Abstract Body (Do not enter title and authors here): Background. Patients (pts) with obstructive hypertrophic cardiomyopathy (oHCM) with severe symptoms despite medical therapy are offered septal reduction therapy (SRT) when available. We report the efficacy and safety of aficamten in SRT-eligible pts in the Phase 2 open-label extension trial FOREST-HCM (NCT04848506).

Methods. Pts completing an aficamten parent study were offered participation in FOREST-HCM. Aficamten was initiated in all participants at 5 mg and escalated (10, 15, and 20 mg) at investigators’ discretion with protocol guidance according to left ventricular ejection fraction (LVEF) and left ventricular outflow obstruction (LVOT) criteria. SRT eligibility was defined per guidelines as both New York Heart Association (NYHA) class III/IV and any peak LVOT-G ≥50 mmHg.

Results. Of 180 oHCM pts (mean age 60.8±13.1 years, 54% male) enrolled in FOREST-HCM from May 28, 2021 to March 15, 2024 with ≥24 weeks of follow-up, 57 (31.6%) were SRT-eligible at baseline. By week 24, only 2 (3.5%) pts remained SRT eligible (32 [56.1%] met neither criteria, 20 [35.1%] had LVOT-G ≥50 mmHg but were NYHA class I/II, and 2 (3.5%) had NYHA III/IV but LVOT-G <50 mmHg). NYHA improved ≥1 class in 52 (92.9%) SRT-eligible pts and in 80 (67.8%) pts of the remaining cohort. Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improved more in SRT-eligible pts than remaining cohort (21.7±19.3 vs 13.5±13.9; p=0.003) {Figure}. Proportional reductions from baseline in NT-proBNP and high-sensitivity troponin were substantial in both groups. A modest reduction in LVEF occurred in both groups (-3.6% ±6.4 vs -3.4% ±6.2 in the SRT-eligible and remaining cohort respectively; between group p=0.34) {Figure}.

Conclusions. A third of pts enrolled in FOREST-HCM were guideline SRT-eligible at baseline despite optimized standard of care therapy, with almost all pts no longer meeting SRT-eligibility criteria by 24 weeks with aficamten treatment. Aficamten may provide an effective alternative to SRT in some patients with oHCM.