Mavacamten for HCM

초록

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder characterized by unexplained left ventricular hypertrophy, commonly associated with pathogenic variants in sarcomere protein genes. Approximately two-thirds of patients develop the obstructive form (oHCM), in which dynamic left ventricular outflow tract (LVOT) obstruction leads to symptoms such as exertional dyspnea, chest pain, and syncope. Conventional management has relied on beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide, which offer symptomatic relief but do not address the underlying hypercontractility. While invasive septal reduction therapies?such as surgical myectomy and alcohol septal ablation?are effective for drug-refractory patients, their accessibility is limited by the need for surgical expertise and appropriate patient selection. This underscores the need for disease-specific pharmacologic therapies in oHCM. Mavacamten is a first-in-class, selective, reversible cardiac myosin inhibitor that directly targets sarcomeric hypercontractility by modulating the myosin-actin cross-bridge cycle. By shifting myosin heads toward a super-relaxed state, mavacamten reduces LVOT gradients and improves diastolic function and myocardial energetics. Its clinical efficacy has been validated in several pivotal trials. In the PIONEER-HCM Phase 2 study, mavacamten significantly reduced LVOT gradients and improved dyspnea and NT-proBNP levels. The EXPLORER-HCM Phase 3 trial demonstrated superiority over placebo, showing improvements in exercise capacity (peak VO₂), NYHA class, LVOT obstruction, and cardiac remodeling. These benefits were sustained in the long-term extension study (EXPLORER-LTE). In the VALOR-HCM trial, conducted among patients referred for septal reduction therapy (SRT), mavacamten reduced SRT eligibility from 77% to 18%, suggesting its potential to delay or avoid invasive intervention.