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

CY 6031 was a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in participants with symptomatic oHCM. Eligible participants were randomized in a 1:1 ratio to receive aficamten or placebo. Randomization was stratified by use of beta-blockers (yes or no) and cardiopulmonary exercise testing (CPET) exercise modality (treadmill or bicycle). Enrollment limits were applied as follows: participants taking beta-blockers were capped at approximately 70% of total enrollment; participants taking disopyramide were capped at approximately 10% of total enrollment; participants with persistent atrial fibrillation (AF) at screening were capped at approximately 15% of total enrollment; and participants using the bicycle CPET exercise modality were capped at approximately 50% of total enrollment.

Investigational product (IP) was administered orally once daily (QD) with or without food for 24 weeks. During the initial 6 weeks of the treatment period, IP doses were individually titrated at Weeks 2, 4, and 6 based on echocardiography-guided criteria. Dose escalation at Weeks 2, 4, and 6 occurred only if a participant had a Valsalva left ventricular outflow tract gradient (LVOT-G) ≥ 30 mmHg and a biplane left ventricular ejection fraction (LVEF) ≥ 55%. Echocardiograms were performed at each subsequent visit during the trial, and the IP dose was down-titrated if the LVEF was < 50%. The primary endpoint of peak oxygen uptake (pVO2) was measured by CPET at screening and at the end of treatment (Week 24). A participant's background HCM therapy was individually optimized according to local practice prior to enrollment in the study.

Key Inclusion Criteria:

• Males and females between 18 and 85 years of age, inclusive, at screening.
• Body mass index <35 kg/m2.
• Diagnosed with HCM per the following criteria:

• Has LV hypertrophy and 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 of:

• ≥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
• Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT G ≥50 mmHg during screening as determined by the echocardiography core laboratory.
• LVEF ≥60% at screening as determined by the echocardiography core laboratory.
• New York Heart Association (NYHA) Functional Class II or III at screening.
• Hemoglobin ≥10g/dL at screening.
• Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory.
• Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.

Key Exclusion Criteria:

• Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
• Significant valvular heart disease (per investigator judgment).

• Moderate-severe valvular aortic stenosis.
• Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
• 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).
• Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
• Documented paroxysmal atrial fibrillation during the screening period.
• Paroxysmal or permanent atrial fibrillation is only excluded IF:

• rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤6 months prior to screening.
• rate control and anticoagulation have not been achieved for at least 6 months prior to screening.
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
• Has received prior treatment with CK-3773274 or mavacamten.