Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM

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:

• ≥ 15 mm in one or more myocardial segments OR
• ≥ 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

• Moderate-severe valvular aortic stenosis or fixed subaortic obstruction
• 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