Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM

Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+/-} 39 and 109 {+/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.