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Chemistry: Generation 2+ LICA

Sapablursen, formerly known as IONIS-TMPRSS6-LRx, is a ligand-conjugated (LICA) investigational antisense medicine 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.