The purpose of this study is to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction

Inclusion Criteria:

• Participants who meet all the following criteria at screening may be included in the trial:

  • Males and females between 18 to 85 years of age, inclusive, at screening

  • Body mass index < 35 kg/m2

  • Diagnosed with oHCM per the following criteria by cardiac magnetic resonance imaging (CMR) or echocardiography -

    • Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease and

    • Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory:

      1. ≥ 15 mm in one or more myocardial segments OR
      2. ≥ 13 mm in one or more wall segments and a known disease-causing gene mutation or positive family history of HCM

  • New York Heart Association (NYHA) class II or III

  • Has a Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) score of ≤ 90 at screening

  • Has a screening echocardiogram with the following determined by the echocardiography core laboratory:

    • Resting left ventricular outflow tract gradient (LVOT-G) > 30 mm Hg and/or post-Valsalva LVOT-G ≥ 50 mmHg at screening AND
    • LVEF ≥ 60%

  • Hemoglobin ≥ 10g/dL

  • Respiratory exchange ratio (RER) ≥ 1.05 and peak oxygen uptake (pVO2) < 100% predicted on the screening cardiopulmonary exercise testing (CPET) per the core laboratory

  • Patients previously exposed to mavacamten are allowed to participate but must be off mavacamten for at least 8 weeks

Exclusion Criteria:

• Any of the following criteria will exclude potential participants from the trial:

  • Medical indication for either beta blocker or calcium-channel blockers prohibiting drug discontinuation other than oHCM

  • History of intolerance or medical contraindication to beta blocker therapy

  • Resting Systolic Blood Pressure (SBP) of > 160 mmHg

  • Resting heart rate of > 100 bpm

  • Significant valvular heart disease

    1. Moderate-severe valvular aortic stenosis or fixed subaortic obstruction
    2. Mitral regurgitation not due to systolic anterior motion of the mitral valve (per Investigator judgment)

  • Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis)

  • History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course

  • Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations)

  • Documented room air oxygen saturation reading < 90% at screening

  • Planned septal reduction treatment that cannot be deferred during the trial period

  • History of septal reduction therapy (surgical myectomy or alcohol septal ablation) within 6 months of screening

  • History of paroxysmal or persistent atrial fibrillation or atrial flutter. Atrial flutter treated with radio frequency ablation without recurrence within the last 6 months prior to screening is allowed.

  • Current or recent (< 4 weeks) therapy with disopyramide

  • History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening

  • Has received prior treatment with aficamten or previously intolerant (reduced LVEF requiring permanent drug discontinuation) to mavacamten