Aficamten, a cardiac myosin inhibitor (CMI), has shown significant improvements in exercise tolerance among patients with hypertrophic obstructive cardiomyopathy (HOCM). The phase-3, placebo-controlled, randomized clinical trial, SEQUIOA-HCM, sponsored by Cytokinetics, Inc., evaluated the effects of aficamten on exercise capacity and cardiac function. The study, whose results were published in JAMA Cardiology, demonstrated marked improvements in peak oxygen uptake and cardiac structure and function measures.
Key Findings from the SEQUOIA-HCM Trial
The study assessed 263 patients who completed exercise testing at the start of the trial and 24 weeks later. Gregory Lewis, MD, Section Head of Heart Failure and Director of Cardiopulmonary Exercise Testing at Massachusetts General Hospital, highlighted the importance of understanding mechanisms of exercise intolerance and exploring therapeutic interventions to improve exercise capacity. The primary endpoint of the study was change in peak oxygen uptake as measured by cardiopulmonary exercise testing.
Significant improvements were observed in several measurements, including:
- Workload achieved
- Breathing efficiency
- Cardiac power generated during exercise
- Submaximum exercise capacity measured at the anaerobic threshold
The investigators also described a novel measurement that combined submaximum and maximum exercise capacity as an integrated way to assess exercise capacity improvement. They found that changes in exercise responses related to changes in cardiac structure and function beyond just outflow obstruction.
Clinical Implications
The findings have important clinical implications for treating HOCM and could also be relevant to broader populations of non-obstructive hypertrophic cardiomyopathy. According to the study, aficamten treatment improved a broad range of exercise performance measures. This integrated exercise measure was significantly improved with aficamten versus placebo in patients with obstructive HCM, indicating that exercise benefits accrue in a combined fashion during both maximal and submaximal activity reflective of all stages of exertion in everyday life.
Aficamten's Impact on Cardiac Function
The study also found that aficamten improved peak exercise performance, as measured by total workload (LSM difference, 12 W; 95% CI, 6-18 W; P < .001), circulatory power (LSM difference, 586 mm Hg × mL/kg/min; 95% CI, 379-793 mm Hg × mL/kg/min; P < .001), exercise duration (LSM difference, 1.0 minute; 95% CI, 0.5-1.4 minutes; P < .001), heart rate reserve (LSM difference, 6 beats per minute; 95% CI, 3-9 beats per minute; P < .001), and peak heart rate (LSM difference, 9 beats per minute; 95% CI, 6-12 beats per minute; P < .001).
Future Directions
These findings support current efforts to understand whether CMI, which has been observed to substantially lower NT-proBNP level in phase 2 studies in nonobstructive HCM, may presage its role in improving functional capacity in nonobstructive HCM also. This approach is currently under investigation in the ongoing Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Nonobstructive HCM (ACACIA-HCM), which will leverage the integrated exercise performance end point first described in this study.
