Clinical Trial Results from MyoKardia’s Phase 2 PIONEER-HCM Study of Mavacamten Published in the Annals of Internal Medicine

Mavacamten is Being Developed to Treat the Most Common Inherited Form of Heart Disease, Hypertrophic Cardiomyopathy, for Which No Targeted Medical Therapies Exist

Twelve-Week Treatment with Mavacamten Demonstrated Reductions in Obstruction and Improvements in Patient Symptoms and Function

Learnings from Phase 2 Trial Informed and Guided Design of the Current Phase 3 EXPLORER-HCM Pivotal Trial

SOUTH SAN FRANCISCO, Calif., April 30, 2019 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK), a clinical-stage biopharmaceutical company pioneering a precision medicine approach for the treatment of serious cardiovascular diseases, today announced the publication of results from the company’s Phase 2 PIONEER-HCM study of mavacamten in an upcoming issue of the Annals of Internal Medicine. A copy of the article, “Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy” is now available online at the following link: http://annals.org/aim/article/doi/10.7326/M18-3016.

There are approximately 100,000 people diagnosed with hypertrophic cardiomyopathy (HCM) in the United States and it is estimated that many more remain undiagnosed. In HCM, the heart muscle is thickened due to excessive contractility, resulting in impaired relaxation.  Mavacamten is a first-in-class investigational therapeutic intended to modulate cardiac muscle contractility by inhibiting the excessive myosin-actin crossbridge formation that underlies HCM.  Approximately two-thirds of HCM patients suffer from the obstructive form of HCM (oHCM) in which blood flow is obstructed at the left ventricular outflow tract (LVOT). Patients with oHCM are at an increased risk of heart failure, atrial fibrillation, stroke and death, including sudden cardiac death.

“The consistency and the magnitude of the effects observed from mavacamten treatment in addressing oHCM patients’ LVOT obstruction, as well as improving symptoms and functional capacity, are impressive, and we have continued to see these effects – as well as a positive safety profile – in the ongoing open-label extension study of PIONEER patients. This is highly encouraging,” said Stephen Heitner, M.D., director of the HCM Clinic, Associate Professor of Medicine at Oregon Health and Science University’s Knight Cardiovascular Institute, and the lead author on the Annals publication of PIONEER-HCM results. “Today, no HCM-specific medical therapy exists, and while a small percentage of patients may elect to undergo invasive surgical procedures, a once-daily pill such as mavacamten has the potential to have a profound effect on the treatment of obstructive hypertrophic cardiomyopathy.”

In the open-label Phase 2 PIONEER-HCM dose-ranging study, treatment with mavacamten for twelve weeks resulted in significant improvements across the primary and secondary endpoints measured. Among the most noteworthy findings were that mavacamten could be dosed to eliminate the LVOT pressure gradient below the guideline-based definition of obstruction (30 mmHg) or below the level used to recommend invasive intervention (50 mmHg), as measured using echocardiography. Along with LVOT gradient reductions, patients experienced improvements in New York Heart Association (NYHA) functional classification and exercise capacity as measured by peak VO₂ levels. Reductions in shortness of breath and in levels of NT-proBNP, a well-established marker of ventricular wall stress, were also observed. Researchers noted that improvements were seen in participants with and without background beta-blocker therapy, with and without sarcomeric genetic variants, and over a wide age range.

“The positive findings from the PIONEER-HCM study guided our dosing approach in the pivotal Phase 3 EXPLORER-HCM trial of mavacamten for the treatment of oHCM, and recently reported results from the PIONEER open-label extension study have further confirmed this approach. Patients start at a daily dose of 5mg and, based on echocardiographic assessment, may be titrated up to eliminate any residual LVOT gradient. In this way, each patient’s dose is individualized, and we believe this approach will reflect real-world usage,” said June Lee, M.D., Chief Development Officer.

The PIONEER-HCM Phase 2 Clinical Trial
The open-label PIONEER-HCM Phase 2 trial was conducted at five academic medical centers in the U.S., including Duke University Medical Center, Mayo Clinic Arizona, Hospital of the University of Pennsylvania, Oregon Health and Science University and Yale School of Medicine. A total of 21 patients with symptomatic obstructive HCM were enrolled into two sequential dose-ranging cohorts, “Cohort A” and “Cohort B”. Cohort A studied 10mg, 15mg and 20mg doses of mavacamten, while Cohort B evaluated lower doses of 2mg and 5mg of mavacamten in patients with oHCM. The primary objective of the study was to assess the effect of mavacamten treatment on reducing post-exercise LVOT obstruction in symptomatic oHCM patients and to identify optimal dosing for later-stage studies. Other endpoints included assessment of changes in resting and Valsalva LVOT gradients, NYHA Functional Class, shortness of breath or dyspnea scores, patients’ exercise capacity, and plasma and echocardiographic biomarkers of cardiac function.

Twenty of the 21 enrolled patients completed twelve weeks of mavacamten therapy, followed by a four-week post-treatment period.

Mavacamten was well tolerated throughout the twelve-week treatment period in both dosing cohorts. Adverse events (AEs) reported were mostly mild and transient in nature. The few AEs deemed potentially related to treatment included decreased left ventricular ejection fraction at elevated plasma concentrations and a few occurrences of atrial fibrillation, including one serious AE which occurred in a patient with a history of paroxysmal atrial fibrillation who had discontinued rate control medications, per the protocol for Cohort A.  No sustained arrhythmias were observed by cardiac rhythm monitoring.  Safety and tolerability findings from the Phase 2 PIONEER-HCM study have persisted past six months in the open-label extension study of PIONEER patients in which there have been no cardiac-related AEs.

Mavacamten is initially being developed for the treatment of symptomatic, oHCM in an ongoing Phase 3 pivotal trial, known as EXPLORER-HCM. The EXPLORER-HCM trial is enrolling 220 patients with oHCM. Patients will be randomized 1:1 to receive mavacamten or placebo for 30 weeks with a primary endpoint of clinical response. EXPLORER-HCM topline data is expected in the second half of 2020, with the completion of enrollment expected in the second half of this year.

Key findings from Cohorts A and B of the PIONEER-HCM Phase 2 study have previously been presented at the Heart Failure Society of America 21^st Annual Meeting in September 2017 and at the American College of Cardiology 67th Annual Scientific Sessions in 2018.

About Obstructive HCM
Hypertrophic cardiomyopathy 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. HCM is a chronic disease and for the majority of patients, the disease is progressive and can be extremely disabling. In approximately two-thirds of HCM patients, (or approximately 65,000 of the 100,000 people diagnosed in the U.S.), 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. Mild exertion can quickly result in fatigue or shortness of breath, and a patient’s ability to participate in normal work, family or recreational activities can be substantially curtailed. Patients with oHCM are at an increased risk of severe heart failure and death. HCM can also cause stroke or sudden cardiac death.^1,2

About Mavacamten (MYK-461)
Mavacamten is a novel, oral, allosteric modulator of cardiac myosin being developed for the treatment of hypertrophic cardiomyopathy (HCM). MyoKardia is currently advancing mavacamten in a pivotal Phase 3 clinical trial, known as the EXPLORER-HCM study, in patients with symptomatic, obstructive HCM (oHCM) and a Phase 2 clinical trial, the MAVERICK-HCM study, in patients with symptomatic non-obstructive HCM (nHCM). Two long-term follow-up studies are also ongoing, the PIONEER open-label extension study of oHCM patients from MyoKardia’s Phase 2 PIONEER trial and the MAVA-LTE, an extension study for patients who have completed either the EXPLORER-HCM or MAVERICK-HCM trials. Mavacamten is intended to reduce cardiac muscle contractility by inhibiting the excessive myosin-actin crossbridge 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.

About MyoKardia
MyoKardia is a clinical-stage biopharmaceutical company pioneering a precision medicine approach to discover, develop and commercialize targeted therapies for the treatment of serious 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’s mission is to change the world for patients with serious cardiovascular disease through bold and innovative science.

1. Maron et al, AJC 2016 & Maron et al, Circulation 2006
2. Ho, et al, Circulation 2018

Forward-Looking Statements
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 clinical and therapeutic potential of mavacamten, mavacamten’s ability to achieve applicable endpoints in the Phase 3 EXPLORER-HCM trial, the completion of enrollment of the Phase 3 EXPLORER-HCM trial, and the availability of data from the Phase 3 EXPLORER-HCM trial, as well as the timing of these events, 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 Annual Report on Form 10-K for the year ended December 31, 2018, 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.

Contacts
Michelle Corral
Senior Director, Corporate Communications and Investor Relations
MyoKardia, Inc.
650-351-4690 
ir@myokardia.com

Hannah Deresiewicz (investors)
Stern Investor Relations, Inc.
212-362-1200
hannah.deresiewicz@sternir.com

Steven Cooper (media)
Edelman
415-486-3264
steven.cooper@edelman.com