EXPLORER-HCM presented at the American College of Cardiology 2021 meeting by John A. Spertus, MD, MPH, and simultaneously published in The Lancet, demonstrated that the use of mavacamten, a first-in-class cardiac myosin inhibitor, was associated with a highly significant improvement in patients’ health status. 1 out of 5 patients treated with mavacamten tended to experience a significant improvement in health status.
Interim analysis of the EXPLORER-HCM (Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy, NCT03470545) trial published in The Lancet revealed that treatment with mavacamten for symptomatic obstructive cardiomyopathy was associated with a reduction in left ventricular outflow tract (LVOT) gradient, symptom improvement, and exercise capacity. The recent analysis aimed at investigating the impact of mavacamten use on overall patient’s health status, a combination of symptoms, exercise tolerability, social function, and quality of life.
Dr. Spertus and his colleagues conducted a multinational, double-blind, placebo-controlled randomized trial in patients with New York Heart Association functional classes II to III and obstructive hypertrophic cardiomyopathy with LVOT gradient of 50 mm Hg or greater at rest. Patients were assigned in a 1:1 ratio to receive once-daily oral mavacamten (initial dose of 5 mg with 2-step dose titration) or placebo for 30 weeks of treatment and an 8-week wash-out period afterward. Kansas City Cardiomyopathy Questionnaire (KCCQ) was applied to quantify the patients’ health status. The KCCQ includes 23 items evaluating symptoms, exercise tolerance, social function, and quality of life, and results in a score ranging from 0 to 100, with higher scores defining better overall health status. Patients completed the KCCQ at baseline, and at 5 more visits including at the end of treatment and wash-out periods.
Among 251 patients included in the study, a total of 123 received mavacamten and 75% of them completed the baseline and 30-week KCCQ. A total of 128 patients received the placebo, and 69% completed the baseline and 30-week KCCQ. Mavacamten use was associated with a promptly evident increase in KCCQ overall score (OS) from base
line compared with placebo (mean score: 14·9 [SD 15·8] vs 5·4 [13·7]). At the end of the treatment period, the difference in KCCQ-OS reported +9·1 [95% CI 5·5–12·8]; p<0·0001), which, according to the author, is the among largest mean KCCQ-OS differences of any medication.
It is important to consider the study limitations. In the EXPLORER-HCM trial, 28% of patients had missing data either in baseline or follow-up KCCQ data. In addition, the trial included patients with hemodynamically significant obstructive hypertrophic cardiomyopathy; therefore, this analysis does not provide evidence for mavacamten use in other patients with hypertrophic cardiomyopathy, which limits the generalizability of the study.
According to this secondary analysis, in patients with obstructive hypertrophic cardiomyopathy, treatment with mavacamten was associated with a substantial increase in KCCQ score emerging early after medication administration and with regress to baseline after treatment withdrawal. Further research is warranted to address what physiological parameters are more strongly associated with benefits from mavacamten (e.g. outflow tract gradient, diastolic dysfunction, etc). It remains unanswered if any patient-related factors predict which patients benefit the most from this medication.
Dr. Spertus is a cardiologist and the Lauer/Missouri Endowed Chair and Tenured Professor of Medicine at the University of Missouri-Kansas City where he serves as Director of Outcomes Research at the Mid America Heart Institute.
Mavacamten, or MYK-461 is a novel small-molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy.
Funding for the EXPLORER-HCM was provided by MyoKardia, a Bristol Myers Squibb company.