Study Design

Eligible patients were randomized in a 1:1 randomized double-blinded fashion to either aficamten (n = 142) or matching placebo (n = 140) once daily.

The starting dose of aficamten was 5 mg, with three subsequent opportunities (at weeks 2, 4, and 6) to increase the dose by 5 mg increments, to a maximum dose of 20 mg. At each visit, an echocardiographic cardiologist who was unaware of the trial group assignments assessed the left ventricular outflow tract (LVOT) gradient at rest and after the Valsalva maneuver and the left ventricular ejection fraction (LVEF). The findings from each assessment were then entered into an interactive Web-response system that determined the associated dose level of aficamten or placebo that would need to be administered on the basis of predetermined criteria.

• Total screened: 543
• Total number of enrollees: 282
• Duration of follow-up: 24 weeks
• Mean patient age: 59.1 years
• Percentage female: 41%

Inclusion criteria:

• Age 18-85 years
• Clinical diagnosis of HCM, which was defined by an LV wall thickness of ≥15 mm in the absence of pressure overload or other discernible causes
• LVEF ≥60% at screening
• LVOT gradients ≥30 mm Hg at rest and ≥50 mm Hg after the Valsalva maneuver
• New York Heart Association functional class II or III heart failure, along with decreased exercise capacity, defined by a predicted peak oxygen uptake of ≤90% on the basis of age and sex
• Stable dose of background therapy

Exclusion criteria:

• Known or suspected infiltrative, genetic, or storage disorder causing cardiac hypertrophy that mimics obstructive HCM (e.g., 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 (e.g., 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 (e.g., 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 ≥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

Other salient features/characteristics:

• White race: 80%
• Family history of HCM: 25%
• Pathogenic sarcomeric variant: 17.5%
• Coronary artery disease: 12.5%
• Background therapy: beta-blocker: 62%, calcium channel blocker: 28%, disopyramide: 13%; none: 14%
• Implantable cardioverter-defibrillator: 13.5%
• Resting LVOT gradient: 55 mm Hg, with Valsalva: 83 mm Hg