Gradual Tapering or Discontinuation of Beta-Blockers After Stabilization With Mavacamten Therapy

Prior treatment

• Heart failure decompensation requiring an emergency department visit, hospitalization, or intravenous treatment within 3 months before randomization; or, within 6 months before randomization, syncope not attributable to a clearly reversible cause, sustained ventricular tachycardia/ventricular fibrillation, or other clinically significant unstable arrhythmia.
• Septal reduction therapy within 6 months before randomization, or anticipated need for surgical septal myectomy, alcohol septal ablation, or other septal reduction therapy during the 24-week study period.
• A definite indication for beta-blocker therapy other than oHCM for which the investigator considers dose reduction or discontinuation unsafe.
• A drug interaction that cannot be adequately modified or avoided and may substantially affect mavacamten exposure, or anticipated need for continued use of a protocol-prohibited medication during the study.

Other illness

• An HCM phenocopy or another disease clearly responsible for left ventricular hypertrophy, including cardiac amyloidosis, Fabry disease, or other infiltrative, storage, or metabolic cardiomyopathies.
• Moderate-to-severe valvular heart disease, fixed left ventricular outflow tract obstruction, or another structural heart disease that may substantially affect LVOT gradients or assessment of the primary outcome.
• Active malignancy, ongoing systemic anticancer therapy that may substantially interfere with study assessments, or an anticipated life expectancy \<1 year because of a serious comorbid condition.
• Other serious systemic disease, inability to complete the required follow-up or comply with the study protocol, or any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.

Lab values

• Previous LVEF \<50% during mavacamten treatment, or previous interruption or discontinuation of mavacamten because of reduced left ventricular systolic function.
• Severe renal impairment (estimated glomerular filtration rate \[eGFR\] \<30 mL/min/1.73 m²), end-stage renal disease, or ongoing dialysis.
• Severe hepatic impairment (Child-Pugh class C), decompensated liver disease, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal at screening, or other severe hepatic dysfunction considered by the investigator to potentially affect the safe use of mavacamten.

Other

• Pregnancy or breastfeeding, planned pregnancy during the study, or, for participants of childbearing potential, inability or unwillingness to use effective contraception.

• Age 18 to 75 years.
• Diagnosis of obstructive hypertrophic cardiomyopathy (oHCM).
• Receiving mavacamten for ≥12 weeks at screening, with the current maintenance dose stable for ≥8 weeks; after completion of the 4-week run-in period, the total duration of mavacamten treatment at randomization should generally be ≥16 weeks.
• Receiving one and only one beta-blocker continuously for at least 4 weeks before randomization, with the beta-blocker type, dosing frequency, and daily dose remaining stable, and without concomitant use of a non-dihydropyridine calcium channel blocker.
• The last qualified echocardiographic assessment before randomization shows a resting left ventricular outflow tract (LVOT) peak gradient \<30 mmHg and a Valsalva-provoked LVOT peak gradient \<50 mmHg.
• Left ventricular ejection fraction (LVEF) ≥55% at randomization baseline.
• Clinically stable and considered by the investigator to be suitable for sequential tapering and discontinuation of beta-blocker therapy.