Therapeutic efficacy of Mavacamten

The efficacy of mavacamten was evaluated in EXPLORER-HCM (NCT-03470545), a Phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial involving 251 symptomatic adult patients with New York Heart Association (NYHA) Functional Class II or III obstructive hypertrophic cardiomyopathy (HCM). Eligible patients had a left ventricular ejection fraction (LVEF) of ≥55% and a peak left ventricular outflow tract (LVOT) gradient of ≥50 mmHg at rest or with provocation.

Patients receiving dual therapy with beta-blockers and calcium channel blockers, or monotherapy with disopyramide or ranolazine were excluded. Patients with known infiltrative or storage disorders that cause cardiac hypertrophy and mimic obstructive HCM (e.g., Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy) were also excluded.

Patients were randomized in a 1:1 ratio to receive mavacamten at an initial dose of 5 mg once daily or matching placebo for 30 weeks. Randomization was stratified by baseline NYHA functional class, baseline beta-blocker use, and ergometer type (treadmill or cycle ergometer).

The two groups were well-balanced in terms of age (mean, 59 years), body mass index (mean, 30 kg/m²), heart rate (mean, 62 beats per minute), blood pressure (mean, 128/76 mmHg), and race (90% White). Males accounted for 54% of the mavacamten group and 65% of the placebo group.

At baseline, approximately 73% of randomized patients were NYHA Functional Class II and 27% were Class III. The mean LVEF was 74%, and the mean Valsalva LVOT gradient was 73 mmHg. Approximately 10% had a history of septal reduction therapy, 75% were receiving beta-blockers, 17% were receiving calcium channel blockers, and 14% had a history of atrial fibrillation.

All patients initiated treatment with mavacamten 5 mg once daily (or matching placebo), with dose adjustments performed periodically to optimize patient response (reduction in Valsalva LVOT gradient) and maintain LVEF at ≥50%. Dosing also took into account plasma concentrations of mavacamten.

In the mavacamten group, at the end of treatment, 49% of patients were receiving the 5 mg dose, 33% the 10 mg dose, and 11% the 15 mg dose. Three patients had temporary treatment interruptions due to LVEF <50%, of whom two resumed treatment at the same dose and one had their dose reduced from 10 mg to 5 mg.

Primary Endpoint

The primary composite functional endpoint was assessed at Week 30, defined as the proportion of patients who achieved either an improvement in peak oxygen consumption (peak VO₂) of ≥1.5 mL/kg/min and an improvement in NYHA functional class of ≥1 grade, or an improvement in peak VO₂ of ≥3.0 mL/kg/min without worsening of NYHA functional class.

At Week 30, a statistically significantly higher proportion of patients in the mavacamten group achieved the primary endpoint compared with the placebo group (37% vs. 17%).

FDA，2025.04