Cytokinetics Poised to Begin Phase 3 after its HCM Drug Registers Encouraging Data

South Francisco, California-based Cytokinetics, Inc. has created an uproar again by announcing positive study findings for an investigational heart drug, CK-274, for treating a chronic cardiovascular disease, Hypertrophic Cardiomyopathy (HCM).

Despite suffering setbacks with its Astellas and Amgen partnerships over the disappointment of its muscle disease drug, reldesemtiv, and heart failure pill, omecamtiv mecarbil (OM), respectively, Cytokinetics is making steady progress. The company is advancing OM to NDA submission following positive Phase 3 results and plans to begin a Phase 3 trial of reldesemtiv based on compelling Phase 2 data.

In addition, the latest promising results from the REDWOOD-HCM trial for a new heart disease candidate, CK-274, have once again brought excitement. The news led Cytokinetics’ stocks to outperform in the market, surging nearly 50% on July 19th.

CK-274 – A Small Molecule Cardiac Myosin Inhibitor

HCM affects an estimated 600,000 to 1.5 million Americans. Currently, there are no FDA-approved medical treatments that directly target hypercontractility underlying HCM.

Cytokinetics, Inc, focuses on developing first-in-class muscle activators and next-gen muscle inhibitors for debilitating cardiovascular or neuromuscular disorders. Its CK-274 is a novel, oral, small molecule cardiac myosin inhibitor.

It is uniquely designed to inhibit hypercontractility associated with HCM by reducing the number of active actin-myosin cross-bridges during each cardiac cycle. In preclinical models, CK-274 reduces myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state.

HCM is most often caused by an abnormality in genes in heart muscle, especially the ventricles (left ventricle), or lower heart chambers to contract harder and become thicker or enlarge (hypertrophy) than normal. As a result, the thickened walls become narrow and stiff resulting in blockage or reduction of blood flow to the muscles and organs from the left ventricle. Stiffness in the left ventricle also causes pressure to increase inside the heart resulting in debilitating conditions such as sudden cardiac arrest, atrial fibrillation, stroke, or heart failure.

Positive Phase 2 Data

The topline data from Phase 2 REDWOOD-HCM trial showed statistically significant reductions from baseline compared to placebo in left ventricular outflow tract gradients (LVOT-G) and average post-Valsalva LVOT-G in patients within two weeks of a 10 weeks-dosing schedule of 3 escalating doses of CK-274.

LVOT-G is a measure of blood flow obstruction from the left ventricle. Of note, the reduction in LVOT-G was dose-dependent and sustained through the 10-weeks dosing regimen.

The majority of patients treated with CK-274 (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of treatment defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg after 10 weeks compared to placebo.

Cytokinetics said the drug was “well-tolerated” with no “treatment-related serious adverse events” leading to “no interruptions or discontinuation of treatment with CK-274”.

The trial was set up to “see how these results may translate into a clinically meaningful impact on patients’ symptoms and exercise tolerance in Phase 3”, said Marty Maron, M.D. of Tufts University School of Medicine, who is also the principal investigator of the study.

Rivalry with MyoKardia’s Potential Blockbuster 

Cytokinetics has a strong portfolio of muscle activators and inhibitors, but it will face tough competition from mavacamten, a potential blockbuster candidate of BMS’s $13.1 billion acquisition, MyoKardia. Albeit the rivalry, Cytokinetics seemingly holds the edge as the high dose of CK-274 hit its target in nearly 93% of patients as opposed to only 74% treated with MyoKardia’s drug. Further, CK-274 reaches its maximum benefit by six weeks in contrast to less than 18 weeks for mavacamten.

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Author

Isha Kapoor