MyoKardia Doses First Patient in Phase 3 VALOR-HCM Trial of Mavacamten
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.
“With the VALOR-HCM study, we hope to determine whether mavacamten can reduce the need for an invasive SRT procedure,” said
Each year, approximately 1,500 people with obstructive HCM undergo invasive septal reduction therapy in
“Today, patients with obstructive hypertrophic cardiomyopathy who have symptoms refractory to current medical therapies are treated with septal reduction therapy – either surgical myectomy or alcohol ablation. These procedures improve symptoms, but require an invasive approach and should ideally be performed at high volume centers of excellence,” said
“The VALOR-HCM trial is a component in our strategy to bring mavacamten to as many people as possible who may be able to benefit from its distinct mechanism,” said
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.
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease in which excessive contraction of the heart muscle and reduced ability of the left ventricle to fill can lead to the development of debilitating symptoms and cardiac dysfunction. HCM is estimated to affect one in every 500 people. The most frequent cause of HCM is mutations in the heart muscle proteins of the sarcomere. In approximately two-thirds of individuals with HCM, the path followed by blood exiting the heart, known as the left ventricular outflow tract (LVOT), becomes obstructed by the enlarged and diseased muscle, restricting the flow of blood from the heart to the rest of the body (obstructive HCM). In other patients, the thickened heart muscle does not block the LVOT, and their disease is driven by diastolic impairment due to the enlarged and stiffened heart muscle (non-obstructive HCM). In individuals with either obstructive or non-obstructive HCM, exertion can result in fatigue or shortness of breath, interfering with a patient’s ability to participate in activities of daily living. HCM has also been associated with increased risks of atrial fibrillation, stroke, heart failure and sudden cardiac death.
About Mavacamten (MYK-461)
Mavacamten is initially being developed for the treatment of hypertrophic cardiomyopathy (HCM) and has received breakthrough therapy and orphan drug designations for symptomatic, obstructive HCM.
MyoKardia’s mission is to change the world for people with serious cardiovascular disease through bold and innovative science.
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Executive Director, Corporate Communications and Investor Relations
Stern Investor Relations, Inc.
* Please note, this version of the press release reflects a correction to Dr. Geske's quote.
Source: MyoKardia, Inc.