Global Efficacy of Aficamten in Nonobstructive Hypertrophic Cardiomyopathy: Results From ACACIA-HCM

BACKGROUND: Nonobstructive hypertrophic cardiomyopathy (nHCM) is associated with significant morbidity with no approved treatment. Aficamten is a cardiac myosin inhibitor targeting excess contractility and diastolic impairment, the predominant mechanism responsible for adverse outcomes in nHCM. In the ACACIA-HCM trial (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults With Non-Obstructive HCM; URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06081894), aficamten significantly improved outcomes in patients with nHCM versus placebo. To contextualize the observed treatment effects, we performed a responder analysis integrating multiple clinically relevant measures. METHODS: Patients with symptomatic nHCM were randomized to daily aficamten (n=258) or placebo (n=259) assessed at week 36, including (1) symptom burden (≥1 improvement in New York Heart Association class or reported improvement in Patient Global Impression of Change); (2) exercise capacity (≥0.5 mL/kg per min in peak oxygen uptake); (3) >10% decrease in left atrial volume index; (4) >10% improvement in septal early diastolic mitral annular velocity (e’); (5) ≥50% reduction in NT-proBNP (N-terminal pro-B-type natriuretic peptide). Overall clinical response was classified by the number of favorable outcomes achieved: nonresponder (none), limited (1 or 2), partial (3 or 4), or complete (all 5). RESULTS: At 36 weeks, a greater proportion of patients treated with aficamten versus placebo experienced improvements in symptom burden (71% versus 53%), peak exercise capacity (45% versus 37%), left atrial volume index (31% versus 23%), septal e’ (51% versus 26%), and NT-proBNP (63% versus 5%) ( P <0.05 for all except peak oxygen uptake, P =0.1). Number needed to treat for aficamten ranged from 1.7 (NT-proBNP reduction) to 14 (peak oxygen uptake improvement) relative to placebo. A partial or complete clinical response (≥3 outcomes) was achieved in 53% of patients on aficamten versus 14% on placebo ( P <0.001). CONCLUSIONS: In patients with nHCM, aficamten was associated with improvements across a broad range of clinically relevant measures including symptom burden and diastolic function. These results underscore a potential benefit of aficamten in the population of patients with nHCM. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06081894.