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

Nov 01, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Cytokinetics
Date Published:
10/28/2024
Date Updated:
11/01/2024
Original Posted Date:
05/23/2024
References

Contribution To Literature:

Highlighted text has been updated as of October 31, 2024.

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.

Description:

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%

Effect on cardiac biomarkers: The median baseline NT-proBNP concentration was 788 ng/L (IQR 346–1699) and high-sensitivity cardiac troponin I (hs-cTnI) was 12.1 ng/L (IQR 7.7–27.3). The effect of aficamten on the change in pVO2 was similar in people with baseline NT-proBNP (p for interaction = 0.68) or hs-cTnI (p for interaction = 0.22) above or below the median. Substantial lowering was noted by week 2; by week 8, the lowering of both biomarkers from aficamten treatment was nearly as large as later in the study; NT-proBNP was reduced by 79% (95% CI 83%–76%, p < 0.001) and hs-cTnI by 41% (95% CI 49%–32%, p < 0.001). By week 2 of treatment, the correlations between change in biomarkers and outcome measures were substantially associated with those at week 24.

Changes in integrated exercise performance: This was defined as the two-component z-score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Data were available for 93% of patients. Integrated composite exercise performance improved in the aficamten group (mean [SD] z-score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z-score, −0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; p < 0.001). Improvements in both components of the primary outcome were significantly correlated with improvements in symptom burden and hemodynamics (all p < 0.05).

Impact on echocardiographic cardiac structure and function: Findings for aficamten vs. placebo at week 24:

  • LVOT gradient at rest: 20 vs. 60 mm Hg (p < 0.0001)
  • LVOT gradient with Valsalva: 35 vs. 86 mm Hg (p < 0.0001)
  • Septal wall thickness: 18.7 vs. 20.4 mm (p = 0.003)
  • LV mass index: 124.6 vs. 141.5 g/m2 (p < 0.0001)
  • LVEF: 68% vs. 73% (p < 0.001)
  • Tricuspid annular plane systolic excursion (TAPSE): 17.9 vs. 20.1 mm (p < 0.001)
  • Left atrial volume index: 37.6 vs. 41.2 (p < 0.001)
  • Several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP

Health status outcomes: Baseline KCCQ–Overall Summary Score (KCCQ-OSS) (69. vs 67.3) and Seattle Angina Questionnaire 7-item (SAQ7)–Summary Score (SAQ7-SS) (72.0 vs 72.4) were similar between aficamten and placebo groups. Compared with placebo, aficamten improved both the mean KCCQ-OSS (13.3 vs. 6.1; mean difference, 7.9; 95% CI, 4.8-11.0; p < 0.001) and SAQ7-SS (11.6 vs. 3.8; mean difference, 7.8; 95% CI, 4.7-11.0; p < 0.001) at 24 weeks.

  • Improvement in KCCQ-OSS ≥20% for aficamten vs. placebo: 29.7% vs. 12.4%
  • Improvement in SAQ7-SS ≥20% for aficamten vs. placebo: 31.2% vs. 13.9%

Interpretation:

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. Aficamten treatment appeared to improve a broad range of exercise performance measures. Improvement in LVOT gradient and quality of life (measured by KCCQ-CSS) and angina (measured by SAQ7) 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. Study participants treated with aficamten achieved rapid and significant improvements in NT-proBNP and hs-cTnI concentrations. These improvements were linked to improvements in cardiac function and structure beyond improvements in LVOT gradient alone. Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function; many of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range.

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.

References:

Hegde SM, Claggett BL, Wang X, et al., on behalf of the SEQUOIA-HCM Investigators. Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2024;84:1789-802.

Sherrod CF, Saberi S, Nassif ME, et al. Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM. J Am Coll Cardiol 2024;84:1773-85.

Editorial Comment: Kittleson MM. Aficamten in Hypertrophic Cardiomyopathy: Roots and Branches of SEQUOIA. J Am Coll Cardiol 2024;84:1835-8.

Coats CJ, Masri A, Barriales-Villa R, et al., on behalf of the SEQUOIA-HCM Investigators. Cardiac Biomarkers and Effects of Aficamten in Obstructive Hypertrophic Cardiomyopathy: The SEQUOIA-HCM Trial. Eur Heart J 2024;Sep 1:[Epub ahead of print].

Yee MM, Masri A, Nassif ME, et al., on behalf of the SEQUOIA-HCM Investigators. Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial. JAMA Cardiol 2024;Sep 4:[Epublished].

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;390:1849-61.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Exercise Tolerance, Hypertrophic Cardiomyopathy, Novel Agents


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