MyoKardia, Inc. announced that the first patient has been dosed in the Phase 3 VALOR-HCM clinical trial. VALOR-HCM will enroll individuals with obstructive hypertrophic cardiomyopathy (HCM) who have been referred for septal reduction therapy (SRT) and are refractory to current therapeutic options, including those who have severe symptoms (NYHA Class IV). VALOR-HCM is designed to provide direct clinical evidence of mavacamten’s ability to mitigate the need for invasive SRT procedures and is the first of several potential studies planned by MyoKardia to expand on the existing body of evidence supporting mavacamten’s use as a potential backbone therapy for HCM. VALOR-HCM is being conducted in partnership with Cleveland Clinic C5Research, an academic research organization, with participation from approximately 15 HCM specialty centers in the U.S. with well-recognized expertise in SRT procedures. HCM is the most common genetic cardiomyopathy, estimated to affect one in every five hundred people. It is a chronic, progressive condition in which the heart muscle thickens due to hypercontractility caused by excess engagement of myosin, a primary motor protein of the heart. In the obstructive form of HCM, the wall of the septum thickens and may block the flow of blood from the left ventricle to the aorta. Mavacamten is the first agent designed to improve the underlying pathophysiology of HCM and has been shown in MyoKardia’s past clinical studies to reduce the obstruction of the left ventricle to below the threshold for guideline-recommended SRT interventions. Each year, approximately 1,500 people with obstructive HCM undergo invasive septal reduction therapy in the United States to remove the obstruction of the left ventricle. SRT is performed as either an open-heart procedure, known as a myectomy, in which the obstruction is surgically reduced, or septal ablation, in which alcohol is injected by catheter into the coronary artery supplying the septal wall to cause muscle cells in the thickened area to die. Both procedures are intended to reduce the thickness of the septal wall and alleviate obstruction. In May, MyoKardia announced positive results from the pivotal Phase 3 EXPLORER-HCM clinical trial of mavacamten in patients with symptomatic, obstructive HCM and the company plans to submit a New Drug Application to the U.S. Food and Drug Administration for regulatory approval in the first quarter of 2021. Data from the VALOR-HCM study will not be part of the initial registration package but may provide supplemental data which could potentially expand the labeled benefit of mavacamten to a population of patients with severe symptoms of obstructive HCM who are refractory to maximal available medical therapy. VALOR-HCM is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA Class III-IV) who meet guideline criteria for septal reduction therapy and have been referred for an invasive procedure. Throughout the course of the study, patients may continue on background heart failure-related medications without change. The study is expected to enroll approximately 100 patients randomized on a 1:1 basis to receive mavacamten or placebo. VALOR-HCM includes three treatment periods over 128 weeks: a 16-week placebo-controlled period, a 16-week active treatment period where all patients will receive mavacamten and a 96-week long-term extension period where all patients will continue to receive mavacamten. Patients receiving mavacamten will start at a dose of 5mg with subsequent echocardiographic assessments for dose adjustment based on the reduction of left ventricular outflow tract (LVOT) gradient, a measure of LVOT obstruction. Dose may be up-titrated for those whose gradient remains above 30mmHg, (the guideline-based threshold for diagnosis of obstructive disease) and whose left ventricular ejection fraction (LVEF) remains at or above 50 percent. Throughout the study, all dose adjustments will occur in a blinded manner and doses may be down-titrated for safety at any time. The primary endpoint will be a composite of 1) the number of subjects who decide to proceed with SRT prior to or at Week 16 and 2) the number of subjects who remain SRT-guideline eligible (LVOT gradient of =50mmHg and NYHA Class III-IV) at Week 16 in the mavacamten group compared with the placebo group. An interim analysis is planned after 50 subjects have completed treatment through Week 16 to assess efficacy. Secondary endpoints include assessment of the outcomes at Week 32 compared with Week 16 to demonstrate persistence of benefit for subjects in the mavacamten group. The study will also measure changes in the LVOT gradient, a direct measure of obstruction of the outflow from the left ventricle, as well as biomarkers, including NT-proBNP and cardiac troponin. Safety assessments include monitoring of adverse events (AEs) and concomitant medications, safety laboratory assessments, physical examinations, vital sign measurements, cardiac/activity monitoring, and electrocardiograms (ECGs). Total study duration will be 138 weeks, including a two-week screening period and an eight-week post-treatment follow-up.