MAVERICK-HCM Phase 2 Clinical Trial Results Consistent with Tolerability Observations from Prior Studies of Mavacamten
Improvement in NT-proBNP and Troponin Levels Support Future Development in Non-Obstructive HCM and Heart Failure with Preserved Ejection Fraction (HFpEF)MyoKardia to Host Webcast Conference Call at 4:30 p.m. EDTBRISBANE, Calif., March 30, 2020 (GLOBE NEWSWIRE) — MyoKardia, Inc. (Nasdaq: MYOK) today announced results from the dose-ranging MAVERICK-HCM Phase 2 clinical trial of mavacamten for the treatment of non-obstructive hypertrophic cardiomyopathy (HCM). Data were presented during a late-breaker session at the American College of Cardiology’s 69^th Annual Scientific Session together with the World Congress of Cardiology (ACC.20/WCC Virtual) In the MAVERICK-HCM study, mavacamten was generally well tolerated, and statistically significant improvements in key biomarkers of cardiac injury and wall stress were observed. Further, subgroup analyses of study participants with indicators of more advanced disease demonstrated clinical responses across multiple parameters among patients on active treatment versus placebo. “Non-obstructive HCM is especially challenging to treat as there are no proven or approved pharmacological therapies. Thus, for patients who develop symptoms refractory to medications, cardiac transplantation may be the only option,” said Carolyn Ho, M.D., Medical Director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital and lead author on behalf of the MAVERICK-HCM study investigators. “Although the primary objective of MAVERICK was to assess the safety and tolerability of mavacamten in non-obstructive HCM, in exploratory analyses we observed an encouraging result with reductions in serum levels of NT-proBNP, a biomarker of hemodynamic stress, and also cardiac troponin I, a biomarker of myocardial injury. We believe MAVERICK is the first study to show an improvement in important serum biomarkers in this patient population and suggests that there is potential physiological benefit from the drug. We were also intrigued by findings that patients with more severe disease expression, those with elevated serum troponin levels or evidence of diastolic dysfunction by echo, may have achieved functional benefit. These findings, combined with mavacamten’s tolerability profile, are encouraging, and they provide direction for further evaluation of mavacamten for patients with non-obstructive HCM.”“MAVERICK has succeeded in providing us with the important data we needed to proceed in our planned clinical trials in non-obstructive HCM, as well as a targeted subset of patients with heart failure with preserved ejection fraction, or HFpEF. We gained unique insights into dosing strategies using markers linked to clinical benefit, as well as how to identify patients who may be most likely to benefit from mavacamten,” said Jay Edelberg, M.D. Ph.D., MyoKardia’s Senior Vice President of Development. “The MAVERICK results also further our confidence in mavacamten’s development in obstructive HCM, as we approach our Phase 3 EXPLORER-HCM readout, which is expected in the second quarter.”MAVERICK-HCM Results
Safety and Tolerability Observations
Mavacamten was generally well tolerated, consistent with prior clinical studies.Adverse events (AEs) reported during the treatment period were predominantly mild or moderate. The most commonly reported AEs were palpitations, dizziness and fatigue. Adverse events were reported by 90% of study participants in the mavacamten treatment arm and 68% of those on placebo.  Of those reported in the active treatment group, 76% of AEs were mild, and 21% were moderate.The percentage of patients experiencing serious adverse events (SAEs) was 21.1% in the placebo arm and 10.3% in the active treatment arm.  Most SAEs reported were cardiovascular in nature, the most frequent of which was atrial fibrillation/flutter. Thirty-nine percent of study participants entered the MAVERICK study with a prior diagnosis of atrial fibrillation, and all of the atrial fibrillation/flutter SAEs that occurred were in patients with a history of atrial fibrillation.As previously disclosed, five of the 39 patients on active treatment in this dose-ranging study reached a pre-specified stopping criterion of left ventricular ejection fraction (LVEF) measurements of ≤45%.  The majority of these patients were asymptomatic for symptoms of heart failure, and LVEF recovered or was recovering within 4-12 weeks.  The mean (SD) reduction in LVEF from baseline to week 16 was 4.1% (8.0) on active treatment when compared to a mean reduction of 2.3% (4.9) in the placebo arm.Effect on Exploratory Endpoints of Efficacy: Biomarkers of Cardiac Wall Stress and Injury
Among several pre-specified endpoints analyzed, treatment with mavacamten resulted in significant changes in circulating biomarkers associated with heightened risks of cardiac complications. Mavacamten treatment resulted in statistically significant reductions in serum NT-proBNP (p=0.0005⁽¹⁾) in the intent-to-treat population. At the conclusion of the 16-week treatment period, the reduction in the geometric mean of NT-proBNP among those receiving mavacamten was 53% vs. 1% in the placebo group. A significant drop in NT-proBNP occurred within the first four weeks of treatment and was maintained throughout the treatment period. NT-proBNP is a well-established biomarker of cardiac wall stress that has been associated with increased mortality in HCM patients.⁽²⁾Mavacamten treatment also resulted in a 34% decrease in the geometric mean of cardiac troponin I levels from baseline to Week 16.  Cardiac troponin I levels increased by 4% in the placebo group (p=0.009).  Cardiac troponin is closely associated with increased incidence of heart failure, atrial fibrillation and death in patients with HCM.⁽³⁾For the intent-to-treat population, no difference was observed between active and placebo groups in the other exploratory endpoints.“The effect of mavacamten on NT-proBNP and cardiac troponin levels in non-obstructive HCM patients is a first-of-its-kind finding for a product candidate in this patient population,” said Michael R. Zile, M.D., Director of Cardiology, Ralph H. Johnson VA Medical Center. “NT-proBNP is a measure of cardiac wall stress, and elevated troponins signal heart muscle injury, both of which have been established in the literature as prognosticators of dire complications in both HCM and HFpEF patients, including the need for hospitalizations, surgical intervention and death.  The reductions in biomarkers associated with poor outcomes are encouraging, and I look forward to seeing the potential for mavacamten to impact outcomes in HCM, as well as certain targeted HFpEF populations, over time.” Patient Subgroups with Advanced Diastolic Disease
MyoKardia also shared its analyses of the effect of mavacamten treatment on two subgroups of patients with advanced disease: one comprising 19 of the 59 enrolled patients (32%) with elevated cardiac troponin levels of >0.03ng/mL and another including 25 patients (42%) who had elevated filling pressures, defined by E/e’ >14⁽⁴⁾. HCM patients with higher cardiac troponin levels are known to be at greater risk for serious complications, and elevated filling pressures are indicative of impaired diastolic compliance, or the ability of the left ventricle to relax and fill with oxygenated blood.A trend toward potential benefit was observed across numerous clinical measurements in patients with elevated cardiac troponin I levels and those with higher diastolic filling pressures versus placebo:Reductions in the plasma biomarkers NT-proBNP and cardiac troponin I were consistent with or greater than those observed across the intent-to-treat population.Changes in echocardiographic imaging measures including E/e’, and left ventricular end diastolic volume, indicated improvements in diastolic relaxation.Mean average E/e’ improved on a placebo-adjusted basis by 4.8 and 3.6 in the elevated troponin and filling pressure subgroups, respectively.Improvements in measures of symptoms and function:Mean peak VO₂ improved by 2.7 and 1.9 mL/kg/min on a placebo-adjusted basis in the subgroups with elevated troponin and filling pressure, respectively.In the troponin subgroup, New York Heart Association classification improved in six of the 13 participants in the mavacamten cohorts versus only one of six individuals on placebo.  No differences were observed in the elevated filling pressure subgroup.The Clinical Kansas City Cardiomyopathy Questionnaire (KCCQ) Summary Score improved by 8.8 in the elevated troponin subgroup and 4.1 in the elevated filling pressure subgroups on a placebo-adjusted basis. KCCQ is designed to measure patients’ perception of their heart failure health status and its impact on activities of daily living. A clinically significant change in KCCQ is considered to be greater than or equal to 6.Composite Functional Endpoint Analysis
A composite functional endpoint⁽⁴⁾ analysis was utilized to compare responses among the intent-to-treat population and the subgroups of patients with more advanced disease to those within the placebo population.Among the intent-to-treat study population (n=59), 23% of participants in the active arm vs. 21% of participants in the placebo arm achieved the composite functional definition of response.  (p=0.92)For the combined subgroups (n=33, patients with either elevated average E/e’ or elevated troponin levels), 33% of patients on mavacamten achieved the composite functional endpoint, compared to none of the subgroup patients in the placebo group. (p=0.03) 
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