American Heart Association, 18 November 2024 – Dr Daniel Judge announced the findings from the ATTRibute-CM OLE study (Eidos Therapeutics; NCT03860935), an open-label extension of the Phase 3 ATTRibute-CM trial. The study aims to evaluate the long-term efficacy and safety of acoramidis in treating transthyretin amyloid cardiomyopathy (ATTR-CM). 

ATTR-CM is a progressive cardiovascular disease caused by misfolded transthyretin (TTR) proteins depositing in the heart, leading to heart failure symptoms. Acoramidis is an investigational TTR stabilizer designed to slow disease progression. The initial 30-month ATTRibute-CM trial demonstrated significant benefits of acoramidis compared to placebo on a hierarchical, sequentially analyzed, combined endpoint of all-cause mortality, frequency of cardiovascular-related hospitalisations, change from baseline in N-terminal pro-B-type natriuretic peptide, and change from baseline in 6-minute walk distance1. This OLE study builds upon these results, extending the observation period to assess long-term effects.

The OLE study involved 389 participants who completed the 30-month ATTRibute-CM trial. Participants who received acoramidis in the initial trial continued  acoramidis, while those who received placebo switched to acoramidis (placebo-to-acoramidis). Those who received tafamidis in ATTRibute-CM had to discontinue it before enrolling in the OLE. The study collected data through Month 42 (12 months of OLE). Key efficacy outcomes included time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, CVH alone, changes in NT-proBNP and 6-minute walk distance (6MWD), and quality of life. Data analysis employed stratified Cox proportional hazards models for time-to-event analyses and negative binomial regression for recurrent events.

The data demonstrated sustained benefits of acoramidis, with significant improvements emerging as early as Month 3 of the original ATTRibute-CM study. In OLE, researchers observed a notable reduction in adjudicated cardiovascular mortality (ACM), with a 36% decrease at Month 36 (p=0.009) and a 34% reduction at Month 42 (p=0.006). Moreover, the composite endpoint of ACM and cardiovascular hospitalisation (CVH) showed an even more impressive reduction, declining by 46% at Month 36 (p<0.0001) and 48% at Month 42 (p<0.0001). 

Participants experienced an improved time to first event (CVH or ACM), with consistent benefits compared to placebo. Throughout the study, patients maintained positive trends in key biomarkers and functional capacity, including improvements in NT-proBNP levels and 6-minute walk distance (6MWD). Additionally, there was a sustained increase in serum transthyretin (TTR) levels, suggesting effective TTR stabilization. Importantly, the treatment remained well-tolerated, with no new clinically significant safety signals emerging during the extended observation period.

The results confirm the sustained clinical benefits of acoramidis in ATTR-CM, suggesting that early intervention leads to long-term positive outcomes. The positive findings from the ATTRibute-CM OLE study, alongside those from the original ATTRibute-CM trial, have led to a New Drug Application (NDA) submission to the FDA, which was approved for the treatment of ATTR-CM on 22 November 2024. The study emphasizes the importance of early diagnosis and continuous treatment with disease-modifying therapy like acoramidis to manage ATTR-CM. There were no new safety signals identified in this long-term evaluation.

Resources:

Judge, D, Et Al. Circulation 2024. DOI: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.072771 

Bridge Bio; open-label extension data confirms sustained benefit of acoramidis on cardiovascular outcomes, including statistically significant reduction in acm within 36 months. Accessed at: https://investor.bridgebio.com/news-releases/news-release-details/open-label-extension-data-confirms-sustained-benefit-acoramidis

ClinicalTrials.gov. Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM). Accessed at: https://clinicaltrials.gov/study/NCT03860935