Evaluation of methodologies for indirect comparison of eplontersen and vutrisiran for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (P12-4.005)

Abstract

<h3>Objective:</h3> To investigate comparative efficacy and safety of eplontersen and vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> Results will become available ahead of AAN2023. <h3>Conclusions:</h3> This ITC feasibility assessment supports interpretation of comparative efficacy and safety analyses, which is important for decision-making by clinicians, payers and researchers. <b>Disclosure:</b> Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroderm. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam Pharmaceuticals. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intellia. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstraZenica. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BridgeBio. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Mrs. Chen has received personal compensation for serving as an employee of AstraZeneca. Mrs. Chen has stock in AstraZeneca. Miss Jenkins has nothing to disclose. Dr. Hale has received research support from Cancer Research UK. Dr. Taylor has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH France. Dr. Chen has received personal compensation for serving as an employee of AstraZeneca. Dr. Chen has stock in AstraZeneca. Nicholas Viney has received personal compensation for serving as an employee of Ionis Pharmaceuticals Inc.. Nicholas Viney has stock in Ionis Pharmaceuticals. Nicholas Viney has received intellectual property interests from a discovery or technology relating to health care. Dr. Schneider has received personal compensation for serving as an employee of ionis pharmaceuticals.