"This analysis of EXPLORER-HCM represents the largest serial assessment of echocardiographic parameters in a prospective, double-blind, placebo-controlled study in patients with obstructive HCM," the study team points out in their Journal of the American College of Cardiology paper.
"Mavacamten treatment improved several key pathophysiological features associated with obstructive HCM, thereby providing additional mechanistic insights into the improvement in exercise capacity and left ventricular outflow tract (LVOT) obstruction previously described," write Dr. Sheila Hegde with Brigham and Women's Hospital in Boston and colleagues.
Mavacamten is an investigational, first-in-class, oral cardiac myosin inhibitor designed to target the underlying cause of HCM. It is currently under review at the U.S. Food and Drug Administration.
In the EXPLORER-HCM trial, 251 patients with symptomatic obstructive HCM were treated with mavacamten or placebo; 75% of patients were also on a beta-blocker and 17% were on a calcium channel blocker.
Over 30 weeks, 80.9% of patients treated with mavacamten, compared with 34.0% treated with placebo, had complete resolution of mitral valve systolic anterior motion, "an important element of dynamic LVOT obstruction," the researchers say. The between-group difference of 46.8% was statistically significant (P<0.0001).
Mavacamten also significantly improved markers of diastolic function compared with placebo, with associated reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP), "an important marker of cardiac wall stress with strong prognostic value," they report.
Left atrial volume index (LAVI) was mildly increased at baseline and decreased significantly with mavacamten, which was associated with improved peak exercise oxygen consumption, they add.
The researchers note that the EXPLORER-HCM study excluded patients with mild NYHA functional class I symptoms, those on disopyramide, and those with LV ejection fraction less than 55%, and there was limited participation of ethnic minorities and patients younger than age 50.
At 30 weeks duration, the study was also relatively short. The ongoing long-term extension study known as MAVA-LTE will help determine whether the early benefits with mavacamten treatment persist beyond 30 weeks, the researchers say.
The author of an accompanying editorial cautions that "negative inotropic properties" of mavacamten treatment "require careful monitoring of left ventricular ejection fraction (LVEF)," which decreased to 50% or less in seven of 123 patients (5.7%) on mavacamten in EXPLORER-HCM.
"Certainly, these reductions in LVEF are undesirable, but they were asymptomatic in four of seven patients and reversible by the end of trial in all but one patient," Dr. Ahmad Masri with Oregon Health and Science University in Portland points out.
"Overall, the current evidence supports an indication for mavacamten use in patients who continue to be symptomatic despite treatment with beta-blockers or calcium channel blockers. The favorable structural and functional effects of mavacamten in EXPLORER- HCM . . . suggest a future shift to first-line obstructive HCM therapy with selective cardiac myosin inhibitors, but further evidence to support such practice is required," Dr. Masri concludes.
The study was funded by MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, which is developing mavacamten. Several authors have disclosed financial relationships with the company.
SOURCE: https://bit.ly/3IPSW3Q and https://bit.ly/3oPzYSE Journal of the American College of Cardiology, online December 13, 2021.
By Reuters Staff
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