MyoKardia Doses First Patient in Phase 2 Clinical Trial of Danicamtiv in Genetic Dilated Cardiomyopathy

Rhea-AI Summary

MyoKardia announced the dosing of the first patient in a Phase 2 clinical trial for danicamtiv, aimed at treating primary dilated cardiomyopathy (DCM) caused by genetic mutations. Danicamtiv, an oral cardiac myosin activator, enhances heart contractility without impairing relaxation. This trial will enroll up to 24 patients with genetic variants in MYH7 or titin, focusing on safety and preliminary efficacy. Topline data is expected in the second half of 2021. DCM affects 250,000 to 500,000 people in the U.S., with significant mortality risks due to limited treatment options.

Positive

• First patient dosed in Phase 2 trial for danicamtiv, indicating progress in the clinical development.
• Danicamtiv has shown potential to enhance cardiac function in patients with genetic DCM, targeting a specific patient population.
• Anticipated robust efficacy signals to guide future clinical trials post-study.

Negative

• Topline data is expected in the second half of 2021, indicating a delay in potential insights or market impact.
• Clinical trials are subject to delays due to conditions related to the COVID-19 pandemic.

BRISBANE, Calif., Sept. 09, 2020 (GLOBE NEWSWIRE) -- MyoKardia, Inc. (Nasdaq: MYOK) today announced that the first patient has been dosed in the company’s Phase 2 clinical trial of danicamtiv (formerly MYK-491) in people with primary dilated cardiomyopathy (DCM) thought to be caused by genetic mutations of the sarcomere. Danicamtiv is MyoKardia’s most advanced clinical candidate being developed for the treatment of genetic dilated cardiomyopathy (DCM) and other targeted populations with conditions of reduced systolic function.

DCM is a disease of the myocardium characterized by left ventricular enlargement. The weakened and distended left ventricle lacks sufficient contractile force to adequately pump oxygenated blood out to meet the body’s needs. Danicamtiv binds directly to and activates myosin, the heart’s motor protein, to boost the power of each contraction without impacting the ability of the heart to relax and fill with oxygenated blood. In clinical studies, danicamtiv has been well tolerated and has been shown to activate myosin, resulting in enhanced left ventricular contractility, including meaningful improvements in stroke volume, and improved left atrial volume and function.¹

“Our precision medicine approach to drug discovery and development starts with matching the biology of disease with the mechanism of our molecule. This Phase 2 proof-of-concept trial of danicamtiv is based on our knowledge of the genetics underpinning reduced contractility among a targeted population of patients with dilated cardiomyopathies, as well as our understanding of danicamtiv’s ability to increase the force of contraction. We anticipate the study providing a robust efficacy signal and numerous new insights which will guide the design of our next set of clinical trials,” said Jay Edelberg, M.D., Ph.D., MyoKardia’s Chief Medical Officer. “With its distinct mechanism, danicamtiv has the potential to make a meaningful difference in the cardiac performance of DCM patients with sarcomeric genetic mutations, for whom treatment options today are non-specific and mostly palliative.”

MyoKardia’s Phase 2 study of danicamtiv will enroll patients with DCM with documented genetic variants of MYH7 or titin. Pathogenic variants in single genes encoding proteins of the sarcomere have been associated with the contractile dysfunction underlying approximately 20-30 percent of dilated cardiomyopathies.² Patients with these genetic mutations may be particularly suited to treatment with danicamtiv since danicamtiv’s mechanism may correct the very defect that results in cardiac dysfunction. The MYH7 gene mutations are known to reduce the force-generating capacity of the heart by impairing the formation of myosin-actin cross-bridges responsible for cardiac muscle contraction. Biochemical assays using cardiac fibers with variants in MYH7 indicate danicamtiv can rescue the impaired force production that the mutation causes. Titin, an essential component of the sarcomere, provides structure, flexibility and stability as the muscle proteins contract and relax. In MyoKardia’s in vitro studies of engineered tissues with titin variant, contractility was augmented by 31 percent using a danicamtiv-like myosin activator.

The Phase 2 open-label trial will enroll up to twenty-four patients with primary MYH7 or titin DCM into two cohorts of twelve. Patients will receive danicamtiv in two sequential dose periods totaling 9-15 days of treatment. The primary endpoint is safety and tolerability, and secondary endpoints will assess the preliminary effect, compared with baseline, of treatment with danicamtiv on cardiac pharmacodynamic parameters as measured by echocardiography. Topline data are anticipated in the second half of 2021, assuming conditions related to the COVID-19 pandemic continue to allow for enrollment and study conduct in line with current expectations.

About Genetic Dilated Cardiomyopathies
Dilated cardiomyopathy is a life-threatening, progressive disease with diverse causes. 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., with the majority of the mutations identified being associated with sarcomeric proteins.^2,3 Such pathogenic variants of the sarcomere, including those associated with titin and MYH7, impair the ability of the heart muscle proteins to function effectively.

People with DCM may suffer from shortness of breath, debilitating fatigue, fainting and swelling of the extremities and irregular heart rhythms. As DCM progresses, the left ventricle of the heart becomes weaker, leading to systolic heart failure, or heart failure with reduced ejection fraction (HFrEF). Dilated cardiomyopathy, regardless of cause, is the most common diagnosis in patients requiring either mechanical circulatory support or a cardiac transplant.⁴

There are currently no therapeutic options that target DCM’s biologic underpinnings to increase the force of contraction and improve cardiac function or slow disease progression. Pharmacologic therapies developed over the past 35 years have improved both the prognosis and quality of life of DCM patients, however 5-year mortality still approaches 50 percent in community-based studies.^5,6

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⁽¹⁾ 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. MyoKardia also plans to study danicamtiv in patients with systolic heart failure and paroxysmal or persistent atrial fibrillation.

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.

1. Voors, et al, European Journal of Heart Failure, 2020
2. Hershberger, et al; Nature Reviews Cardiology, 2013
3. Sinagra, et al, (editors), Dilated Cardiomyopathy: From Genetics to Clinical Management, Springer 2019
4. Lund et al. Journal of Heart Lung Transplant; 2016.
5. Levy, et al; NEJM, 2002
6. Roger, et al; JAMA, 2004

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 danicamtiv’s sustained tolerability as well as its ability to provide enhanced left ventricular contractility, including meaningful improvements in stroke volume, and improved left atrial volume and function, our belief that danicamtiv’s mechanism may correct the defect that results in cardiac dysfunction, danicamtiv’s ability to increase the force of contraction, our ability to enroll the requisite number of patients, our anticipation of the study providing enough robust efficacy signals and insights to help guide the design of our next set of clinical trials, danicamtiv’s potential to make a meaningful difference in the cardiac performance of DCM patients with sarcomeric genetic mutations, the impact of danicamtiv’s emerging clinical and preclinical evidence, as well as our plans to advance danicamtiv in further clinical studies including in patients with systolic heart failure and paroxysmal or persistent atrial fibrillation 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 June 30, 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
Executive 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

Julie Normant (media)
W2O
628-213-3754
jnormart@w2ogroup.com

FAQ

What is the purpose of MyoKardia's Phase 2 clinical trial with danicamtiv?

The trial aims to evaluate the safety and preliminary efficacy of danicamtiv in treating primary dilated cardiomyopathy caused by genetic mutations.

When can we expect results from the danicamtiv clinical trial?

Topline data from the trial is anticipated in the second half of 2021.

What are the main endpoints of the danicamtiv Phase 2 trial?

The primary endpoint is safety and tolerability, while secondary endpoints will assess cardiac pharmacodynamic parameters.

What patient population is targeted in the danicamtiv trial?

The trial focuses on patients with documented genetic variants of MYH7 or titin associated with dilated cardiomyopathy.

What is the significance of genetic mutations in the context of the danicamtiv trial?

Genetic mutations in MYH7 or titin are linked to contractile dysfunction in DCM, making them suitable candidates for treatment with danicamtiv.