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AKCEA-APOCIII-L

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.

ION663

Generation 2.5 antisense drug

AKCEA-TTR-L

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.

IONIS-TMPRSS6-L

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.

IONIS-PKK-L

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.