Inotersen for the Treatment of Hereditary Transthyretin Amyloidosis.

Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant condition in which mutations in the transthyretin gene cause amyloid fibrils to develop and deposit into tissues, affecting primarily the nerves and heart, causing polyneuropathy and cardiomyopathy, respectively. Standard treatment has been liver transplants to try to eliminate the mutated transthyretin products, as the liver is the main source of transthyretin production. Inotersen (brand name Tegsedi), also known as IONIS-TTRRX, has been approved by the United States Food and Drug Administration, Health Canada, and the European Commission in 2018 for adults with stages 1 and 2 hATTR polyneuropathy. Inotersen is a second-generation antisense oligonucleotide with 2'-O-methoxyethyl modification designed to bind to the 3' untranslated region of the transthyretin mRNA in hepatic cells, reducing both mutant and wild-type transthyretin protein production. Phase 3 and long-term studies demonstrate durable transthyretin suppression with stabilization or improvement of neuropathy and quality-of-life outcomes, and emerging phase 2 data suggest a potential benefit in ATTR cardiomyopathy. This article reviews inotersen's mechanism of action and safety profile, highlights key safety monitoring, and considers future directions in antisense therapy, including next-generation GalNAc-conjugated agents, such as eplontersen, which help define inotersen's evolving clinical role.