MyoKardia sets design of Phase 3 cardiomyopathy therapy trial

MyoKardia announced the design of its pivotal Phase 3 EXPLORER-HCM clinical trial to evaluate the use of mavacamten for the potential treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy. The company has incorporated input on the study design from the Division of Cardiovascular and Renal Products of the U.S. Food and Drug Administration, and plans to conduct this single pivotal study along with a long-term extension study to support registration. MyoKardia expects to dose the first patient in the EXPLORER-HCM trial in the second quarter of 2018 and expects that data from the Phase 3 trial will be available in the second half of 2020.EXPLORER-HCM is a multi-national randomized double-blind study designed to assess the effects of a 30-week treatment of mavacamten versus placebo with a primary endpoint of clinical response. The clinical response endpoint is intended to broadly capture the potential benefits of treatment with mavacamten on how patients feel and function by utilizing both peak oxygen consumption and New York Heart Association functional classification. Clinical response can be achieved by meeting either of two definitions: 1) an improvement of at least 1.5 mL/kg/min in peak VO2 accompanied by a reduction from baseline of at least one NYHA functional class or 2) an improvement from baseline of 3.0 mL/kg/min or greater in peak VO2 without worsening in NYHA functional class. Approximately 220 patients will be enrolled and randomized on a 1:1 basis to receive either mavacamten or placebo. The EXPLORER-HCM trial design includes two opportunities for individualized dose adjustment throughout the 30-week treatment period. Patients in the active treatment arm will start on a once-daily 5mg dose of mavacamten. At Weeks 8 and 14, daily doses may be increased to 10mg or 15mg, or remain unchanged, based on measurements of provoked left ventricular outflow tract gradient conducted at Weeks 6 and 12. A reduction in provoked LVOT gradient under 50 mmHg has been shown in PIONEER to correlate to improvements in several clinical measurements, including NYHA class and peak VO2. All assessments and dose adjustments will be conducted in a blinded fashion. Patients will be allowed to maintain their HCM-related background medications for the duration of the EXPLORER-HCM Phase 3 trial, including beta blockers or calcium channel blockers. Secondary endpoints in the Phase 3 EXPLORER-HCM trial will include the average change from baseline in post-exercise peak LVOT gradient, NYHA functional class, peak VO2, the proportion of patients achieving post-exercise peak LVOT gradient below 50 mmHg or 30 mmHg at Week 30 and patient-reported outcome measures. Exploratory endpoints will include changes in echocardiographic indices of cardiac structure and function, N-terminal pro b-type natriuretic peptide concentrations, quality of life questionnaire scores and daily physical activity assessed using a wearable accelerometer. Throughout the EXPLORER-HCM study, patients will be monitored for adverse events and certain assessments will be performed. If at any time during the trial, a patient’s plasma concentration is above an upper target range or LVEF falls below the normal range, doses of mavacamten may be decreased. Following the 30-week treatment period and eight-week post-treatment wash-out period, patients will be able to participate in a long-term extension study of mavacamten

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