Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial
Matthew M Y Lee1, Ahmad Masri2, Michael E Nassif3
1School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland.
Insights
Aficamten significantly improved exercise performance in patients with obstructive hypertrophic cardiomyopathy (HCM). This cardiac myosin inhibitor offers a promising new treatment option for improving daily function and quality of life in HCM patients.
Area of Science:
- Cardiology
- Pharmacology
- Exercise Physiology
Background:
- Obstructive hypertrophic cardiomyopathy (HCM) is characterized by impaired exercise capacity.
- Aficamten is a novel cardiac myosin inhibitor designed to treat symptomatic obstructive HCM.
- The SEQUOIA-HCM trial evaluates aficamten's efficacy and safety in this patient population.
Purpose of the Study:
- To assess the impact of aficamten on exercise performance using integrated measures.
- To evaluate changes in maximal and submaximal exercise capacity.
- To correlate exercise improvements with clinical outcomes and cardiac biomarkers.
Main Methods:
- A prespecified analysis from the double-blind, placebo-controlled SEQUOIA-HCM trial.
- 282 patients with symptomatic obstructive HCM were randomized 1:1 to aficamten or placebo for 24 weeks.
- Primary outcome: change in a 2-component z score of peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2 slope).
Main Results:
- Aficamten significantly improved integrated exercise performance (z score change: 0.17 vs -0.19 for placebo; P<.001).
- Aficamten demonstrated improvements in workload, circulatory power, exercise duration, and ventilatory efficiency (all P<.001).
- Clinically meaningful improvements in pVO2 were more frequent with aficamten; improvements correlated with symptom burden and hemodynamics.
Conclusions:
- Aficamten treatment led to a broad range of exercise performance improvements in patients with obstructive HCM.
- These findings support aficamten as a potential therapeutic option for improving functional capacity in obstructive HCM.
- The study provides valuable insights into the clinical benefits of cardiac myosin inhibition.
Importance:
Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures.
Objective:
To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates.
Design, Setting, And Participants:
This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024.
Interventions:
Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks.
Main Outcomes And Measures:
The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed.
Results:
Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. 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 <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05).
Conclusions And Relevance:
This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten.
Trial Registration:
ClinicalTrials.gov Identifier: NCT05186818.
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