MSR11 A Multi-Method Approach to an Indirect Treatment Comparison of Eplontersen and Vutrisiran for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

Abstract

Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN) is a rare, fatal neuropathy caused by TTR gene mutations leading to accumulation of amyloid deposits composed of TTR protein in multiple tissues, including the peripheral nervous system. Targeted gene silencers include vutrisiran (recently approved by the FDA and EMA) and eplontersen, which is in development. Eplontersen met its co-primary efficacy endpoints and was well tolerated in a planned week 35 interim analysis of the phase III NEURO-TTRansform trial (NCT04136184). In the absence of head-to-head trials, indirect treatment comparisons (ITCs) may help compare efficacy and safety of eplontersen vs vutrisiran. However, challenges include use of different external placebo arms in each pivotal trial, differences in the primary endpoint assessment scale version, endpoint timepoints and missing data handling. There is no established ITC practice in ATTRv-PN to address these challenges, therefore this study evaluated multiple ITC methods.