Durable survival benefits of acoramidis over 54 months in variant transthyretin amyloid cardiomyopathy (ATTR-CM), including p.V142I: interim findings from ATTRibute-CM and its open-label extension

Background The transthyretin (TTR) tetramer in patients with variant ATTR-CM (ATTRv-CM) is less stable than wild-type TTR, leading to earlier disease onset, more rapid progression, and worse outcomes. The p.V142I variant is the most common variant in the USA and has a higher mortality vs wild-type. Acoramidis is an approved oral treatment for ATTR-CM and achieves near-complete (≥90%) TTR stabilization. In the phase 3 ATTRibute-CM study and the first 12 months of its open-label extension (OLE), continuous acoramidis reduced all-cause mortality (ACM) with consistent treatment effects across p.V142I and non-p.V142I subgroups. Long-term efficacy and safety outcomes through Month (M) 54 in variant subgroups, including p.V142I, have not been fully characterised. This analysis is the first to report M54 mortality outcomes in p.V142I and to characterize serum TTR (sTTR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectories within the OLE variant subgroup population through M54. Purpose To evaluate the long-term efficacy and safety outcomes of acoramidis in participants with ATTRv-CM, including the p.V142I subgroup. Methods In ATTRibute-CM, participants were randomized 2:1 to receive acoramidis HCl 800 mg or placebo twice daily for 30 months. After M30, participants were invited to enrol in the OLE, in which all received acoramidis. Exploratory post-hoc analyses were conducted in the p.V142I and non-p.V142I variant subgroups (n=56) of the full analysis set. ACM, cardiovascular-related mortality (CVM), and changes from baseline in sTTR and NT-proBNP concentrations were assessed over 54 months. Data are summarized descriptively. Results Thirty-five participants with ATTRv-CM (62.5%) had the p.V142I variant (acoramidis=23; placebo=12) and lower mean sTTR and higher median NT-proBNP at baseline than non-p.V142I participants. Through M54, ACM and CVM were markedly lower in the continuous acoramidis arm vs placebo-to-acoramidis across variant subgroups (Figure 1A). Twenty-seven participants with ATTRv-CM enrolled in the OLE after M30 (continuous acoramidis, n=22; placebo-to-acoramidis, n=5). During 24 months of OLE (M31–M54), 3 ACM events occurred in the 17 participants with p.V142I (Figure 1B); no ACM events occurred in the 10 participants with non-p.V142I. Continuous acoramidis achieved sustained increases in sTTR and persistent attenuation of NT-proBNP rise through M54 in both participants with p.V142I or non-p.V142I variants (Figure 2). Long-term treatment was well tolerated, with no new safety signals in either the p.V142I or non-p.V142I subgroups. Conclusions These M54 findings extend the survival benefit and favourable biomarker trends previously reported at M30, demonstrating the long-term durability of efficacy and safety of acoramidis in ATTRv-CM, including in the p.V142I subgroup.