Background and Aims: Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Methods: Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. Results: At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0–228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, −40.3 (32.7) mmHg; Valsalva, −55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): −562 (−1162.5, −209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). Conclusions: Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM). Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤30 mmHg, left ventricular ejection fraction [LVEF] ≥60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] >300 pg/mL) received aficamten 5-20 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. 41 patients were enrolled (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF <50% (range: 41-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. Aficamten administration for symptomatic nHCM was generally safe and associated with improvements in heart failure symptoms and cardiac biomarkers. ClinicalTrials.gov Identifier: NCT04219826 LAY SUMMARY: Non-obstructive hypertrophic cardiomyopathy (nHCM) is a disease in which the heart muscle becomes abnormally thickened. There are no proven medical therapies. Aficamten is a new cardiac myosin inhibitor designed to target the underlying cause of HCM. REDWOOD-HCM Cohort 4 was the first study exploring the efficacy and safety of aficamten in people with symptoms from nHCM. Most patients reported improved health and functional status. There was also significant decrease in blood levels of biomarkers indicating excessive pressure within the heart and damage to heart muscle cells. These results support a larger placebo-controlled study of aficamten for people with nHCM (ACACIA-HCM).

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8–24), and washout (weeks 24–28), and included major adverse cardiac events, new‐onset atrial fibrillation, implantable cardioverter‐defibrillator discharges, LVEF <50%, and treatment‐emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5‐, 10‐, 15‐, and 20‐mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by −0.9% (95% CI, −1.3 to −0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per‐protocol dose reduction for site‐interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment‐emergent adverse events were similar between treatment groups, including atrial fibrillation. Conclusions: A site‐based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA‐HCM. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05186818.