The poster titled, "Direct Activation of Cardiac Myosin by CK-1827452 Improves Cardiac Function in a Dog Heart Failure Model." [Poster Presentation #017] has been displayed today and will be presented at 5:45 pm ET by Fady Malik, M.D., Ph.D., F.A.C.C., Director, Cardiovascular Programs, Cytokinetics. The presentation details research directed to the discovery and optimization of small molecules that improve cardiac function in a manner consistent with the therapeutic hypothesis, specifically that improving cardiac contractility by directly activating cardiac myosin can potentially address the liabilities of current inotropic drugs. The data demonstrate that CK-1827452 selectively activates cardiac myosin. In cardiac myocytes, CK-1827452 increases contractility without changes in the cellular calcium transient, a finding consistent with its mechanism of action. In addition, CK-1827452 demonstrates an improvement in cardiac function and output, hemodynamics and efficiency in a dog model of heart failure in a manner that supports the therapeutic hypothesis.
The presentation details non-clinical support for the Company's novel therapeutic approach of directly activating the cardiac myosin motor protein as a potential next-generation approach to managing acute and chronic heart failure. In prior presentations, Cytokinetics scientists presented results that demonstrate that cardiac myosin activators increase cardiac contractility without increasing intracellular calcium and without stimulating beta-adrenergic receptors or inhibiting phosphodiesterase activity, mechanisms that may be arrhythmogenic and associated with other adverse clinical effects.
"We are very pleased to have the opportunity to present these research findings which characterize the mechanism of action of CK-1827452," stated David Morgans, Jr., Ph.D., Senior Vice President of Drug Discovery and Development. "This presentation builds on presentations related to prior compounds, and further demonstrates the breadth and depth of our knowledge related to our cardiac myosin activators by extending validation of the therapeutic hypothesis through pharmacologic models for this drug candidate." "Cardiac myosin activators represent a novel class of drug candidates that may improve the treatment of acute and chronic heart failure without the liabilities associated with current inotropes," stated James Sabry, M.D., Ph.D., President and Chief Executive Officer. "Today's data provide in vivo validation which led to the advancement of CK-1827452. The recent initiation of a Phase I clinical trial for this drug candidate is an important step forward for Cytokinetics and this program."
Development Status of CK-1827452
CK-1827452, a novel, small-molecule, direct activator of cardiac myosin, is currently in a Phase I clinical trial. The first-in-humans Phase I clinical trial is a double-blind, randomized, placebo-controlled, dose-escalation study being conducted to investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of CK-1827452 in normal healthy volunteers. The clinical trial is designed to identify the maximum tolerated dose of a 6-hour intravenous infusion of CK-1827452. The effect of CK-1827452 on the left ventricular function of these healthy volunteers will be evaluated using serial echocardiograms. The cross-over design of this clinical trial will ensure that each volunteer will serve as his own control to compare the effects of escalating doses of CK-1827452 to those of placebo. The clinical trial is being conducted under a Clinical Trial Application at a clinical investigative center in the United Kingdom.
Background on Cardiac Contractility and Cardiac Myosin Activators
Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into mechanical force, resulting in cardiac contraction. Cardiac contractility is driven by the cardiac sarcomere, the fundamental unit of muscle contraction in the heart that is a highly ordered cytoskeletal structure composed of cardiac myosin, actin and a set of regulatory proteins. The sarcomere represents one of the most thoroughly characterized protein machines in human biology.
Cytokinetics' heart failure program is focused towards the discovery and development of small molecule cardiac myosin activators in order to create next-generation treatments to manage acute and chronic heart failure. Cytokinetics' program is based on the hypothesis that activators of cardiac myosin may address certain mechanistic liabilities of existing pharmaceuticals by increasing cardiac contractility without increasing intracellular calcium and without stimulating beta-adrenergic receptors or inhibiting phosphodiesterase activity, mechanisms that may be arrhythmogenic and associated with other adverse clinical effects. Existing drugs that seek to improve cardiac cell contractility increase the concentration of intracellular calcium, which indirectly activates cardiac myosin, but this effect on calcium levels also has been linked to potentially life threatening arrhythmias. In contrast, cardiac myosin activators have been shown to work by a novel mechanism that directly stimulates the activity of the cardiac myosin motor protein by accelerating the rate-limiting step of the myosin enzymatic cycle, thereby shifting the enzymatic cycle in favor of the force producing state.
About Cytokinetics
Cytokinetics is a leading biopharmaceutical company focused on the discovery, development and commercialization of novel small molecule drugs that specifically target the cytoskeleton. The cytoskeleton is a complex biological infrastructure that plays a fundamental role within every human cell. Cytokinetics' focus on the cytoskeleton enables it to develop novel and potentially safer and more effective classes of drugs directed at treatments for cancer, cardiovascular disease and other diseases. Cytokinetics has developed a cell biology driven approach and proprietary technologies to evaluate the function of many interacting proteins in the complex environment of the intact human cell.
Cytokinetics employs the PUMA
Cytokinetics and GlaxoSmithKline have entered into a strategic alliance to discover, develop and commercialize small molecule therapeutics targeting human mitotic kinesins for applications in the treatment of cancer and other diseases. GlaxoSmithKline is conducting Phase II and Phase Ib clinical trials for ispinesib (SB-715992) and a Phase I clinical trial for SB-743921, each a drug candidate that has emerged from the strategic alliance.
Cytokinetics' heart failure program is the second program to leverage the company's expertise in cytoskeletal pharmacology. Cytokinetics recently initiated a Phase I clinical trial with CK-1827452, a novel small molecule cardiac myosin activator, for the treatment of heart failure. Additional information about Cytokinetics can be obtained at www.cytokinetics.com.
This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the "Act"). Cytokinetics disclaims any intent or obligation to update these forward-looking statements, and claims the protection of the Safe Harbor for forward-looking statements contained in the Act. Examples of such statements include, but are not limited to, statements relating to the statements regarding the potential benefits of our drug candidates and potential drug candidates and the enabling capabilities of our proprietary technologies and biological focus. Such statements are based on management's current expectations, but actual results may differ materially due to various factors. Such statements involve risks and uncertainties, including, but not limited to, those risks and uncertainties relating to development, testing, regulatory approval, production and marketing of Cytokinetics' drug candidates that could slow or prevent clinical development, product approval or market acceptance.
For further information regarding these and other risks related to Cytokinetics' business, investors should consult Cytokinetics' filings with the Securities and Exchange Commission.
Contacts:
Cytokinetics, Incorporated
Robert I. Blum
EVP, Corporate Development and Commercial Operations & CBO
(650) 624-3000
Burns McClellan, Inc.
Clay Kramer (investors)
Justin Jackson (media)
(212) 213-0006