MyoKardia Announces Positive Six-Month Safety and Efficacy Data from PIONEER-OLE Study of Mavacamten for the Treatment of Symptomatic, Obstructive HCM

Mavacamten Well Tolerated; Results Show Statistically Significant Elimination of Obstruction and Durable NYHA Class Improvements

Statistically Significant Improvement in Several Key Biomarkers Suggest Potential for Mavacamten to Slow or Reverse Disease Progression

Conference Call Today at 8:30 a.m. ET (5:30 a.m. PT);
Data Presentation at American College of Cardiology on Sunday, March 17, 2019

SOUTH SAN FRANCISCO, Calif., March 04, 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 positive 12- and 24-week safety, efficacy and biomarker data for its investigational drug, mavacamten, from the company’s PIONEER open-label extension (OLE) study. The PIONEER-OLE study enrolled a total of thirteen patients who previously completed the Phase 2 PIONEER-HCM trial.  These data reflect the longest duration of mavacamten treatment reported to date.

Mavacamten is being developed for the treatment of symptomatic, obstructive hypertrophic cardiomyopathy (oHCM), in an ongoing Phase 3 pivotal trial, known as EXPLORER-HCM.  Patients with oHCM are at an increased risk of heart failure, atrial fibrillation, stroke and death, including sudden cardiac death.  There are an estimated 410,000 people with oHCM in the United States, with approximately 65,000 currently diagnosed and seeking medical attention.  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.

“The interim results reported today from our PIONEER-OLE study provide us with new and encouraging evidence supporting the safety, consistency and durability of mavacamten’s effects across multiple important endpoints,” said June Lee, M.D., Executive Vice President and Chief Development Officer of MyoKardia.  Data from this study show that we can safely dose mavacamten to achieve significant reductions in obstruction of the left ventricle while preserving left ventricular ejection fraction above normal for all patients over a sustained period of time.  Significant improvements in patient symptoms were also observed, as measured by NYHA classification, a key component of our EXPLORER primary endpoint.  At six months, NYHA Class improved in eight of ten patients, and seven of those eight patients were considered asymptomatic.  The similarities between PIONEER-OLE and our Phase 3 EXPLORER-HCM trial in terms of patients enrolled and dosing approach further increase our confidence in EXPLORER’s design and potential for success.”

“In addition to the safety profile and improvement in patient symptoms observed in PIONEER-OLE, we observed a return toward normal levels of biomarkers of cardiac wall stress, filling pressure and cardiac structure, including left atrial size.  In HCM, elevated chamber pressures and wall stress due to excessive contraction and hypertrophy impair the heart’s ability to fill with oxygenated blood,” said Marc Semigran, M.D., MyoKardia’s Chief Medical Officer.  “Changes such as those we’re observing from our PIONEER-OLE study in the pressure and volume characteristics of the HCM heart could ultimately be very meaningful in terms of mavacamten’s potential to slow or even reverse disease progression.”

PIONEER-OLE 12- and 24-week Results
Patients in PIONEER-OLE received once-daily oral doses of 5mg mavacamten, with an individualized dose adjustment at Week 6 aimed at eliminating the obstruction of the left ventricular outflow tract (LVOT).  Patients either remained at the 5mg starting dose or were adjusted to 10mg or 15 mg.  Twelve of the thirteen PIONEER-OLE participants remained on their prior therapy of beta blockers. 

Data for ten patients at 24 weeks of treatment were reported today.  Six patients in PIONEER-OLE have completed 36 weeks of treatment.  The longest continuous duration on mavacamten in the study is 42.5 weeks.

Mavacamten was well tolerated throughout the treatment period.  There were no cardiac-related adverse events (AEs). Adverse events reported were mostly mild and transient in nature. 

Mavacamten reduced or eliminated obstruction of the LVOT to levels below the guideline-based threshold for diagnosis (30 mmHg resting) and for invasive intervention (50 mmHg provoked/post-exercise) in all patients, without reducing left ventricular ejection fraction (LVEF) below normal (50%).  No patient experienced a reduction in LVEF under 55% at the time of any assessment during the study.  Elimination of LVOT gradient is an established surrogate for improvements in patient symptoms and exercise capacity, as measured by peak VO₂. ⁽¹⁾ 

• Reductions in provoked gradient were observed from a baseline mean of 89.9 mmHg to 22.5 mmHg at Week 12 (N=13), and 21.1 mmHg at Week 24 (N=10). 
• Treatment with mavacamten had little impact on LVEF, a measure of the percentage of blood ejected with each heartbeat, which remained above normal (50%) in all patients at all time points (4, 8, 12 and 24 weeks) measured.
• At 24 weeks, significant improvements in symptoms and function were observed for eight of ten patients (80%) evaluable for NYHA class, a four-category physician assessment scale of heart failure symptoms.  Seven of those eight achieved an asymptomatic NYHA classification (Class I). 

PIONEER-OLE: Observed Mean Values

* p<0.05 for the change from baseline

Mavacamten also demonstrated statistically significant improvements in key biomarkers that measure cardiac stress, filling pressure and cardiac structure, which were maintained over the duration of the six-month period. 

• NT-proBNP, an established circulating blood marker of cardiac wall stress, decreased approximately 10-fold.  At baseline, the mean NT-proBNP for the 13 patients enrolled in PIONEER-OLE was 1836 pg/mL, and at Week 24 the mean value for ten evaluable patients was 170 pg/mL.  NT-proBNP levels in HCM patients of <310 pg/mL have been associated with a 75 percent reduction in the rate of heart failure-related death or hospitalization, progression to end-stage disease, and stroke, as compared with patients with levels ≥310 pg/mL. ⁽²⁾
• E/e’, a non-invasive marker for left ventricular filling pressure, decreased from 12.8 to 9.8 at Week 12 among the 13 patients enrolled and remained at 10.3 at Week 24 for the ten patients evaluable for response. ⁽³⁾   
• Left atrial volume index is a measure of the pressure in the left ventricle. It increases when pressure is elevated and decreases when filling pressure in the left ventricle returns to normal levels.  Left atrial volume index (mL/m²) decreased from 40.9 at baseline to 31.8 at Week 12 and 29.7 at Week 24.  Elevated left atrial volume has been shown to be prognostic of atrial fibrillation in HCM patients.  A recent multicenter publication in Circulation: EP identified HCM patients with a left atrial volume index of ≥ 37 mL/m² as having a 2.7-fold greater five-year risk of developing new-onset atrial fibrillation than those with smaller left atria.⁽⁴⁾

PIONEER-OLE: Biomarker Measurements, Mean (SD)

* p<0.05 for the change from baseline

On behalf of the PIONEER investigators, Stephen Heitner, M.D., will present 12- and 24-week results from the open-label extension on Sunday, March 17, 2019 in a poster titled, “Long-term Safety and Effectiveness of Mavacamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy Patients, PIONEER-Open Label Extension Study (PIONEER-OLE)” (Poster Board #518) during the American College of Cardiology’s 68th Annual Scientific Session in New Orleans. 

Conference Call and Webcast
MyoKardia management will host a conference call and live audio webcast this morning at 8:30 a.m. ET / 5:30 a.m. PT to provide an operational update and to review new data from the PIONEER-OLE study.  The call may be accessed by phone by calling 844-494-0193 from the U.S. and Canada or 508-637-5584 internationally and using the conference ID 7688075.  The webcast may be accessed live on the Investor Relations section of the Company's website at http://investors.myokardia.com. A replay of the webcast will be available on the MyoKardia website for 90 days following the call.

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 an estimated 410,000 people 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.

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.  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⁾ S. Firoozi, et al, European Heart Journal, 2002
⁽²⁾ Amato, et al, American Journal of Cardiology, 2013
⁽³⁾ Nagueh, et al, Circulation, 1999
⁽⁴⁾ Debonnaire, et al, Circulation: Arrhythmia and Electrophysiology, 2017

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, the Company’s ability to enroll patients into its Phase 3 EXPLORER-HCM study of mavacamten in symptomatic oHCM and the completion of such enrollment, and the availability of data from EXPLORER-HCM, the Company’s expectation with respect to release of data from these studies, as well as the Company’s expectations for the potential for success of EXPLORER-HCM, 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.