Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).