Results from the phase III EXPLORER- HCM trial, published in The Lancet, revealed that treatment with mavacamten, the selective allosteric inhibitor of cardiac myosin ATPase, is linked with enhancements in exercise capacity, left ventricular outflow tract (LVOT) obstruction, New York Heart Association (NYHA) functional class, and health status in patients with obstructive hypertrophic cardiomyopathy.

The goal of this trial was to assess mavacamten compared with placebo among patients with hypertrophic obstructive cardiomyopathy. This agent was developed to target the underlying pathophysiology of hypertrophic cardiomyopathy by reducing cardiac contractility and enhancing myocardial energetics. The findings of this trial were presented at the recent 2020 European Society of Cardiology Virtual Congress.  

In the randomized, double blind, placebo-controlled phase III trial, patients with hypertrophic cardiomyopathy were recruited from 68 clinical cardiovascular centers in 13 countries. All trial subjects had an LVOT gradient ≥50 mmHg and a NYHA functional class of 2 to 3 and were randomly allocated to receive mavacamten (n = 123) or placebo (n = 128) for 30 weeks. Individualized doses of mavacamten were 2.5 mg, 5 mg, 10 mg, and 15 mg to achieve a target decrease in LVOT gradient <30 mmHg and a mavacamten plasma concentration between 350 ng/mL and 700 ng/mL. 

The primary study endpoint was an escalation in peak oxygen consumption (pVO2)  ≥1.5 mL/kg/minute and a decrease ≥1 in NYHA class or an increase in pVO2 ≥3.0 mL/kg/minute without deterioration of NYHA class. Other endpoints included changes in postexercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). Results of the study indicated that a larger percentage of participants receiving mavacamten versus placebo met the primary endpoint (37% vs. 17%, respectively; difference, +19.4%; 95% CI, 8.7-30.1; P  = .0005). The results also revealed that larger decreases in postexercise LVOT gradient were observed in the mavacamten group versus the placebo group (difference, –36 mmHg; 95% CI, –43.2 to –28.1; P <.0001). 

Furthermore, treatment with mavacamten versus placebo was linked with a greater increase in pVO2 (difference, +1.4 mL/kg/minute; 95% CI, 0.6-2.1; P =.0006) and greater improvements in KCCQ-CSS (difference, +9.1; 95% CI, 5.5-12.7; P <.0001) and HCMSQ-SoB (difference, –1.8; 95% CI, –2.4 to –1.2; P <.0001) scores. 

Other results indicated that a greater percentage of patients treated with mavacamten versus placebo experienced a ≥1 improvement in NYHA class (65% vs. 31%, respectively; 95% CI, 22.2-45.4; P <.0001). No variances were found between the two treatment groups in safety, and tolerability outcomes and results were comparable. Nearly 88% of patients in the mavacamten arm and 79% of patients in the placebo group experienced ≥1 treatment-emergent event, with the majority reported as mild in severity. Additionally, there was one sudden death in the placebo group. 

The authors concluded that treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. They also noted that the promising results of this pivotal trial emphasize the clinical benefits of disease-specific treatment for obstructive hypertrophic cardiomyopathy. It is anticipated that the manufacturer will file a new drug application in early 2021. 
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