Eplontersen for the Treatment of Hereditary Transthyretin Amyloidosis

Hereditary transthyretin-mediated amyloidosis (ATTRv) is an autosomal dominant disease and the most common form of familial amyloidosis globally. ATTRv is characterized by a mutation in the transthyretin gene that leads to the development and accumulation of amyloid fibrils in organs, specifically in the nerves and heart. This leads to the development of symptoms of cardiomyopathy and polyneuropathy in patients. The current standard of treatment consists of transthyretin-targeted therapies, including the antisense oligonucleotide (ASO) inotersen, while liver transplantation is reserved for selected patients. In 2023, a new drug, Eplontersen (brand name Wainua), was approved by the FDA for the treatment of ATTRv with polyneuropathy. Eplontersen is a second-generation ASO based on the structure of Inotersen with an important conjugation that targets the drug to hepatocytes in the liver, where it binds to the 3' untranslated region(UTR) of the transthyretin mRNA. This binding leads to the destruction of the mRNA, preventing the production of transthyretin protein, and further prevents the progression of ATTRv. This article explores the structure, mechanism of action, history of development, and future directions for the drug Eplontersen.