Phase 3 Evidence and Safety Framework for Myosin Inhibitors: EXPLORER, VALOR, SEQUOIA, and REMS

Here, Dr Masri outlines the pivotal phase 3 data for mavacamten, beginning with the EXPLORER-HCM trial, a randomized, placebo-controlled study that demonstrated significant improvements in peak oxygen consumption and New York Heart Association (NYHA) functional class in symptomatic obstructive HCM. These clinical benefits paralleled substantial reductions in LVOT gradients and favorable changes in biomarkers of wall stress and myocardial injury. The subsequent VALOR-HCM trial enrolled patients already referred for septal reduction therapy and showed that mavacamten could avert or defer invasive intervention in a large proportion of participants by effectively lowering gradients and improving symptoms.

Dr Maron then summarizes phase 3 experience with aficamten, particularly the SEQUOIA-HCM trial, which similarly showed marked gradient reduction, consistent symptom relief, and improvement in health status metrics such as NYHA class and Kansas City Cardiomyopathy Questionnaire scores. Both physicians stress that, across studies, a high percentage of treated patients achieve LVOT gradients below 30 mm Hg, aligning hemodynamic improvements with observed functional gains. These data underpin the positioning of cardiac myosin inhibitors as high-benefit therapies capable of restoring many patients to good or excellent quality of life.

The discussion transitions to safety, especially treatment-emergent systolic dysfunction. Maron notes that both mavacamten and aficamten can, in a minority of patients, reduce left ventricular ejection fraction (LVEF) below the desired range. Consequently, the FDA mandated Risk Evaluation and Mitigation Strategy (REMS) programs for both agents, centered on serial echocardiographic monitoring and algorithmic dose adjustment. Masri highlights that aficamten’s development relied exclusively on echocardiographic guidance (without drug-level monitoring), showed a lower incidence of systolic dysfunction, and was not associated with clinical heart failure events in SEQUOIA-HCM. These features, along with fewer drug–drug interactions and more flexible titration, are reflected in a comparatively streamlined and clinician-friendly REMS structure for aficamten.