Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (SEQUOIA-HCM)

The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction.

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 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.

Eligibility Criteria:
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.
* 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.