Improved Left Ventricular Compliance Demonstrated in Genetic Pig Model of Non-Obstructed Hypertrophic Cardiomyopathy
Results Add to Growing Body of Evidence of Mavacamten’s Dual Activity in Increasing Compliance and Reducing Hypercontractility
MyoKardia to Conduct Conference Call at 8:00 a.m. ET Today to Discuss Clinical, Preclinical and Registry Data Presented at AHA 2018
SOUTH SAN FRANCISCO, Calif., Nov. 12, 2018 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK), a clinical-stage biopharmaceutical company pioneering precision medicine for the treatment of cardiovascular diseases, presented preclinical data at the American Heart Association (AHA) Scientific Sessions 2018 that demonstrated that targeting the heart’s motor protein, myosin, improved ventricular relaxation and compliance and normalized systolic function.
MyoKardia is developing mavacamten for the chronic treatment of hypertrophic cardiomyopathy (HCM), a heritable disease caused by the presence of too many cross-bridges formed between the heart muscle proteins myosin and actin. Mavacamten is intended to normalize this excess cross-bridge formation, which underlies the hypercontractility, or elevated force of contraction, and the reduced compliance, or ability of the left ventricle to relax and fill with oxygenated blood, that are both characteristic of HCM.
“We know that the HCM heart is plagued by two central problems: excessive contractility and impaired diastolic relaxation. We’ve shown in clinical studies that by modulating myosin, mavacamten can reduce hypercontractility, as demonstrated by the reduction or elimination of the left ventricle outflow tract obstruction. A growing body of evidence from our preclinical studies and PIONEER-HCM Phase 2 in patients with obstructive HCM indicates that mavacamten may also have a beneficial effect on diastolic function by increasing the ability for the left ventricle to relax and fill,” said Robert McDowell, Ph.D., Chief Scientific Officer. “We continue to assess the effect of mavacamten on diastolic function and expect to gain deeper insights from the ongoing MAVERICK-HCM dose-ranging study in non-obstructive HCM patients, which is expected to read out in the second half of 2019.”
Using a novel genetic mini-pig model of non-obstructive HCM (nHCM), researchers evaluated the cardiac output, systolic function and diastolic function of healthy and nHCM animals treated with MYK-581, a mavacamten analog. At baseline, the nHCM models were hypercontractile with elevated left ventricular (LV) ejection fraction. LV end-diastolic pressure was elevated, indicative of impaired myocardial relaxation and decreased compliance. Non-obstructive HCM animals were also unresponsive to β-adrenergic stimulation, resulting in depressed stroke volume and cardiac output. Treatment with MYK-581 restored systolic function to normal levels and reduced end diastolic pressures while increasing end diastolic dimensions. The net result was an improvement in diastolic compliance that preserved and slightly increased stroke volume. MYK-581 also restored the ability of β-adrenergic stimulation to increase stroke volume. In a separate experiment comparing MYK-581 with metoprolol, a beta blocker widely prescribed to control symptoms of HCM, MYK-581 decreased end diastolic pressure and facilitated compliance, while metoprolol increased diastolic pressure and did not improve compliance.
These data were presented by Carlos Del Rio, Ph.D., MyoKardia Staff Scientist, in an oral presentation titled “Acute Effects of a Small-Molecule Direct Myosin-Attenuator (MYK-581) in a Mini-Pig Genetic Model of Non-Obstructed Hypertrophic Cardiomyopathy: In Vivo Evidence for Contractile Regulation with Improved Compliance and Functional Reserve” during the “Drug Discovery-Heart Failure Oral Abstracts Session I” on Sunday, November 11, 2018.
Including these preclinical data, a total of twelve abstracts advancing an understanding of mavacamten and of HCM were accepted for presentation during this year’s AHA Scientific Sessions. Among the highlights were clinical data looking at multiple parameters of diastolic function from the Phase 2 PIONEER-HCM clinical trial of patients with obstructive HCM (oHCM). Additionally, a number of abstracts based on analysis from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) were presented, adding to an understanding of the roles that genetics, gender, race and physical health may play in the development and progression of HCM.
Conference Call and Webcast
MyoKardia management will host a conference call today at 8:00 a.m. EDT to briefly review and field questions regarding the preclinical and clinical diastolic function data presented at the AHA Scientific Sessions. Investors and analysts are invited to participate in the call by dialing +1-844-494-0193 (U.S.) or +1-508-637-5584 using the conference ID 8998395. The webcast may be accessed live on the Investor Relations section of the MyoKardia website at http://investors.myokardia.com. A replay of the webcast will be available on MyoKardia’s website for 90 days following the call.
Mavacamten is a novel, oral, allosteric modulator of cardiac myosin being developed for the treatment of hypertrophic cardiomyopathy (HCM). 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. Mavacamten is intended to reduce cardiac muscle contractility by inhibiting the excessive myosin-actin cross-bridge formation that underlies the excessive contractility, left ventricular hypertrophy and reduced compliance characteristic of HCM. In April 2016, the U.S. FDA granted Orphan Drug Designation for mavacamten for the treatment of symptomatic oHCM, a subset of HCM. Mavacamten is being developed in an ongoing collaboration between MyoKardia and Sanofi.
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(1). HCM is a chronic, progressive disease that can be extremely disabling. According to recent research published in the journal Circulation(2), 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.
- Maron et al, AJC 2016; Maron et al, Circulation 2006
- Ho, et al, Circulation 2018
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Hannah Deresiewicz (investors)
Stern Investor Relations, Inc.
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