Danicamtiv was Well Tolerated; Demonstrated Improvements in Cardiac Contractility and Preserved Diastolic Function in Patients with Stable Heart Failure with Reduced Ejection Fraction
New Observations Show Improvements in Left Atrial Volume and Function, Key Prognostic Indicators of Atrial Fibrillation
Additional Nonclinical Studies Also Presented Demonstrating Danicamtiv’s Differentiated Mechanistic Profile Including Direct Activation of the Left Atrium
MyoKardia to Host Webcast Conference Call on Today at 8:30 a.m. EDT/5:30 a.m. PDT
BRISBANE, Calif., June 22, 2020 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK) today announced the presentation and publication of positive data from the company’s Phase 2a clinical trial of danicamtiv (formerly MYK-491) along with nonclinical data elucidating danicamtiv’s novel mechanism of action. Results from both the clinical and nonclinical studies of danicamtiv were featured at the European Society of Cardiology’s Heart Failure Association (HFA) Discoveries online event and published simultaneously in the European Journal of Heart Failure. Danicamtiv is MyoKardia’s most advanced clinical candidate being developed for the treatment of conditions driven primarily from reduced systolic function, including genetic dilated cardiomyopathy (DCM) and other targeted segments of heart failure with reduced ejection fraction (HFrEF). Chronic HFrEF is a debilitating syndrome with a five-year mortality rate of 50 percent.(1)
In the Phase 2a study, danicamtiv, administered orally for seven days in patients with stable chronic heart failure, was generally well-tolerated, and was associated with clinically meaningful improvements in left ventricular (LV) contractility, including statistically significant increases in LV stroke volume, without impairing the heart’s ability to relax and fill. Danicamtiv treatment also improved left atrial (LA) volume and function, a new and potentially important finding given left atrial size is a well-established prognostic factor for atrial fibrillation.(2) Nonclinical studies also published as part of HFA Discoveries indicated danicamtiv directly activates the left ventricle and left atrium, providing compelling mechanistic rationale for the robust changes observed clinically.
“The Phase 2a clinical trial showed that danicamtiv is increasing multiple important parameters of systolic function with no clinically meaningful impact on the heart’s ability to relax and fill, observations that are right on target with the molecule’s intended mechanism,” said Jay Edelberg, M.D., MyoKardia’s Senior Vice President, Development. “The discovery that danicamtiv is also directly activating the contractility of the left atrium and improving left atrial volume and function is both new and intriguing. These favorable direct effects on both the left ventricle and the left atrium point to a distinctive therapeutic profile with the potential to be best-in-class in several patient subgroups. We plan to study danicamtiv further in clinical trials of patients with genetic dilated cardiomyopathies and among patients with reduced systolic function and atrial fibrillation.”
MyoKardia intends to advance danicamtiv into two Phase 2 clinical trials in distinct patient subgroups: dilated cardiomyopathy patients with certain genetic mutations, and patients with reduced systolic function and atrial fibrillation.
- Genetic mutations of the sarcomere impair the ability of the heart muscle proteins to function effectively, leading to progressive worsening of function. The genetic DCM Phase 2 study will test the hypothesis that danicamtiv may correct the main pathological driver of disease in certain types of genetic DCM. MyoKardia plans to start the Phase 2 genetic DCM study in the second half of 2020, pending circumstances related to the coronavirus pandemic.
- Atrial fibrillation co-exists with heart failure in approximately 35% of patients with HFrEF.(3) Individuals with both conditions are known to suffer worse symptoms and outcomes, as most anti-arrhythmic therapies are not well tolerated or are contra-indicated.(4) MyoKardia expects to initiate its Phase 2 study in patients with systolic heart failure and paroxysmal or persistent atrial fibrillation in the first half of 2021.
Phase 2a Multiple-Ascending Dose Results
The primary endpoint for the Phase 2a study was to assess the clinical safety and tolerability of danicamtiv in patients with chronic HFrEF. Danicamtiv was generally well tolerated with no dose-limiting toxicities observed. The safety profile was consistent with observations from MyoKardia’s Phase 1 study in healthy volunteers.
- Adverse events (AEs) reported during the treatment period were predominantly mild or not considered related to study treatment. AEs were reported by 57% of study participants in the active treatment arm and 40% of those on placebo.
- Cardiac AEs during treatment reported with danicamtiv included asymptomatic, mild, transient increases in troponin, ventricular extrasystoles, and in two patients, non-sustained ventricular tachycardia (NSVT) episodes which were observed at baseline (before treatment) and again during study treatment. All were mild, required no adjustment of medication and resolved without treatment. An analysis of Holter monitoring of cardiac rhythm in all patients revealed no increase in atrial or ventricular arrhythmias with danicamtiv compared with placebo.
- The one serious adverse event reported during the study was an incidence of hyperkalemia which resolved. This event occurred in the active treatment arm and was considered to be unrelated to study treatment by the investigator.
Secondary and exploratory endpoints in the Phase 2a study focused on echocardiographic measures of danicamtiv’s effects on systolic function, diastolic function and left atrial volume and function, as well as pharmacokinetics and pharmacodynamic measures. At concentrations higher than 2,000ng/mL (achieved with twice daily danicamtiv doses of 50mg to 100mg), danicamtiv demonstrated clinically meaningful and statistically significant (p<0.05) improvements in multiple measures of left ventricular contractility as compared to placebo. Stroke volume, global longitudinal and circumferential strain, and systolic ejection time improved with little to no clinically meaningful impact on diastolic function.
New observations show a marked improvement in left atrial function and volume associated with danicamtiv treatment. Statistically significant (p<0.05), concentration-dependent improvements in left atrial volume and function were observed compared to placebo using multiple echocardiographic measures, including LA minimal volume, LA emptying fraction and LA function index (an integrated measure of LA size, LA function and LV stroke volume). These left atrium parameters are strongly associated with adverse cardiovascular outcomes, including atrial fibrillation, heart failure and mortality (1, 5, 6).
“Impaired contractility of the heart, leading to insufficient blood circulation to meet the body’s requirements, remains in need of new, targeted treatment options,” said Adriaan Voors, M.D., University of Groningen, Groningen, Netherlands, study investigator and presenting author. “Danicamtiv is a promising candidate which appears to act directly on the proteins of the heart muscle underlying contractility. Danicamtiv improved the contractility of the left ventricle and atrium and represents a differentiated approach to existing therapeutic options in systolic heart failure.”
The Phase 2a study of danicamtiv was a randomized, double-blind, placebo-controlled, adaptive designed study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending oral doses of danicamtiv in patients with stable heart failure with reduced ejection fraction. A total of forty patients were randomized in consecutive cohorts: thirty patients received danicamtiv 50mg, 75mg, or 100mg twice daily for 7 days, and 10 patients received placebo.
Nonclinical Evidence of Danicamtiv’s Direct Effect on the Left Atrium
Experiments examining the effects of danicamtiv on cardiac muscle fibers and in an established canine model of heart failure elucidate the novel mechanism underlying the observations from the Phase 2a study. In vitro experiments established that danicamtiv is directly enhancing the function of myosin, the key motor protein of the heart. In doing so, danicamtiv directly increased active force production in both ventricular and atrial muscle fibers, thereby enhancing sarcomere function. Consistent with clinical observations, studies in animal models showed that a single dose of danicamtiv improved systolic function by increasing stroke volume and cardiac output and enhanced left atrial performance by reducing left atrial volumes, with negligible changes to end diastolic dimensions and left ventricular filling pressures.
“The clinical observations of danicamtiv’s effect on the left atrium were recapitulated in a series of experiments which established that danicamtiv directly activates both the left ventricle and the left atrium, a key novel finding,” said Robert McDowell, Ph.D., MyoKardia’s Chief Scientific Officer. “Taken together, these data point to a distinctive therapeutic profile; danicamtiv enhances the degree of contraction and preserves relaxation in the left ventricle, while providing direct beneficial effects on the left atrium.”
Danicamtiv Phase 2a data were featured in a Late-Breaking Science Session during the HFA Discoveries online event from the Heart Failure Association of the European Society of Cardiology (ESC) by Dr. Voors in a presentation titled “Phase 2a Study of Danicamtiv (MYK-491) in Patients with Chronic Heart Failure with Reduced Ejection Fraction (HFrEF)”. Nonclinical findings were featured at HFA Discoveries by Carlos del Rio, PhD, FACC, MyoKardia Staff Scientist, Pharmacology, in a presentation titled, “Danicamtiv (MYK-491) A Novel Small-Molecule Cardiac Activator: in vitro/in vivo Evidence for Overall Myocardial Inotropy”. The nonclinical and Phase 2a clinical data were simultaneously published in an article titled, “Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a Phase 2a trial.”
Conference Call and Webcast
MyoKardia management will host a conference call and webcast for investors and analysts today to review the data from the Phase 2a study and to discuss future development plans for danicamtiv in targeted groups of patients with systolic disease at 8:30 a.m. ET/5:30 a.m. PT.
To access the call, please dial (844) 494-0193 (U.S.) or (508) 637-5584 (international), and reference the conference ID 4787504. A live webcast of the event will be available on the Investors section of MyoKardia’s website at http://investors.myokardia.com. A replay of the webcast, and accompanying slides, will be available on the MyoKardia website for 90 days following the call.
About Danicamtiv
Danicamtiv (formerly MYK-491) is an oral, small molecule, selective cardiac myosin activator. In the heart, myosin is the motor protein that binds to actin to generate the force and movement of contraction. In patients with dilated cardiomyopathy and systolic heart failure, the left ventricle of the heart is too distended and weak to adequately pump blood to meet the body’s needs. Danicamtiv has been shown to increase the probability for myosin-actin engagement while preserving the detachment of myosin from actin at the end of contraction, thereby improving cardiac contractility while preserving diastolic function and allowing for normal filling.
Emerging clinical and preclinical evidence show that danicamtiv also directly activates myosin to improve left atrial volume and function. Danicamtiv has been well tolerated in early clinical studies intended to assess safety and tolerability. MyoKardia intends to advance danicamtiv in further clinical studies to characterize clinical benefit, starting with a Phase 2 clinical trial in patients with genetic dilated cardiomyopathy. Genetic abnormalities contributing to DCM are estimated to be present in about 30-40% of DCM patients, corresponding to an estimated prevalence of 250,000 to 500,000 people in the U.S.(7, 8) MyoKardia also plans to study danicamtiv in patients with systolic heart failure and paroxysmal or persistent atrial fibrillation. Atrial fibrillation occurs in more than half of individuals with heart failure and the presence of both atrial fibrillation and HFrEF increases mortality risk 2.7-fold compared to those with the general population.(3)
About MyoKardia
MyoKardia is a clinical-stage biopharmaceutical company discovering and developing targeted therapies for the treatment of serious cardiovascular diseases. The company is pioneering a precision medicine approach to its discovery and development efforts by 1) understanding the biomechanical underpinnings of disease; 2) targeting the proteins that modulate a given condition; 3) identifying patient populations with shared disease characteristics; and 4) applying learnings from research and clinical studies to inform and guide pipeline growth and product advancement. MyoKardia’s initial focus is on small molecule therapeutics aimed at the proteins of the heart that modulate cardiac muscle contraction to address diseases driven by excessive contraction, impaired relaxation, or insufficient contraction. Among its discoveries are three clinical-stage therapeutics: mavacamten (formerly MYK-461); danicamtiv (formerly MYK-491) and MYK-224.
MyoKardia’s mission is to change the world for people with serious cardiovascular disease through bold and innovative science.
--------------------------------------
- Owan, et al, NEJM 2006
- Sardana, et al, Journal of the American Heart Association 2018
- Shah, et al, JACC 2017
- Bavishi, et al, International Journal of Cardiology 2015
- Modin, et al, Journal of Cardiac Failure 2019
- Sargento, et al, European Heart Journal of Cardiovasc Imaging 2017
- Hershberger, et al; Nature, 2013
- Sinagra, et al, (editors), Dilated Cardiomyopathy: From Genetics to Clinical Management, Springer 2019
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 danicamtiv, the plans to begin a Phase 2 clinical trial of danicamtiv in genetic DCM patients and the timing of such trial, and the plans to begin a Phase 2 clinical trial of danicamtiv in patients with atrial fibrillation with systolic heart failure and the timing of such trial, 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 Quarterly Report on Form 10-Q for the quarter ended March 31, 2020, 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 MyoKardia, Inc. 650-351-4690 ir@myokardia.com Hannah Deresiewicz (investors) Stern Investor Relations, Inc. 212-362-1200 hannah.deresiewicz@sternir.com Julie Normant (media) W2O 628-213-3754 jnormart@w2ogroup.com
