(M1330-05-28) Acoramidis Effect on All-Cause Mortality in Patients with p.V142I (V122I) Variant ATTR-CM: Findings from the ATTRibute-CM Study

Purpose: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) arises from amyloidogenic aggregates of destabilized TTR protein in variant (ATTRv-CM) or acquired wild-type TTR (ATTRwt-CM). The p.V142I (V122I) variant is the most common pathogenic TTR allele in the USA and has higher mortality than wild type. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in the USA, UK, Europe, and Japan for treating ATTR-CM in adults. In ATTRibute-CM (NCT03860935), acoramidis showed a reduction in all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) versus placebo (PBO), with consistent benefit in ATTRwt-CM and ATTRv-CM (all variants). We report clinical outcomes (ACM, CVH) in participants with p.V142I ATTRv-CM in ATTRibute-CM.

Methods: In ATTRibute-CM, 632 participants were randomized 2:1 to receive acoramidis HCl 800 mg or PBO twice daily for 30 months. All participants enrolled in the open-label extension (OLE) received acoramidis only. Exploratory post hoc analyses were done in the p.V142I ATTRv-CM subgroup. Time-to-event analyses used a stratified Cox proportional hazards model using treatment group as an explanatory factor and baseline 6MWD as a covariate, stratified by randomization factors: serum NT-proBNP and eGFR. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + 12 months OLE).

Results: Of the 59 participants with ATTRv-CM reported at randomization, 35 (59.3%) had p.V142I (23 acoramidis, 12 PBO) with comparable baseline characteristics; 4 were homozygous for p.V142I (1 acoramidis, 3 PBO). Through Month 30, ACM/first CVH occurred in 43.5% (10/23) of acoramidis versus 83.3% (10/12) in PBO (HR 0.311, 95% CI 0.120–0.805, Figure 1). Through Month 42, ACM occurred in 26.1% (6/23) of continuous acoramidis versus 66.7% (8/12) in PBO to acoramidis (HR 0.307, 95% CI 0.097–0.973, Figure 2).

Conclusion: In participants with p.V142I ATTRv-CM, acoramidis use was associated with 69% risk reduction in ACM/first CVH through Month 30 and ACM through Month 42 versus PBO. This is the first report of clinical benefit of this magnitude observed in this high-risk population. These findings have biologic plausibility and may reflect the near-complete stabilization observed experimentally with acoramidis in p.V142I ATTR fibrils. These observations require confirmation in larger cohort studies.

Acknowledgements: This study was funded by BridgeBio Pharma Inc., San Francisco, CA, USA. Medical writing and editorial assistance were provided by Caudex, an IPG Health Company, and funded by BridgeBio Pharma, Inc. We gratefully acknowledge the authorship contributions of Michelle Kittleson, Michel G. Khouri, Daniel Judge, Chris Chen, Jean-François Tamby, Adam Castaño, Jonathan C. Fox, Marianna Fontana, and Julian Gillmore to the original abstract on which this encore abstract is based. Souhiela Fawaz has been designated presenter on behalf of the abstract authors.

Figure 1. Survival curve for ACM/first CVH through Month 30 in the p.V142I subgroup

Figure 2. Survival curve for ACM through Month 42 in the p.V142I subgroup