SOUTH SAN FRANCISCO, Calif., Dec. 14 /PRNewswire-FirstCall/ -- Cytokinetics, Incorporated announced today that seven posters relating to the company’s research activities were presented this week at the 45th Annual American Society of Cell Biology (ASCB) Meeting in San Francisco. Two of the poster presentations relate to the company’s heart failure program and five additional poster presentations relate to other research activities in the area of the cytoskeleton.
The presentations related to the company’s heart failure program were as follows:
-- “In Vitro and In Vivo Efficacy of the Cardiac Myosin Activator CK-1827452,” was presented on Tuesday, December 13, 2005. This presentation covered the characterization of CK-1827452, the company’s novel small molecule activator of cardiac myosin, in in vitro and in vivo studies. In biochemical studies, CK-1827452 was shown to selectively activate cardiac myosin. In isolated cardiac myocytes, CK-1827452 increased contractility without changes in the cellular calcium transient or inhibition of phosphodiesterase activity. In addition, CK-1827452 improved cardiac contractility in a rat model of heart failure. The poster presentation provides further non-clinical support for the novel mechanism of directly stimulating the activity of the cardiac myosin motor protein as a potential next-generation approach to managing acute and chronic heart failure. In addition, the presentation summarized findings that are consistent with the hypothesis that CK-1827452 may address certain mechanistic liabilities of existing pharmaceuticals by increasing cardiac contractility without increasing intracellular calcium or inhibiting phosphodiesterase activity, each of which may be associated with adverse clinical effects.
-- “A Multiplexed and Automated Imaging Assay of Cardiac Myocyte Contractility,” also was presented on Tuesday, December 13, 2005. This presentation described the proprietary automated cardiac myocyte imaging assay invented by Cytokinetics and utilized to characterize small molecule compounds in its heart failure program. While cardiac myocyte contractility has traditionally been measured using single fiber assays, Cytokinetics has developed and uses a parallel approach in which multiple cells are individually measured and multiple conditions are tested in computer-controlled experiments that employ custom software for image acquisition and analysis. The assay achieves a throughput of more than a thousand cells per experimentalist-day, providing increased throughput, statistical power and quantitative measurement of the effects of small molecule compounds on cardiac myocyte contractility compared to traditional approaches. The platform may be adaptable to other assays, cell types and imaging modalities.
“We are pleased to have the opportunity to present these non-clinical data for CK-1827452 and the details on the cell-imaging technology that we have integrated into the discovery and optimization paradigm for our heart failure program,” stated David J. Morgans, Jr., Ph.D., Cytokinetics’ Senior Vice President of Drug Discovery and Development. “The in vitro and in vivo findings for CK-1827452 complement the non-clinical data from a dog model of heart failure that we recently presented at the 2005 Annual Heart Failure Society of America Meeting in September. The description of our automated cardiac myocyte imaging assay illustrates an elegant and sophisticated approach for the use of these primary cells in a relatively high throughput lead optimization effort.”
Other Presentations
The five additional poster presentations relate to the company’s efforts to develop and successfully use biochemical and cell-based imaging assays to identify and characterize small molecule modulators of multiple classes of cytoskeletal proteins. In addition to providing valuable insight to advance drug discovery and development efforts, the small molecule compounds identified using these assays may prove useful as tools in elucidating the identity, roles and regulation of cytoskeletal proteins involved in various processes, such as actin and microtubule dynamics in pathogens including various Candida species, E. coli, Mycobacterium tuberculosis, Staphylcoccus aureus and Listeria.
“These poster presentations reflect our focus on cytoskeletal pharmacology,” stated Jay Trautman, Ph.D., Cytokinetics’ Vice President of Discovery Biology and Technology. “We are pleased to present data from our early stage research efforts into new biologies, underscoring our expertise in the cytoskeleton.”
Development Status of CK-1827452
CK-1827452, a novel, small-molecule, direct activator of cardiac myosin, is currently in a Phase I, first-in-humans clinical trial for treatment of acute heart failure. The 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 allows each volunteer to 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 Authorization at a clinical investigative center in the United Kingdom.
In addition, Cytokinetics recently announced the selection of CK-1827452 as a development candidate for the potential treatment of patients with chronic heart failure treated in an outpatient setting. Pharmacokinetic data arising from the ongoing Phase I clinical trial evaluating an intravenous formulation of CK-1827452 confirms that it has a sufficiently long half-life to support development of an oral dosing formulation. Additional preclinical studies to support oral dosing in humans with CK-1827452 are currently underway. Following successful completion of the enabling preclinical studies, Cytokinetics intends to submit a regulatory filing for the initiation of a Phase I clinical trial meant to confirm in humans the bioavailability seen in preclinical species with an orally administered formulation of CK-1827452.
Background on Cardiac Myosin Activators and Cardiac Contractility
Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the 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 positive inotropic agents by increasing cardiac contractility without stimulating beta-adrenergic receptors inhibiting phosphodiesterase activity to increase intracellular calcium, each of which may be associated with adverse clinical effects in heart failure patients. 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 side effects. 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 and thereby shifting the enzymatic cycle in favor of the force producing state.
Background on the Cytoskeleton
The cytoskeleton is a diverse, multicomponent framework upon which the cell interior is ordered. As such it plays a fundamental role in all aspects of cell mechanics including cell division, intracellular transport, cell motility and the establishment and regulation of cell polarity and organization. In many ways, this framework can be considered to be analogous to a highly organized city plan, where cellular activities are regulated in systematized locations connected by highways upon which components are transported by motor cars. However, in the case of cells, the cytoskeletal highways are protein structures called microtubules and microfilaments and the motor cars are enzymes, termed molecular motors, which more recently have been discovered to generate the mechanical forces critical to cellular function. The cytoskeleton has been implicated in a variety of disease pathologies, ranging from cancer to cardiovascular diseases to infectious diseases.
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(TM) system and Cytometrix(TM) technologies to enable early identification and automated prioritization of compounds that are highly selective for their intended protein targets without other cellular effects, and may therefore be less likely to give rise to clinical side effects. 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 human 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 expected regulatory filings and potential future clinical trials concerning CK-1827452, and statements relating to 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 difficulties or delays in development, testing, regulatory approval, production and marketing of Cytokinetics’ drug candidates that could slow or prevent clinical development or product approval (including the risks relating to uncertainty of patent protection for Cytokinetics’ intellectual property or trade secrets, Cytokinetics’ ability to obtain additional financing if necessary and unanticipated research and development and other costs). For further information regarding these and other risks related to Cytokinetics’ business, investors should consult Cytokinetics’ filings with the Securities and Exchange Commission.
Cytokinetics, Incorporated
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