Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy: An Integrated Safety Analysis

ABSTRACT BACKGROUND Aficamten is a next-in-class, oral, selective cardiac myosin inhibitor approved for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). A comprehensive understanding of long-term safety is essential to inform clinical use. OBJECTIVE To assess the integrated safety profile of aficamten across phase 2/3 clinical trials in patients with oHCM. METHODS This integrated safety analysis pooled data from patients with oHCM who received ≥1 dose of aficamten or placebo/metoprolol in REDWOOD-HCM, SEQUOIA-HCM, MAPLE-HCM, and FOREST-HCM. Safety outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest, occurrences of site-read left ventricular ejection fraction (LVEF) <50%, and echocardiography-guided treatment modifications. Events were summarized descriptively and using exposure-adjusted incidence rates (EAIRs) per 100-patient-years. RESULTS The cumulative aficamten-treated pool included 463 unique patients, representing 697 patient-years of exposure. Aficamten was well tolerated, with permanent treatment discontinuation occurring in 4 (0.9%) aficamten-treated patients (EAIR 0.6). In the control group pool, rates of TEAEs were comparable between aficamten and placebo/metoprolol, except hypertension was more common in aficamten-treated patients. In the cumulative aficamten-treated pool, LVEF <50% occurred in 19 (4.1%) patients (EAIR 2.8). There were no cases of LVEF <50% associated with clinical heart failure that were attributable to aficamten, and no excursions of LVEF <40%. New-onset atrial fibrillation was uncommon (EAIR 2.4). CONCLUSIONS Over nearly 700 patient-years of exposure, aficamten was well tolerated with a favorable safety profile in patients with oHCM. The rates of clinically relevant systolic dysfunction, atrial fibrillation, and other major cardiovascular events were low and similar to placebo or metoprolol. Clinical trial registration REDWOOD-HCM ( NCT04219826 ); SEQUOIA-HCM ( NCT05186818 ); MAPLE-HCM ( NCT05767346 ); FOREST-HCM ( NCT04848506 )