London, UK – Treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) with acoramidis may significantly improve the 4-step primary hierarchical outcome containing components of mortality, morbidity, and function, with similar safety as placebo, according to an article published in The New England Journal of Medicine.
“Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo,” said Professor Julian Gillmore, M.D., Ph.D., head of University College London’s Centre for Amyloidosis and research lead at the UK National Amyloidosis Centre.
The ATTRibute-CM study demonstrated a significant treatment effect of acoramidis in the primary analysis that compared, in a hierarchical manner, all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and 6-minute walk distance (6MWD). Findings presented in the NEJM support acoramidis as an effective and safe treatment option for patients with ATTR-CM and reinforce the hypothesis that greater stabilization of TTR may be associated with improved clinical outcomes.
This phase 3, double-blind trial enrolled 632 patients with ATTR-CM and randomly assigned them in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or a matching placebo for 30 months.
The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide level, and the change from baseline in the 6-minute walk distance. The researchers used the Finkelstein-Schoenfeld method to compare all possible pairs of patients within strata to generate a P value.
The efficacy of the novel drug was evaluated in patients with an estimated glomerular filtration rate of at least 30 mL per minute per 1.73 m2 of body surface area. Secondary outcome measures included death from any cause, the 6-minute walk distance, the Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and the level of TTR in serum.
According to the primary analysis results, acoramidis was more effective than placebo and the win ratio was 1.8, with 63.7% of pairwise comparisons supporting acoramidis and 35.9% supporting placebo.
“Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); N-terminal pro-B-type natriuretic peptide pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%),” the researchers added.
Acoramidis and placebo had a similar safety profile, with the overall incidence of adverse events being 98.1% and 97.6%, respectively. Further, 54.6% of patients receiving acoramidis experienced serious adverse events compared with 64.9% of the patients receiving placebo.
“These results add to the totality of the available data supporting the concept that the greater the degree of stabilization of tetrameric TTR, the greater the observed clinical benefit,” said Jonathan Fox, M.D., Ph.D., president and chief medical officer of BridgeBio Cardiorenal. “With the submission of our NDA to register acoramidis with the FDA, and with additional regional and national regulatory submissions planned, we look forward to making acoramidis available to patients who might benefit from its demonstrated efficacy and safety.”
In July, BridgeBio announced positive topline results from ATTRibute-CM. BridgeBio has also presented additional detailed results from ATTRibute-CM at the European Society of Cardiology Congress 2023 in August and at the American Heart Association Scientific Sessions 2023 in November.
Contact
Julian D. Gillmore, M.D.
University College London