syndrome presents early in life with profound and severe developmental delays in motor, language and cognitive functioning, seizures and ataxia. It is a non-degenerative, life-long disorder that generally remains clinically unchanged, resulting in complete dependence on a caregiver throughout their life. Some symptoms can be managed with existing drugs; however, there is no disease modifying therapy.

Select Publications
  1. Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015 Feb 19;518(7539):409-12. doi: 10.1038/nature13975. Epub 2014 Dec 1.

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

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ION260
(Undisclosed)
Neurological Disease
Biogen

Generation 2+ antisense drug

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ION283
(GYS1)
Lafora Disease
Ionis-Owned

Generation 2+ antisense drug

ION283 is an antisense drug designed to reduce the accumulation of glycogen by inhibiting the production of brain glycogen synthase type 1 (GYS1), the enzyme that makes glycogen in the brain. Mutations that are the genetic cause of Lafora disease (LD) result in the accumulation of excess glycogen and result in the formation of Lafora Bodies in the brain and spinal cord, which results in neurodegeneration.  In animal models of LD, reduction of GYS1 reduced glycogen accumulation and prevented the formation of Lafora Bodies and neurodegeneration.

About Lafora Disease

Lafora disease (LD) is an inherited and very severe epilepsy syndrome.  Although children are born with LD, the disease does not manifest itself until adolescence when seizures begin.

LD is characterized by a progressive increase in intensity of seizures, a rapid cognitive decline (dementia) and motor incoordination (ataxia).  Patients who suffer from this devastating disease have difficulty walking, speaking and eating and will eventually become wheelchair bound, and lose the ability to speak and feed themselves.  Lafora patients typically die within 10 years.

LD is autosomal recessive disease caused by mutations in the laforin or malin genes. The underlying pathology is the result of glycogen accumulation in neurons and glial cells that form toxic Lafora Bodies. Currently, there is no disease-modifying therapy and seizures are poorly managed with anti-epileptic drugs.

Select Publications
  1. Duran, J. et al. (2014) Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. 23, 3147-56
  2. Pederson, B.A. et al. (2013) Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Annals of Neurology. 74, 297-300.

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

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ION373
(GFAP)
Alexander Disease
Ionis-Owned

Generation 2+ antisense drug

ION373 is an antisense oligonucleotide (ASO) targeting glial fibrillary acidic protein (GFAP) messenger ribonucleic acid (mRNA). ION373 is designed to inhibit the production of GFAP and is being developed as a potential therapy for Alexander disease (AxD). Nearly all cases of AxD are caused by gain-of-function mutations in GFAP that lead to spontaneous overproduction and toxic accumulation of GFAP into abnormal protein deposits called Rosenthal fibers in the brain. ASO-mediated reduction of GFAP has the potential to ameliorate the underlying cause of disease pathology and reverse or prevent disease progression.

About Alexander disease

Alexander disease (AxD) is a rare neurological condition characterized as a leukodystrophy, or a disease affecting the myelin sheath (the fatty insulation that protects a nerve fiber and supports signal conduction). Two major types of AxD have been defined. Type I onset typically occurs before 4 years of age and patients can experience head enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of 4 and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most often fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.

Clinical trials posting

Not yet posted

Select Publications
  1. Hagemann et al. (2018) Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease. Annals of Neurology. 83, 27-39.

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

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ION541
(ATXN2)
Amyotrophic Lateral Sclerosis
Biogen

Generation 2+ antisense drug

ION541, also known as BIIB105, is an investigational antisense medicine targeting ataxin 2 (ATXN2) RNA. It is designed to prevent the production of ATXN2 protein and is being developed as a potential therapy for sporadic Amyotrophic Lateral Sclerosis (ALS), and other indications. About 90% of ALS1 is sporadic, with no apparent familial history. Aggregates of TDP-43 protein in motor neurons is a pathological hallmark of sporadic ALS and induces toxicity in motor neurons. ATXN2 has been shown to modulate TDP-43 toxicity2-3. In addition, human genetic data has also identified a link between ATXN2 and ALS4. It is hypothesized that reduction of ATXN2 will ameliorate the underlying TDP-43 pathology and reverse or prevent disease progression in sporadic ALS1.

About Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder characterized by loss and dysfunction of neurons in motor pathways with a prevalence of approximately five cases per 100,000 persons in the U.S.1 There are two forms of ALS: inherited (familial) and sporadic. The sporadic form accounts for about 90% all ALS cases. People with ALS suffer progressive degeneration of motor neurons, which results in a declining quality of life and ultimately death. People with ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Select Publications
  1. Mehta, P. et al. (2018) Prevalence of Amyotrophic Lateral Sclerosis — United States, 2014. MMWR Morb Mortal Wkly Rep. 67(7):216–218.
  2. Neumann et al. (2006) Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science 314(5796):130-133.
  3. Becker et al. (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544:367-371.
  4. Elden et al. (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069-1075.

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

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ION363
(FUS)
Amyotrophic Lateral Sclerosis
Ionis-Owned

Generation 2+ antisense drug

ION363 is a Generation 2+ antisense drug designed to prevent the production of the Fused in Sarcoma (FUS) protein. It is being developed as a potential therapy for an inherited form of amyotrophic lateral sclerosis (ALS) in patients with mutations in the FUS gene. FUS-ALS is the third most common inherited form of ALS1. Mutant FUS causes motor neuron degeneration through a toxic gain of function mechanism2. In patients, mutant FUS protein aggregates in motor neurons3. Antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model prevents motor neuron loss. It is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients.

Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder characterized by loss and dysfunction of neurons in motor pathways with a prevalence of approximately five cases per 100,000 persons in the U.S.4About 15 to 20 percent of all ALS cases are familial, and FUS-ALS accounts for approximately 5 percent of familial ALS. Like all ALS, people with FUS-ALS suffer progressive degeneration of motor neurons, which results in a declining quality of life and ultimately death. People with ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Select Publications
  1. Da Cruz, S. et al. (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol. 21:904-919.
  2. Sharma, A. et al. (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun. 7:10465.
  3. Mackenzie, I.R. et al. (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9:995-1007.
  4. Mehta, P. et al. (2018) Prevalence of Amyotrophic Lateral Sclerosis — United States, 2014. MMWR Morb Mortal Wkly Rep. 67(7):216–218.

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

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Infectious Disease

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-HBVRx
(Hepatitis B Infection)
Hepatitis B Virus Infection
GSK

Generation 2+ antisense drug

IONIS-HBVRx is an antisense drug designed to reduce the production of viral proteins associated with hepatitis B virus (HBV) infection and replication, including hepatitis B surface antigen, which is present in both acute and chronic infections and is associated with a poor prognosis in patients with chronic HBV infection.

About Hepatitis B virus infection

Hepatitis B virus 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. Currently available therapies, although effective in reducing circulating HBV in the blood, do not efficiently inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.

 

Select Publications
  1. Grimm, D. et al. (2011) HBV life cycle and novel drug targets. Hepatol Int. 5, 644-653.
  2. Youssef, S.S. et al.  (2014) In vitro inhibition of hepatitis C virus by antisense oligonucleotides in PBMC compared to hepatoma cells. Biomed Res Int.

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

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Cancer

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-AR-2.5Rx
(AR)
Prostate Cancer
Suzhou-Ribo (China only)

Generation 2.5 antisense drug

IONIS-AR-2.5Rx, formerly known as AZD5312, is a Generation 2.5 antisense drug designed to reduce the production of all known forms of androgen receptor, or AR, including variants of the AR gene, to treat patients with prostate cancer. Prostate cancer growth, proliferation and progression are all androgen-dependent, and AR function is involved in disease progression at all stages of prostate cancer. For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens.

About Prostate Cancer

Prostate cancer is the second leading cause of cancer deaths in American men, with approximately 30,000 deaths each year in the United States. For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens. Although androgen deprivation therapy approaches are initially effective in delaying disease progression in patients with metastatic prostate cancer, over time the course of the disease will progress in many of these patients. Resistance to current therapies is frequent and can occur through a variety of mechanisms including the activation of AR signaling in tumor cells through the amplification, overexpression and mutation of the AR gene.

Select Publications
  1. Augello, M.A. et al.  (2014) AR function in promoting metastatic prostate cancer. Cancer Metastasis Rev. 33, 399-411.
  2. Feraldeschi, R. et al.  (2014) Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. Epub ahead of print.

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

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Danvatirsen
(STAT3)
Cancer
Ionis-Owned

Generation 2.5 antisense drug

Danvatirsen, formerly known as IONIS-STAT3-2.5Rx and AZD9150, is a Generation 2.5 antisense drug designed to reduce the production of signal transducer and activator of transcription 3, or STAT3, for the treatment of patients with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma. Overactivity in STAT3 is believed to prevent cell death and promote tumor cell growth.

About STAT3 and Cancer

STAT3, or signal transducer and activator of transcription 3, is an important mediator of signaling in the JAK2/STAT3 pathway. Mutations in STAT3 and other regulatory genes could result in constitutively active STAT3. Numerous studies have demonstrated constitutive STAT3 activation promotes tumor cell growth and survival. Indeed, activated STAT3 are present in a wide variety of human tumors, including hematological malignancies (leukemia, lymphomas, and multiple myeloma) as well as diverse solid tumors (head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancer).

Select Publications
  1. Burel, S.A. et al. (2013) Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther. 23, 213-227.
  2. Siveen, K.S. et al.  (2014) Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845, 136-154.

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

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ION929
(Undisclosed)
Cancer
Ionis-Owned

Generation 2.5 antisense drug

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ION537
(Undisclosed)
Cancer
MD Anderson

Generation 2.5 antisense drug

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ION251
(IRF4)
Multiple Myeloma
Ionis-Owned

Generation 2.5 antisense drug

ION251, formerly known as IONIS-IRF4-2.5Rx.

Interferon Regulatory Factor 4 (IRF4) is a transcription factor expressed in lymphocytes, where it directs terminal differentiation of B-cells to plasma cells and also has roles in T cell functions such as T cell exhaustion. IRF4 has emerged as a key regulator of multiple genes controlling the survival of multiple myeloma (MM) tumor cells as well as other B-cell malignancies. IRF4 is overexpressed in MM as a result of several mechanisms including activating mutations in the DNA binding domain and translocations. Even limited depletion of IRF4 leads to rapid cell death of MM tumor cells, and as such MM is considered to be “addicted” to IRF4. Taken together, selective inhibition of IRF4 with a therapeutic antisense oligonucleotides (ASO) is an attractive strategy for the treatment of MM with the potential for potent MM cell kill with limited effects on normal cells.​

About Multiple Myeloma

Multiple Myeloma (MM) is an incurable cancer characterized by uncontrolled proliferation of bone marrow plasma cells. Despite their initial responses to current therapies, almost all MM patients eventually relapse with a median overall survival time of 13 months following relapse, presenting a strong need for new treatments. Interferon Regulatory Factor 4 (IRF4) is a transcription factor involved in immune cell development and is essential for plasma cell differentiation. IRF4 has emerged as a key regulator of multiple genes controlling the survival of MM and other B-cell malignancy such as c-Myc and is aberrantly expressed in MM as a result of activating mutations and translocations.

Select Publications
  1. Mittrucker, H.W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 1997;275:540-3.
  2. Shaffer, A.L. et al. IRF4 addiction in multiple myeloma. Nature 2008;454:226-31.

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

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ION674
(EZH2)
Lymphomas
Suzhou-Ribo (China only)

Generation 2.5 antisense drug

ION674, formerly known as IONIS-EZH2-2.5Rx, is an epigenetic modulator as the catalytic subunit of the polycomb repressive complex 2 (PRC2). It functions as a histone methyltransferase which catalyzes the mono- through tri-methylation of lysine 27 residue of histone 3 (H3K27me3) and suppresses the transcription of specific genes. It is involved in early embryogenesis, self-renewal and proliferation of embryo and adult stem cells. Increased expression or activity of EZH2 has been reported in multiple solid tumors as well as hematological malignancies, which associates with poor prognosis. Aberrant expression of EZH2 can be caused by multiple mechanisms in a variety of cancer types. For example, activating mutations leading to enhanced catalytic activity of EZH2 are found in certain types of B-cell lymphoma including GCB-DLBCL and follicular lymphoma. There is also evidence that solid tumors with a loss of function in tumor suppressor genes such as SWI/SNF complex, BAP1, and UTX are highly dependent on EZH2 for their growth. Finally, EZH2 can promote tumor growth by creating immune-suppressive tumor microenvironment such as T cell exhaustion. Collectively, selective depletion of EZH2 by ASO is expected to be highly efficacious in treating tumors with aberrant expression of EZH2.

GCB-DLBCL and Follicular Lymphoma

GCB-DLBCL and follicular lymphoma belong to B-cell non-Hodgkin lymphoma (NHL), a lymphoproliferative disorder originating in B lymphocytes. Even though the initial response rate to the standard of care treatment composed of chemotherapy in combination with anti-CD20 antibody (R-CHOP) is relatively good, the disease either relapses or becomes refractory to the therapy. Heterozygous somatic mutations leading to increased EZH2 activity have been found in approximately 20% of patients with GCB-DLBCL and follicular lymphoma, where EZH2 plays an important role in promoting tumor growth, suggesting that these tumor types might be sensitive to antisense inhibition by EZH2 production.

Select Publications
  1. Morin, R.D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet 2010; 42:181-15
  2. McCabe, M.T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492:108-12
  3. Galaznick, A. et al. ,Systematic review of therapy used in relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma Future Sci OA 2018; 4:FSO322

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

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ION736
(Undisclosed)
Cancer
AstraZeneca

Generation 2.5 antisense drug

ION736, formerly known as IONIS-AZ7-2.5Rx.

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Ophthalmology

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-FB-LRx
(Complement Factor B)
Geographic Atrophy/AMD
Roche

Generation 2+ LICA antisense drug

IONIS-FB-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of complement factor B (FB). Genetic association studies have shown that overaction of this cascade has been associated with the development of several complement-mediated diseases, including dry age-related macular degeneration (AMD). FB, a key regulatory protein, is produced predominately in the liver and circulates at high levels throughout the vascular system, including in capillaries in the eye. 1-5

About AMD

AMD is the leading cause of central vision loss in developed countries. It is estimated that more than three million people in the United States will be affected by the disease by 2020.6. AMD is believed to be a systemic disease with local disease manifestation at the aging retinal macula. AMD gradually destroys vision in the center of the visual field due to progressive damage of the retina.7

Select Publications
  1. Ricklin, D. et al. Complement-targeted therapeutics. Nat Biotechnol 2007; 25(11): 1265-1275.
  2. Silva, A.S. et al. Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of Complement Factor H Tyr402His polymorphism. Mol Vision 2012; 18: 2288-2299. Koskimies et al. Complement In_amm. 1991;8(5-6):257-60.
  3. Grossman et al. Reduction in Ocular Complement Factor B Protein in Mice and Monkeys by Systemic Administration of Factor B Antisense Oligonucleotide. Mol Vision 2017; 23: 561-571.
  4. Loyet et al. Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. IOVS 2012; 53(10): 6628-6637.
  5. Gold et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genetics. 2006; 38:458-462.
  6. Friedman et al. Eye diseases prevalence research group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564-572.
  7. Sunness et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999; 106: 1768-1779.

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

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ION357
(RHO)
Autosomal Dominant Retinitis Pigmentosa
ProQR

Generation 2.5 antisense drug

ION357, formerly known as IONIS-RHO-2.5Rx, is an antisense oligonucleotide (ASO) drug designed to selectively reduce the production of the rhodopsin P23H mutant protein in the eye while allowing normal protein to be expressed. The allele-selective targeting of the ASO to the single-base P23H mutation prevents degeneration of rod photoreceptor cells and preserves cone photoreceptor cell function. ION357 provides a novel approach to treating autosomal dominant retinitis pigmentosa, in which patients have limited therapeutic options.

About Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of rare inherited eye disorders causing photoreceptor degeneration that leads to progressive vision loss. The disease is clinically and genetically heterogeneous and can have an autosomal recessive, autosomaldominant, or X-linked pattern of inheritance. Affected patients first experience defective dark adaptation during adolescence or young adulthood, followed by loss of peripheral visual field when rod photoreceptor function declines. Patients eventually have only a residual central island of vision, which ultimately leads to complete blindness around the age of sixty.

 

Select Publications
  1. Campochiaro, P.A. et al. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018 Jan;62:24-37. doi: 10.1016/j.preteyeres.2017.08.004.
  2. Daiger, S.P. et al. Genes and Mutations Causing Retinitis Pigmentosa. Clin Genet. 2013 Aug; 84(2): 10.1111/cge.12203
  3. Hartong, D.T. et al. Dyja RP. Retinitis pigmentosa. Lancet 2006; 368(9549):1795 809
  4. Murray, S.F. et al. Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. Invest Ophthalmol Vis Sci. 2015; 56(11):6362-75

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

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Pulmonology & Allergy

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-ENAC-2.5Rx
(ENAC)
Cystic Fibrosis
Ionis-Owned

Generation 2.5 antisense drug

IONIS-ENAC-2.5Rx is an antisense drug designed to reduce the production of epithelial sodium channel (ENaC) protein in the lung. ENaC is believed to be hyperactive in cystic fibrosis (CF), which is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Reduction of ENaC with antisense oligonucleotides (ASOs) in preclinical mouse models of cystic fibrosis lung disease leads to significant decrease of mucus accumulation and inflammation, hallmarks of CF lung disease, and improved lung function. This drug is delivered to the lung via aerosol delivery, which results in broad distribution of ASO in the lung with minimal systemic exposure.

About Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common life-threatening genetic diseases, affecting ~30,000 people within US and about 70,000 worldwide. It is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel expressed in epithelial cells in the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Although CF is a multisystem disease, the main cause of morbidity and mortality is lung disease that is characterized by small airway obstruction due to mucus accumulation, decreased mucociliary clearance, and subsequent inflammation and infections.

Select Publications

1. Crosby, J.R. et al. (2017) Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice. Journal of Cystic Fibrosis , Volume 16 , Issue 6 , 671 – 680

Clinical trial post

https://clinicaltrials.gov/ct2/show/NCT03647228?type=lntr&lead=lonis&rank=4

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

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IONIS-PKK-LRx
(PKK)
Hereditary Angioedema
Ionis-Owned

Generation 2+ LICA antisense drug

IONIS-PKK-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of prekallikrein, or PKK, to treat patients with hereditary angioedema, or HAE. PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. HAE is a rare genetic disease characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea. HAE can be fatal if swelling occurs in the larynx. In patients with frequent or severe attacks, doctors may use prophylactic treatment approaches to prevent and reduce the severity of HAE attacks. However, current prophylactic treatment approaches are very limited and have major tolerability issues due to challenging administration requirements leaving patients with few therapeutic options.

About Hereditary Angioedema

HAE is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea. HAE affects approximately 20,000 patients in the United States and Europe and can be fatal if swelling occurs in the larynx. In patients with frequent or severe attacks, doctors may use prophylactic treatment approaches to prevent and reduce the severity of HAE attacks. However, current prophylactic treatment approaches are very limited and have major tolerability issues due to challenging administration requirements leaving patients with few therapeutic options.

Select Publications
  1. Bhattacharjee, G. et al.  (2013) Inhibition of vascular permeability by antisense-mediated inhibition of plasma kallikrein and coagulation factor 12. Nucleic Acid Ther. 23, 175-187.
  2. Revenko, A.S. et al.  (2011) Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 118, 5302-5311.

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

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ION663
(Undisclosed)
Pulmonary
Ionis-Owned

Generation 2.5 antisense drug

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Hematology

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
IONIS-TMPRSS6-LRx
(TMPRSS6)
β-Thalassemia
Ionis-Owned

Generation 2+ LICA antisense drug

IONIS-TMPRSS6-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of transmembrane protease, serine 6, or TMPRSS6, to treat anemia and iron toxicity in patients with beta-thalassemia; a disease caused by mutations in the beta globin gene. TMPRSS6 is a protein produced in the liver that plays an important role in the regulation of the body’s iron homeostasis through the control of the iron regulatory protein hepcidin. Inhibition of TMPRSS6 leads to increased production of hepcidin, which results in more effective red blood cell production (erythropoiesis) in the bone marrow and reduced iron toxicity in the liver as a result of improved control of iron availability. Results from preclinical and clinical studies suggest that reducing levels of TMPRSS6 may be an effective strategy to control iron availability, improve liver iron toxicity and increase red blood cell production under conditions of beta-thalassemia.

About Beta-thalassemia

Beta-thalassemia is an inherited blood disorder caused by a genetic mutation in the beta globin gene resulting in defective red blood cell production. Patients with beta-thalassemia can experience severe anemia, splenomegaly, marrow expansion, bone deformities, as well as iron toxicity. While the severity of anemia varies between patients, iron toxicity is a common complication leading to high rates of mortality as a result of iron accumulation in major organs, such as the heart and liver. Currently there are no effective therapies for patients with beta-thalassemia. The current standard of care is managing patients’ symptoms with blood transfusions, hydroxyurea, iron chelation and splenectomy.

Beta-thalassemia can be further subdivided into patients with transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT), such as beta-thalassemia intermedia. Although transfusions are not needed to support life in patients with NTDT, the associated complications of the disease are severe and often fatal.

Select Publications
  1. Guo, S. et al. (2013) Reducing TMPRSS6 ameliorates hemochromatosis and ?-thalassemia in mice. J Clin Invest. 123(4):1531-41.
  2. Finberg, K.E. (2013) Striking the target in iron overload disorders. J Clin Invest. 123:1424-1427.
  3. Camaschella, C. (2013) Treating Iron Overload. N Engl J Med 2013; 368:2325-2327.
  4. Musallam, K.M. et al. (2013) Non-Transfusion-Dependent Thalassemias. Haematologica. June 2013; 98:833-44.

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

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Other

Partner
Preclinical
P
Phase 1
P1
Phase 2
P2
Phase 3
P3
Registration
R
ION253
(Undisclosed)
Immune-Mediated GI Disease
Janssen

Generation 2.5 antisense drug

ION253, formerly known as IONIS-JBI2-2.5Rx.

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Future-creating, antisense medicines

Our antisense technology has allowed us to create treatments that disrupt the disease process, may change its course, and we hope make a positive difference in patients' lives.

Once in a lifetime breakthroughs again and again

Meet Chuck. Active throughout his life, hATTR, a rare disease, started to rob him of the things he loved: riding his bicycle, dancing, racing motorcycles, and picking up his grandchildren. Just about to give up, news of a clinical trial renewed his hope.