MyoKardia announced 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.
“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. 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.
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. 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 h...
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