Aficamten and Cardiopulmonary Exercise Test Performance

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 pVO 2 ≤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 pVO 2 and ventilatory efficiency throughout exercise (minute ventilation VE/carbon dioxide output VCO 2 slope). Response rates for achieving clinically meaningful thresholds for change in pVO 2 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 lt;.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 lt;.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO 2 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, pVO 2 and VE/VCO 2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P lt;.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