VALOR-HCM Designed to Generate Direct Evidence of Improved Outcomes for People with HCM by Reducing the Need for Invasive Septal Reduction Therapy
BRISBANE, Calif., Aug. 03, 2020 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK) 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.
“With the VALOR-HCM study, we hope to determine whether mavacamten can reduce the need for an invasive SRT procedure,” said Milind Desai, M.D., Director, HCM Center, Cleveland Clinic Heart and Vascular Institute, and Principal Investigator of the VALOR-HCM study. “Mavacamten aims to address the biomechanical defects in cardiac muscle contractility underlying HCM and has shown promise in prior clinical studies in reducing obstruction of the left ventricle and improving symptoms and cardiac function.”
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.
“Today, septal reduction therapy – either surgical myectomy or alcohol ablation – is the only means of reducing the obstruction of the left ventricle in people with HCM who are refractory to current therapies. While these procedures have shown success in improving symptoms for patients with HCM, they are available to relatively few of the estimated thousands of obstructive HCM patients who meet guideline-based criteria,” said Jeffrey B. Geske, M.D., Cardiologist at the Mayo Clinic and member of the VALOR-HCM Executive Committee. “The prospect of a once-daily pill providing a non-invasive alternative to SRT is an exciting one and we are hopeful that it may prove effective in providing relief and improving care of these patients.”
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.
“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 Jay Edelberg, M.D., Ph.D., MyoKardia’s Chief Medical Officer. “The study expands on the body of existing mavacamten clinical data from EXPLORER which demonstrated improvements in symptoms and exercise capacity in patients with NYHA Class II-III. VALOR has the potential to demonstrate improved outcomes in a more severe segment of the HCM population and reflects a broader range of anticipated real-world practices. We will be enrolling patients regardless of current background medications and including those who are NYHA Class IV with more severe symptoms. Additionally, the VALOR-HCM study uses individualized dosing based solely on widely-used, non-invasive echocardiographic measures. As part of this study, we are thrilled to be able to collaborate with many new clinical sites, including surgical centers of excellence and their referring centers.”
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)
MyoKardia is developing mavacamten, a first-in-class, oral, allosteric modulator of cardiac myosin, for the treatment of conditions in which excessive cardiac contractility and impaired diastolic filling of the heart are the underlying cause. Mavacamten is reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance. In clinical and preclinical studies, mavacamten has consistently reduced biomarkers of cardiac wall stress, lessened excessive cardiac contractility and increased diastolic compliance.
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 plans to submit a New Drug Application (NDA) for U.S. regulatory approval in this indication in the first quarter of 2021. Based on its mechanism of action and evidence of therapeutic activity, mavacamten is also being studied in the clinic for the treatment of symptomatic non-obstructive HCM and among a targeted population of patients with heart failure with preserved ejection fraction (HFpEF).
MyoKardia is a clinical-stage biopharmaceutical company discovering and developing targeted therapies for the treatment of serious cardiovascular diseases. The company is pioneering a precision medicine approach to its discovery and development efforts by 1) understanding the biomechanical underpinnings of disease; 2) targeting the proteins that modulate a given condition; 3) identifying patient populations with shared disease characteristics; and 4) applying learnings from research and clinical studies to inform and guide pipeline growth and product advancement. MyoKardia’s initial focus is on small molecule therapeutics aimed at the proteins of the heart that modulate cardiac muscle contraction to address diseases driven by excessive contraction, impaired relaxation, or insufficient contraction. Among its discoveries are three clinical-stage therapeutics: mavacamten (formerly MYK-461); danicamtiv (formerly MYK-491) and MYK-224.
MyoKardia’s mission is to change the world for people with serious cardiovascular disease through bold and innovative science.
Statements we make in this press release may include statements which are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are usually identified by the use of words such as "anticipates," "believes," "estimates," "expects," "intends," "may," "plans," "projects," "seeks," "should," "will," and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements regarding the ongoing enrollment of patients in the Phase 3 VALOR-HCM clinical trial as well as our expectation that the clinical trial design will result in direct clinical evidence supporting mavacamten’s expansion of the existing body of evidence supporting mavacamten’s use as a potential backbone therapy, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, risks associated with the development and regulation of our product candidates, as well as those set forth in our Quarterly Report on Form 10-Q for the quarter ended March 31, 2020, and our other filings with the SEC. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.
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