Diastolic Relaxation Typically Impaired in HCM Patients; Data Indicate Mavacamten May Improve Ability of the Left Ventricle to Relax and Fill
Additional Clinical Evidence of Mavacamten’s Effect on Diastolic Function Expected in 2H 2019 from MyoKardia’s MAVERICK-HCM Phase 2 Trial in Patients with Non-Obstructive HCM
SOUTH SAN FRANCISCO, Calif., Nov. 05, 2018 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK), a clinical-stage biopharmaceutical company pioneering precision medicine for the treatment of cardiovascular diseases, today announced new clinical data describing mavacamten’s effect on diastolic function will be presented at the upcoming American Heart Association (AHA) Scientific Sessions 2018 taking place November 10-12, 2018 in Chicago. The diastolic function data published in an online abstract today focus on measurements of left ventricular relaxation and compliance from an analysis of MyoKardia’s Phase 2 PIONEER-HCM clinical trial of mavacamten in 20 patients with symptomatic, obstructive HCM (oHCM). These data demonstrated that mavacamten treatment improved left ventricular relaxation and compliance along with previously reported reductions in left ventricular outflow tract (LVOT) obstruction(1).
MyoKardia is developing mavacamten for the treatment of hypertrophic cardiomyopathy (HCM), a disease characterized by thickened heart muscle, excessive contraction and impaired relaxation of the heart. Mavacamten is intended to target the myosin-actin cross-bridge formation that underlies the hypercontractility, left ventricular hypertrophy and reduced compliance characteristic of HCM.
“Data from the Phase 2 PIONEER-HCM study of mavacamten provide new insights into how targeting the contractile machinery of the heart, in particular myosin, may provide a means of increasing left ventricular compliance,” said Stephen Heitner, M.D., director of the HCM Clinic at Oregon Health and Science University’s Knight Cardiovascular Institute, and the lead investigator in the PIONEER-HCM study. “One of the hallmarks of the HCM heart is increased stiffness with resultant increased pressures required for left ventricular filling. This seems to result directly from over-engagement of myosin heads with actin. It appears that the inhibition of myosin binding may not only reduce the force of contraction, but also increase myocardial compliance. Lower filling pressure and increase in filling volume is a very attractive solution for improving myocardial efficiency for these patients suffering from heart failure. It will be of critical importance for us to better define these features in the ongoing clinical trials with mavacamten, as well as in preclinical studies.”
At baseline, PIONEER-HCM patients showed evidence of diastolic dysfunction based on multiple echocardiographic measures: early mitral annular velocity (e’), a correlate of the rate of relaxation; the ratio of early peak transmitral blood flow velocity (E)/e’, a measure of diastolic filling pressure; and left ventricular end diastolic volume (LVEDV), an indicator of the heart’s ability to fill with oxygenated blood. Abnormalities in these variables in cardiomyopathy patients have been associated with impaired exercise capacity and a poor prognosis. Following twelve weeks of mavacamten treatment, patients in Cohort A of the study, who received daily mavacamten doses of 10mg, 15mg or 20mg, experienced statistically significant improvements in e’, E/e’ and LVEDV, indicating reductions in left ventricular filling pressure and increases in filling volume. Similar directional changes in left ventricular relaxation and compliance were observed at low doses of mavacamten (2 mg, 5mg) studied in Cohort B. In addition, NT-pro-BNP, a measure of left ventricular wall stress, decreased across both cohorts. Updated figures for each of these measurements will be presented in detail by Dr. Heitner in a moderated poster “Mavacamten Improves Left Ventricular Relaxation and Compliance in Obstructive Hypertrophic Cardiomyopathy Through Direct Myosin Modulation” during the “A Potpourri of Hypertrophic Cardiomyopathy” session on Saturday, November 10 at 3:30 PM CT.
“The simultaneous increases in left ventricular volume accompanied by a decrease in left ventricular pressure and in NT-pro-BNP observed among individual patients and the group as a whole, provide encouraging evidence of mavacamten’s ability to improve diastolic function,” said Marc Semigran, MyoKardia’s Chief Medical Officer. “We are very encouraged by the body of emerging evidence of mavacamten’s potential benefit to diastolic function, something that physicians struggle to achieve with currently available therapies. Being able to positively impact diastolic relaxation and compliance directly targets the underlying mechanisms of HCM and could have profound implications for how we may pursue future development of drugs targeting diastolic heart failure. We believe the results of our ongoing MAVERICK-HCM Phase 2 trial in non-obstructive HCM patients may provide us with additional insights on this potential effect of mavacamten treatment and look forward to reporting topline data from that study in the second half of 2019.”
Mavacamten is currently being evaluated for safety and efficacy in the EXPLORER-HCM Phase 3 pivotal trial in patients with symptomatic, obstructive HCM and in the Phase 2 MAVERICK-HCM clinical trial in patients with non-obstructive HCM. MyoKardia is also pursuing the discovery and development of additional HCM-targeting therapeutics, including MYK-224, that target both hypercontractility and left ventricular relaxation and compliance, and novel therapeutic compounds aimed directly at lusitropic benefits for the treatment of diseases of diastolic dysfunction.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common genetic cause of heart disease, in which the walls of the heart thicken and prevent the left ventricle from expanding, resulting in a reduced pumping capacity. In the U.S., approximately 100,000 patients have been diagnosed with HCM and an estimated 65 percent of these have obstructive disease(2). HCM is a chronic, progressive disease that can be extremely disabling. According to recent research published in the journal Circulation(3), HCM patients are at substantially elevated risks of long-term complications and comorbidities, such as atrial fibrillation and heart failure. HCM patients also have significantly higher mortality rates compared to that of the general U.S. population. Current treatment options are inadequate and limited. Beta blockers are used in the majority of patients and have minimal impact on symptoms and do not impact disease progression. Surgical alternatives for oHCM patients (e.g., septal myectomy and alcohol septal ablation) are complex, available on a limited basis, and do not address the underlying cause of disease.
MyoKardia is a clinical-stage biopharmaceutical company pioneering a precision medicine approach to discover, develop and commercialize targeted therapies for the treatment of serious and rare cardiovascular diseases. MyoKardia’s initial focus is on the development of small molecule therapeutics aimed at the cardiac muscle proteins that modulate cardiac muscle contraction and underlie diseases of systolic and diastolic dysfunction. Based on an in-depth understanding of disease biology, MyoKardia applies a precision medicine approach to develop its therapeutic candidates for patient populations with shared characteristics, such as causal genetic mutations or disease subtypes. MyoKardia’s most advanced product candidate is mavacamten (formerly MYK-461), a novel, oral, allosteric modulator of cardiac myosin intended to reduce hypercontractility. Mavacamten has advanced into a pivotal Phase 3 clinical trial, known as EXPLORER-HCM in patients with symptomatic, obstructive hypertrophic cardiomyopathy (HCM). MyoKardia is also developing mavacamten in a second indication, non-obstructive HCM, in the Phase 2 MAVERICK-HCM clinical trial. MYK-491, MyoKardia’s second product candidate, is designed to increase cardiac output among patients with systolic heart dysfunction by increasing the overall extent of the heart’s cardiac contractility. MyoKardia is currently evaluating MYK-491 in a Phase 1b/2a study in stable heart failure patients. MyoKardia has formed a collaboration with Sanofi to support the commercialization of mavacamten outside the U.S. and for MYK-491’s worldwide late-stage development and commercialization. MyoKardia’s mission is to change the world for patients with serious cardiovascular disease through bold and innovative science.
- Jacoby, et al; ACC 2018
- Maron et al, AJC 2016; Maron et al, Circulation 2006
- Ho, et al, Circulation 2018
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