Abstract 16466: EXPLORER-HCM: Phase 3 Randomized, Multi-Center, Double-Blind, Placebo-Controlled Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy

IntroductionHypertrophic cardiomyopathy, carries substantial lifelong morbidity, often associated with dynamic left ventricular outflow tract (LVOT) obstruction (oHCM). Since its original description >50 years ago, there have been few randomized studies in HCM, and there are no disease modifying therapies. Sarcomeric gene mutations associated with HCM result in hypercontractility, poor relaxation, and inefficient energy utilization. Mavacamten (MAVA), a first-in-class small molecule, is a selective modulator of cardiac myosin that inhibits cardiac myosin ATPase, thereby reversibly attenuating cardiac contractility and obstructive physiology. The Phase 2 PIONEER-HCM study, showed that MAVA was well tolerated and significantly reduced LVOT obstruction, leading to improvements in exercise capacity and symptoms in oHCM patients. The Phase 3 EXPLORER-HCM study aims to further substantiate the safety and efficacy of MAVA.MethodsThis double-blind study will enroll 220 oHCM patients with LVOT gradient ≥50 mmHg (resting or provoked), NYHA Class II or III, and LVEF ≥55%. Patients will be randomized 1:1 to MAVA or placebo and treated for 30 weeks. Starting dose of MAVA is 5 mg with two-step dose titration at Weeks 8 and 14 (maximum 15 mg) based on individual pharmacodynamic (PD) response and plasma drug concentration. PD parameters include LVOT gradient and LVEF. Pre-defined criteria will guide blinded dose adjustment or temporary discontinuation if indicated. Cardiopulmonary exercise testing (CPET) will be performed at baseline and Week 30. The primary endpoint is clinical response at Week 30 defined by either 1) improvement of ≥1.5 mL/kg/min in peak oxygen consumption (pVO2) at CPET and reduction of ≥1 NYHA class, OR 2) improvement of ≥3.0 mL/kg/min in pVO2 at CPET and no worsening of NYHA class. Multiple secondary endpoints and a cardiac magnetic resonance imaging sub-study are included. A steering committee, including patient representative, and an independent data monitoring committee will safeguard study integrity.ConclusionsEXPLORER-HCM is testing a novel therapy to improve symptom burden in oHCM. By targeting an underlying molecular mechanism of disease, this type of therapy has the potential to modify natural history.