Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM

Inclusion Criteria:

• Between 18-85 years of age

• Body mass index < 40 kg/m2

• Diagnosed with nHCM and has a screening echocardiogram with the following:

• End-diastolic left ventricular (LV) wall thickness:

• ≥ 15 mm in one or more myocardial segments OR

• ≥ 13 mm in one or more wall segments and a known disease-causing genemutation or positive family history of HCM AND

• Resting LVOT-G < 30 mmHg AND Valsalva LVOT-G < 50 mmHg AND

• LVEF ≥ 60%

• Participants with a history of intracavitary obstruction are eligible.

• NYHA class II or III

• Respiratory exchange ratio of ≥ 1.00 at screening by cardiopulmonary exercisetesting (CPET) and predicted peak oxygen uptake (pVO2) ≤ 90% for age and sex

• KCCQ-CSS score of ≥ 30 and ≤ 85

• NT-proBNP of:

• NT-pro BNP ≥ 300 pg/mL or NT-proBNP ≥ 900 pg/mL if in atrial fibrillation oratrial flutter OR

• For Black participants, an NT-pro BNP ≥ 225 pg/mL or NT-proBNP ≥ 675 pg/mL ifin atrial fibrillation or atrial flutter

Exclusion Criteria:

• Significant valvular heart disease (per Investigator judgment)

• Moderate or severe valvular aortic stenosis or fixed subaortic obstruction

• Moderate or severe mitral regurgitation

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

• Known current unrevascularized coronary artery stenosis of ≥ 70% or documentedhistory of myocardial infarction.

• History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy

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

• Documented room air oxygen saturation reading < 90% at screening or history ofsignificant chronic obstructive pulmonary disease or severe/significant pulmonaryhypertension

• History of syncope, symptomatic ventricular arrhythmia, or sustained ventriculartachyarrhythmia with exercise within 3 months prior to screening

• History of resistant hypertension (persistently elevated blood pressure despitemaximal doses of 3 or more classes of medications for hypertension control)

• Screening diastolic blood pressure ≥ 100 mmHg

• Received prior treatment with aficamten

• Received treatment with mavacamten within 3 months prior to screening (must bediscussed with the medical monitor prior to screening)

• Undergone septal reduction therapy < 6 months prior to screening

• Is being considered for or is likely to be considered for heart transplant listingor left ventricular assist device placement during the study period

• Paroxysmal or permanent atrial fibrillation is excluded only if:

• rhythm restoring treatment (e.g., direct-current cardioversion, atrialfibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤ 3 months prior to screening

• rate control and anticoagulation have not been achieved for at least 3 monthsprior to screening.