Efficacy and safety of long-term treatment with aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy: results from FOREST-HCM

Abstract Background/Introduction Aficamten is a next-in-class, oral selective cardiac myosin inhibitor developed to treat symptomatic hypertrophic cardiomyopathy (HCM). Purpose To assess safety and efficacy of long-term treatment with aficamten in patients with symptomatic obstructive HCM. Methods Patients who completed a parent study with aficamten were eligible to enroll in the ongoing open-label extension study FOREST-HCM designed to evaluate long-term efficacy and safety of aficamten. Treatment was initiated with 5mg daily and doses adjusted based on site-read echocardiogram data and investigator judgement. Results From May 28, 2021 to August 31, 2024, 296 patients (mean age±SD 61±12.3 years, 44.3% female) with oHCM were enrolled. The total cumulative exposure to aficamten was 352 patient-years (py) over a mean follow-up of 62 weeks (range 0.3-170.3 weeks). Treatment with aficamten resulted in significant reduction in site-read Valsalva left ventricular outflow tract gradients by week 12 (mean±SD change -56±43 mmHg, p0.0001), which was sustained during treatment, with minimal reduction in mean LV ejection fraction (-3.2±6.1%) (Figure). By week 12, 69% of patients reported ≥1 New York Heart Association (NYHA) functional class (FC) improvement from baseline, which persisted at each visit after week 12. At week 12, only 4% of patients were NYHA FC III, a 10-fold reduction from baseline (40%) (Figure). By week 12, patients reported an improvement of 15±16 (mean±SD) points in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score versus baseline (85±16 vs 70±19, p0.0001; Figure), and 32% had a large to very large (≥20-point) improvement compared to baseline at each visit after week 12. Mirroring clinical improvements, early (by week 12) and significant reductions in N-terminal pro-B-type natriuretic peptide (median change –532.0 pg/mL 95% CI -621.6, -442.4; p0.0001) and high-sensitivity cardiac troponin I (95% CI –3.4 ng/L 4.3, -2.5; p0.0001) were also observed. Treatment emergent serious adverse events (TESAE) occurred in 36 (12.2%) patients; there were no deaths. There was one (0.3%) patient who terminated therapy due to a TEAE (ischemic colitis). Site-read left ventricular ejection fraction 50% necessitating dose reduction occurred in 10 (3.4%) patients (exposure adjusted incidence rate EAIR of 2.9 per 100 py), of whom 8 were asymptomatic and 2 had a reported non-serious AE of dyspnea or heart failure (one mild and one moderate). None of the site-read LVEF50% were corroborated by the core lab. There were no patients with LVEF40%. New-onset atrial fibrillation (AF) occurred in 3 (1%) patients with EAIR of 0.9 per 100 py. Conclusions Long-term treatment with aficamten in patients with symptomatic oHCM resulted in an early and sustained hemodynamic and clinical response with low incidence of LVEF50% and new onset AF.