Vutrisiran: A Review in Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

Silencing the transthyretin (TTR) gene is an effective strategy in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. Vutrisiran (Amvuttra (R)), an RNA interference (RNAi) therapeutic targeting TTR mRNA, is approved in the USA and EU for the treatment of adults with polyneuropathy of hATTR amyloidosis. N-acetylgalactosamine conjugation and enhanced stabilisation chemistry are utilised to target vutrisiran to the liver and increase stability, respectively, allowing for subcutaneous administration once every 3 months. In a pivotal phase 3 study in patients with hATTR amyloidosis with polyneuropathy, subcutaneous vutrisiran 25 mg every 3 months significantly reduced neuropathy impairment versus external placebo. Vutrisiran was also associated with significant improvements in neuropathy-specific quality of life, gait speed, nutritional status and disability scores. Vutrisiran was generally well tolerated; the only common adverse events to occur at a greater incidence than with external placebo were pain in extremity and arthralgia. Vutrisiran reduces serum vitamin A levels and vitamin A supplementation is recommended. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, which has the potential advantage of infrequent subcutaneous dosage. Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive and disabling disease caused by variants in the transthyretin (TTR) gene, which cause destabilisation and misfolding of the TTR protein. Deposition of misfolded TTR protein (amyloid) around nerves causes a range of neuropathic symptoms. Vutrisiran (Amvuttra (R)) silences the TTR gene via RNA interference (RNAi). Vutrisiran, administered subcutaneously once every 3 months, is approved in the USA and EU for the treatment of polyneuropathy of hATTR amyloidosis in adults. In a phase 3 study in patients with hATTR amyloidosis with polyneuropathy, vutrisiran significantly reduced neuropathy impairment and improved other disease-related outcomes versus external placebo. Vutrisiran was generally well tolerated, with most adverse events being mild or moderate in severity. As vutrisiran decreases vitamin A levels, patients undergoing vutrisiran treatment should supplement with vitamin A. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, with a convenient dosage regimen.