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

Phase 3

Completed

• Conditions: Obstructive Hypertrophic Cardiomyopathy (oHCM)
• Interventions: Drug: Aficamten (5 mg, 10 mg, 15 mg, and 20 mg); Drug: Placebo to match aficamten

• Registration Number: NCT05186818
• Lead Sponsor: Cytokinetics

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2021-12-23
• Study First Submitted QC: 2021-12-23
• Study First Posted: 2022-01-11
• Study Start: 2022-02-01
• Primary Completion: 2023-11-10
• Study Completion: 2023-12-18
• Disposition First Posted: 2024-01-08
• Disposition First Submitted: 2024-11-27
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-24
• Last Update Posted: 2025-02-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 282

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aficamten up to 20 mg	Aficamten (5 mg, 10 mg, 15 mg, and 20 mg)	Participants received 5 mg, 10 mg, 15 mg, or 20 mg of aficamten; dose levels were guided by echocardiography assessments. Treatment was administered for up to 24 weeks.
Placebo to match aficamten	Placebo to match aficamten	Participants received placebo for up to 24 weeks.

Primary Outcome Measures

Name	Time	Method
Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET)	Baseline to Week 24	Effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM

Secondary Outcome Measures

Name	Time	Method
Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS)	Baseline to Week 12 and Week 24	Effect of CK-3773274 on patient health status
Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class	Baseline to Week 12 and Week 24	Effect of CK-3773274 on NYHA Functional Classification
Change in post-Valsalva left ventricular outflow tract gradients (LVOT-G)	Baseline to Week 12 and Week 24	Effect of CK-3773274 on post-Valsalva LVOT-G
Proportion of patients with post-Valsalva LVOT G <30 mmHg	Baseline to Week 12 and Week 24	Effect of CK-3773274 on post-Valsalva LVOT-G
Change in total workload during CPET	Baseline to Week 24	Effect of CK-3773274 on exercise capacity
Duration of eligibility for septal reduction therapy (SRT)	Baseline to Week 24	Effect of CK-3773274 on duration of eligibility for septal reduction therapy

Trial Locations

Locations (113)

Alaska Heart and Vascular Institute; 🇺🇸 Anchorage, Alaska, United States

UC San Diego Health - Sulpizio Cardiovascular Center; 🇺🇸 La Jolla, California, United States

Cedars-Sinai Medical Center - Smidt Heart Institute Clinic; 🇺🇸 Los Angeles, California, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Stanford University Hospital; 🇺🇸 Stanford, California, United States

Yale School of Medicine; 🇺🇸 New Haven, Connecticut, United States

Yale University School of Medicine; 🇺🇸 New Haven, Connecticut, United States

MedStar Washington Hospital Center; 🇺🇸 Washington, District of Columbia, United States

Holy Cross Hospital / Cardiology Associates; 🇺🇸 Fort Lauderdale, Florida, United States

Mayo Clinic Florida; 🇺🇸 Jacksonville, Florida, United States

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