Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM - SEQUOIA-HCM

Contribution To Literature:

The SEQUOIA-HCM trial showed that aficamten improved exercise capacity as assessed by cardiopulmonary exercise testing over a 24-week treatment period compared with placebo among patients with symptomatic HCM.


The goal of the trial was to compare the safety and efficacy of aficamten compared with placebo among patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

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

Principal Findings:

The primary endpoint, mean change from baseline to week 24 in peak VO2 uptake, for aficamten vs. placebo, was: 1.8 vs. 0.0 mL/kg/min, least square mean difference: 1.7 mL/kg/min (p < 0.0001).

Secondary outcomes for aficamten vs. placebo:

  • Change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at week 24: 12 vs. 5 (p < 0.001)
  • LVOT gradient ≤30 mm Hg after Valsalva at week 24: 49.3% vs. 3.6% (p < 0.001)
  • Change in LVOT gradient at week 24: -47.6 vs. 1.8 mm Hg (p < 0.001)
  • Geometric mean proportional change in NTproBNP at week 24: 0.20 vs. 0.20 (p > 0.05)
  • Serious adverse events: 5.6% vs. 9.3%


The results of this trial indicate that aficamten at a dose of 5-20 mg daily improved exercise capacity as assessed by cardiopulmonary exercise testing over a 24-week treatment period compared with placebo among patients with symptomatic HCM, the majority of whom were already on background therapy. Improvement in LVOT gradient and quality of life (measured by KCCQ-CSS) were also observed with aficamten. Results for the primary endpoint appeared to be preserved among patients on background beta-blocker therapy and those with a pathogenic sarcomeric variant.

Both mavacamten and aficamten are cardiac myosin inhibitors. They reduce LV contractility by decreasing the number of active actin–myosin cross-bridges within the sarcomere. Aficamten has a shallow dose-response relationship and plasma half-life that allows for dose adjustment as often as every 2 weeks (in contrast to mavacamten, where dose adjustments can be made every 4 weeks or so). A head-to-head comparison and cost considerations are important next steps.


Maron MS, Masri A, Nassif ME, et al., on behalf of the SEQUOIA-HCM Investigators. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med 2024;May 13:[Epub ahead of print].

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Exercise Tolerance, Hypertrophic Cardiomyopathy, Novel Agents

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