On July 23, 2020, in a press release, the manufacturer of mavacamten announced that the FDA granted Breakthrough Therapy Designation to this agent. Mavacamten is a novel oral allosteric modulator of cardiac myosin for the treatment of symptomatic, obstructive hypertrophic cardiomyopathy (HCM). In May 2020, the manufacturer announced positive results from the pivotal phase III EXPLORER clinical trial of mavacamten for the treatment of symptomatic patients with obstructive HCM. 

The EXPLORER-HCM phase III trial enrolled 251 patients with symptomatic New York Heart Association (NYHA Class II or III) obstructive hypertrophic cardiomyopathy. All participants had measurable left ventricular outflow tract (LVOT) gradient (resting and/or provoked) ≥50 mmHg at baseline. Patients were randomized on a 1:1 basis to receive individualized, once-daily dosing of mavacamten or placebo. Patients started on a dose of 5 mg, with up to two opportunities for dose adjustments (2.5 mg-15 mg) based on a combination of LVOT gradient, drug plasma concentration and left ventricular ejection fraction (LVEF) levels. 

The primary endpoint for EXPLORER-HCM was a composite functional evaluation intended to capture the clinical effect of mavacamten on both symptoms and function. The composite functional endpoint is defined by either 1) the attainment of a ≥1.5mL/kg/min improvement in peak VO2 accompanied by an improvement of ≥1 NYHA functional class, or 2) the accomplishment of a ≥3.0-mL/kg/min improvement of peak VO2 with no deterioration in NYHA functional class. 

In addition to the endpoints, the EXPLORER-HCM study assessed mavacamten’s effect on patient-reported outcomes, health-related quality of life and symptom severity assessments, changes from baseline to Week 30 in echocardiographic indices, circulating biomarkers, cardiac rhythm patterns, and accelerometry. The data indicated that mavacamten was well tolerated, with a safety profile analogous to placebo, and demonstrated a strong treatment effect, with patients experiencing clinically meaningful responses, including reductions in symptoms, improvements in cardiac function, and reduction or elimination of left ventricle obstruction. 

The manufacturer, MyoKardia, is presently preparing a New Drug Application (NDA) for mavacamten, with plans to submit the NDA to the FDA in the first quarter of 2021. 
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