Key Points:
- Transthyretin amyloid cardiomyopathy develops because of mis-folded proteins infiltrating the myocardium, leading to clinical heart failure. Currently, tafamidis is the only commercially approved medication and is the most expensive cardiovascular drug on the market.
- Acoramidis is a once-daily medication that stabilizes the transthyretin tetrameric protein, preventing its degradation and subsequent deposition into the myocardium.
- Acoramidis in ATTR-CM resulted in a statistically significant reduction in hospitalization for heart failure and mortality based on a hierarchical analysis of a composite outcome with an overall win ratio of 1.8 (p<0.0001) compared to placebo.
Acoramidis, a medication that stabilizes the protein transthyretin, was effective in treating patients with transthyretin amyloid cardiomyopathy (ATTR-CM) based on the phase III clinical trial ATTRibute-CM. In this randomized, double-blind, placebo-controlled trial, Acoramidis, significantly reduced the risk of hospitalization and mortality. The results were presented at the European Society of Cardiology annual meeting by Professor Julian Gillmore of University College London at the Royal Free London NHS Foundation Trust.
ATTR-CM develops because of mis-folded proteins that deposit into the myocardium, leading to heart failure. The misfolding is linked to a variant TTR V221 gene that is inherited in an autosomal dominant fashion or as a wild-type protein. The drug binds to and stabilizes the tetrameric protein produced by the liver, preventing its degradation and eventual deposition into the myocardium.
ATTRibute-CM was a multinational, randomised, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of acoramidis in patients with ATTR-CM. Eligible patients with wild-type or variant symptomatic ATTR-CM were randomly allocated in a 2:1 ratio to oral acoramidis 800 mg twice daily or placebo for 30 months. Participants in both arms had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Patients were invited to participate in an open-label, long term extension study of acoramidis if they completed the 30- month ATTRibute-CM study. The primary endpoint, analysed at 30 months, was a hierarchical analysis by the Finklestein-Schoenfeld method of all-cause mortality, cardiovascular-related hospitalisation, NT-proBNP, and 6MWD. Secondary endpoints included the components of the primary endpoint, KCCQ-OS, and serum transthyretin levels.
Six hundred and thirty-two patients with symptomatic ATTR-CM were enrolled with a median age of 78 years. Of those, 90% were male, 10% had a variant TTR genotype and 72% had New York Heart Association Class II symptoms. Among them, 421 were randomized to 800mg of acoramidis twice-daily or twice-daily placebo for 30 months.
A statistically significant difference was observed in the primary composite outcome as demonstrated by a win-ratio of 1.8 (p<0.0001) in a hierarchical analysis prioritizing in order: all-cause mortality, then frequency of cardiovascular-related hospitalization, then change from baseline in NT-proBNP, then change from baseline in 6-minute walk distance. Notably, 58% of the win ratio ties were broken by all-cause mortality and cardiovascular-related hospitalizations. Furthermore, acoramidis led to a 50% relative risk reduction of cardiovascular-related hospitalization (p<0.0001).
NT-proBNP was lower in the acoramidis arm than in the placebo arm at month 30 (ratio of adjusted geometric mean fold-change 0.529; 95% CI 0.463 to 0.604; p<0.0001) and the decline in change from baseline in 6MWD was reduced with a least squares mean difference of 39.64 m at month 30 in favor of acoramidis (95% CI 21.07 to 58.22; p<0.0001). Quality of life and function as assessed by the The Kansas City Cardiomyopathy Questionnaire and 6-minute walk test were higher with acoramidis compared to placebo (p<0.0001). Pharmacodynamic assessment of TTR stabilization demonstrated a 42% greater increase in TTR levels in vivo compared to tafamidis, suggesting greater efficacy. There was no significant difference in adverse events between the treatment and placebo groups. BridgeBio Pharma has applied to the FDA. If approved, acoramidis will become one of two commercially available treatments for ATTR-CM, alongside tafamadis.
