(M1230-05-28) Acoramidis Reduces All-Cause Mortality and First Cardiovascular Hospitalization in Patients with Variant Transthyretin Amyloid Cardiomyopathy: Results from the ATTRibute-CM Study

Purpose: Patients with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) experience early onset disease, rapid progression, and poor outcomes due to amyloid aggregated from destabilized tetrameric TTR. Acoramidis, a highly selective, oral TTR stabilizer, achieves ≥90% TTR stabilization and is approved in the USA, EU, Japan, and UK for adults with wild-type (ATTRwt-CM) or ATTRv-CM. In the phase 3 ATTRibute-CM study and its open-label extension (OLE), acoramidis reduced both the risk of all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) through Month 30 and risk of ACM through Month 42 by 36%. We assessed acoramidis efficacy in ATTRv-CM to determine consistency with efficacy observed in the overall ATTRibute-CM population.

Methods: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to acoramidis HCl 800 mg or PBO, twice daily (BID) for 30 months. After Month 30, all participants enrolled in the OLE received acoramidis HCl 800 mg BID. Genotype (ATTRwt-CM or ATTRv-CM) was captured at randomization; efficacy was analyzed separately in ATTRv-CM. Time-to-event analyses used a stratified Cox model with terms for treatment, baseline 6MWT, genotype, and genotype×treatment interaction, stratified by randomization NT-proBNP and eGFR levels. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + OLE 12 months).

Results: The ATTRv-CM group comprised 59 participants (39 acoramidis, 20 PBO). Baseline characteristics were mostly similar in both groups (Table). The three most common variants reported were p.V142I (n=35), p.I88L (n=7), and p.T80A (n=5). Compared with PBO, acoramidis reduced the risk of ACM/first CVH through Month 30 by 59% (acoramidis, 46.2%; PBO, 75.0%; HR 0.41; 95% CI 0.21–0.81; P=0.011; Figure 1) and ACM through Month 42 by 59% (continuous acoramidis, 30.8%; PBO to acoramidis, 60.0%; HR 0.41; 95% CI 0.19–0.93; P=0.032; Figure 2), with Kaplan–Meier curves separating at Months 5 and 10, respectively.

Conclusion: In ATTRibute-CM, acoramidis use was associated with clinical benefit in the ATTRv-CM group as demonstrated by a 59% risk reduction in both ACM/first CVH at Month 30 and ACM at Month 42 compared to PBO. These previously unreported findings support the hypothesis that near complete TTR stabilization observed experimentally with acoramidis across multiple TTR mutations translates into improvement in long-term outcomes. Further validation by individual TTR variant is warranted.

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 Francesco Cappelli, Michelle Kittleson, John Berk, Xiaofan Cao, Jean-François Tamby, Adam Castaño, and Jonathan C. Fox 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. Kaplan–Meier survival curve for ACM or first CVH through Month 30 in the ATTRv-CM group.
ACM, all-cause mortality, ATTRv-CM, variant transthyretin amyloid cardiomyopathy; CI, confidence interval; CVH, cardiovascular-related hospitalization.

Figure 2. Kaplan–Meier survival curve for ACM through Month 42 in the ATTRv-CM group.
ACM, all-cause mortality, ATTRv-CM, variant transthyretin amyloid cardiomyopathy; CI, confidence interval.

Baseline demographics and characteristics of ATTRv-CM participants (mITT population)