OBJECTIVES: 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.

METHODS: Several population-adjustment methods exist for ITCs, each with strengths and limitations. This study used matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC), including both anchored and unanchored approaches, alongside Bucher analysis. Efficacy was compared using modified Neuropathy Impairment +7 (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) scores and components/domains. Safety endpoints were also assessed.

RESULTS: Data for eplontersen from NEURO-TTRansform (N=144) and external placebo from NEURO-TTR (N=60) were adjusted against data for vutrisiran from HELIOS-A (N=122) and external placebo from APOLLO (N=77). Baseline characteristics were compared and, where possible, population adjustment performed for the outcomes described in the methods, using eight covariables: age, sex, race, prior treatment, V30M mutation, familial amyloid polyneuropathy score, cardiac involvement and baseline value of outcome of interest. Missing data were limited. Additional results will be presented at ISPOR2023.

CONCLUSIONS: This research demonstrates the value of applying different ITC approaches to assess the impact of methodological assumptions on decision making in ATTRv-PN.