To investigate comparative efficacy and safety of eplontersen and vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN).

ATTRv-PN is a rare, autosomal dominant disease caused by mutations in the gene encoding transthyretin (TTR) protein, resulting in accumulation of ATTR amyloid in multiple tissues including the peripheral nervous system. TTR silencers developed and in development to treat ATTRv-PN include vutrisiran (recently approved by the FDA and EMA), and eplontersen, which met its co-primary endpoints and demonstrated an overall favourable safety profile in a planned Week 35 interim analysis of the phase III NEURO-TTRansform trial (NCT04136184). The eplontersen and vutrisiran trials both used an external placebo arm from earlier trials.

No head-to-head studies have been conducted for eplontersen and vutrisiran to date. Therefore, the feasibility and implications of indirect treatment comparisons (ITCs) should be evaluated. ATTRv-PN exhibits substantial clinical heterogeneity, which challenges traditional ITC methods. Additional challenges relate to the trial designs, including the use of external placebo comparators. Different ITC approaches will be evaluated to assess the impact of these factors on the ability to compare efficacy and safety of eplontersen and vutrisiran.

In addition to a naïve comparison, population-adjusted methods that attempt to account for heterogeneity and differences in trial designs were evaluated, including matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). Whilst MAIC may fail to match characteristics demonstrating substantial heterogeneity, this is not an issue for STC. However, unlike MAIC, STC can falter when dealing with non-linear outcomes. Efficacy will be assessed based on the Modified Neuropathy Impairment +7 and Norfolk Quality of Life-Diabetic Neuropathy scores, and safety will also be assessed.

Results will become available ahead of AAN2023.

This ITC feasibility assessment supports interpretation of comparative efficacy and safety analyses, which is important for decision-making by clinicians, payers and researchers.