Abstract

Background: Mavacamten, an orally administered, small-molecule modulator of cardiac myosin, targets underlying biomechanical abnormalities in obstructive hypertrophic cardiomyopathy (oHCM). Objective: To characterize the effect of mavacamten on left ventricular outflow tract (LVOT) gradient. Design: Open-label, nonrandomized, phase 2 trial. (ClinicalTrials.gov: NCT02842242) Setting: 5 academic centers. Participants: 21 symptomatic patients with oHCM. Intervention: Patients in cohort A received mavacamten, 10 to 20 mg/d, without background medications. Those in cohort B received mavacamten, 2 to 5 mg/d, with β-blockers allowed. Measurements: The primary end point was change in postexercise LVOT gradient at 12 weeks. Secondary end points included changes in peak oxygen consumption (pVO2), resting and Valsalva LVOT gradients, left ventricular ejection fraction (LVEF), and numerical rating scale dyspnea score. Results: In cohort A, mavacamten reduced mean postexercise LVOT gradient from 103 mm Hg (SD, 50) at baseline to 19 mm Hg (SD, 13) at 12 weeks (mean change, −89.5 mm Hg [95% CI, −138.3 to −40.7 mm Hg]; P = 0.008). Resting LVEF was also reduced (mean change, −15% [CI, −23% to −6%]). Peak VO2 increased by a mean of 3.5 mL/kg/min (CI, 1.2 to 5.9 mL/kg/min). In cohort B, the mean postexercise LVOT gradient decreased from 86 mm Hg (SD, 43) to 64 mm Hg (SD, 26) (mean change, −25.0 mm Hg [CI, −47.1 to −3.0 mm Hg]; P = 0.020), and mean change in resting LVEF was −6% (CI, −10% to −1%). Peak VO2 increased by a mean of 1.7 mL/kg/min (SD, 2.3) (CI, 0.03 to 3.3 mL/kg/min). Dyspnea scores improved in both cohorts. Mavacamten was well tolerated, with mostly mild (80%), moderate (19%), and unrelated (79%) adverse events. The most common adverse events definitely or possibly related to mavacamten were decreased LVEF at higher plasma concentrations and atrial fibrillation. Limitation: Small size; open-label design. Conclusion: Mavacamten can reduce LVOT obstruction and improve exercise capacity and symptoms in patients with oHCM. Primary Funding Source: MyoKardia.