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

Background: : Aficamten is a next-in-class cardiac myosin inhibitor developed to treat symptomatic hypertrophic cardiomyopathy (HCM).

Objective: : To assess safety and efficacy of long-term treatment with aficamten in patients with symptomatic obstructive HCM.

Methods: : Patients completing an aficamten parent study were eligible for the ongoing open-label extension study FOREST-HCM (NCT04848506) designed to evaluate long-term aficamten efficacy and safety. Treatment was initiated at 5mg daily and doses adjusted based on site-read echocardiogram data and investigator judgement.

Results: : From May 28, 2021 to August 31, 2024, 296 oHCM patients (mean age±SD 61±12.3 years, 44.3% female) were enrolled. Total cumulative exposure to aficamten was 352 patient-years (py) over a mean follow-up of 62 weeks (0.3-170.3 weeks). Aficamten treatment resulted in significant site-read Valsalva left ventricular outflow tract gradient reduction by week 12 (mean±SD change -56±43 mmHg, p< 0.0001), which was sustained with minimal reduction in mean LV ejection fraction (LVEF, -3.2±6.1%). By week 12, 69% of patients had ≥1 New York Heart Association (NYHA) functional class (FC) improvement from baseline, which persisted after week 12. Only 4% of patients were NYHA FC III at week 12 (10-fold reduction from baseline). Patients had a 15±16 point improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at week 12 versus baseline (85±16 vs 70±19, p< 0.0001), and 32% had a ≥20-point improvement after week 12. Additionally, 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]; p< 0.0001) and high-sensitivity cardiac troponin I (95% CI –3.4 ng/L [4.3, -2.5]; p< 0.0001) were observed. Treatment emergent serious adverse events (TESAE) occurred in 36 (12.2%) patients; there were no deaths. One (0.3%) patient terminated therapy due to a TEAE (ischemic colitis). Site-read LVEF < 50% necessitating dose reduction occurred in 10 (3.4%) patients (exposure adjusted incidence rate [EAIR] 2.9/100 py), of whom 8 were asymptomatic and 2 had a non-serious AE of dyspnea or heart failure (one mild and one moderate). No site-read LVEF < 50% were corroborated by the core lab. There were no patients with LVEF < 40%. New-onset atrial fibrillation (AF) occurred in 3 (1%) patients with EAIR of 0.9/100 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 LVEF < 50% and new onset AF.

Sponsorship:: Cytokinetics, Inc.