MyoKardia Announces Positive Data from Phase 2a Clinical Trial of Danicamtiv Presented at ESC’s HFA Discoveries with Simultaneous Publication in European Journal of Heart Failure
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
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
“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
- 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.
MyoKardiaplans 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)
MyoKardiaexpects 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
“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
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
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
Danicamtiv Phase 2a data were featured in a Late-Breaking Science Session during the HFA Discoveries online event from the
Conference Call and Webcast
To access the call, please dial (844) 494-0193 (
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’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 Association2018
- Shah, et al, JACC 2017
- Bavishi, et al,
International Journal of Cardiology2015
- Modin, et al,
Journal of Cardiac Failure2019
- Sargento, et al,
European Heart Journal of Cardiovasc Imaging2017
- Hershberger, et al; Nature, 2013
- Sinagra, et al, (editors), Dilated Cardiomyopathy: From Genetics to Clinical Management, Springer 2019
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
Michelle Corral MyoKardia, Inc.650-351-4690 firstname.lastname@example.org Hannah Deresiewicz(investors) Stern Investor Relations, Inc. 212-362-1200 email@example.com Julie Normant(media) W2O 628-213-3754 firstname.lastname@example.org
Source: MyoKardia, Inc.