Cardiology
Cardiac Myosin Activators : Next-Generation Agents in Treatment of Acute Heart Failure
By Akanksha, Pharmacology Correspondent
Mar 4, 2005, 09:27

Cytokinetics, Inc. announced today that it has recently selected a compound arising from its heart failure drug discovery program for development. The selected compound is currently in preclinical studies. Based on the successful completion of the preclinical program, Cytokinetics intends to submit a regulatory filing for the initiation of first-time-in-human clinical studies in 2005.

Cytokinetics' heart failure program focuses on the discovery and development of small molecules that directly activate cardiac myosin, a cytoskeletal protein that drives cardiac muscle contractility.

This mechanism of action results in increased cardiac contractility without increasing intracellular calcium or inhibiting phosphodiesterase activity, which are properties of existing pharmaceuticals that may be associated with adverse clinical effects in heart failure patients.

Cardiac myosin activators represent a potential next-generation approach to the treatment of acute and chronic congestive heart failure.

This newly advanced compound replaces another cardiac myosin activator identified in 2004 as the lead drug candidate arising from this program.

Cytokinetics had nominated that particular compound for development while continuing to further optimize other compounds in this series. Through this process, the company identified this newer compound that additional research has demonstrated to be a more attractive drug candidate for pharmaceutical development due to properties that include improved potency, tolerability, pharmacokinetics and pharmaceutics.

These properties increase the possibility of developing a novel, next-generation pharmaceutical for the treatment of acute heart failure, while still providing opportunity for exploration of this class of compounds in the treatment of chronic heart failure.

"We are excited about the potential for this compound," stated James H. Sabry, M.D., Ph.D., Cytokinetics' President and Chief Executive Officer. "Cytokinetics' expertise in cytoskeletal pharmacology has now generated a development compound with potential application as a next-generation treatment for both acute and chronic heart failure patients. This achievement provides further validation of our cytoskeletal pharmacology platform which has generated development stage compounds in two distinct therapeutic areas, heart failure and cancer."

"The selection of this compound represents an important step forward for the development of activators of cardiac myosin as novel therapeutics in the treatment of heart failure," said David J. Morgans, Jr., Ph.D., Cytokinetics' Senior Vice President of Drug Discovery and Development.

"Through an extensive optimization process, we identified and characterized a broad array of compounds in order to inform our decision to advance this particular drug candidate. As a result, we now have a greater knowledge base of multiple compounds that act by this novel mechanism and have generated an extensive data set on our selected drug candidate which may improve our ability to conduct clinical trials in this area. In addition, we can now explore the potential for this class of compounds in the treatment of chronic heart failure."

Congestive heart failure is a widespread disease affecting approximately five million people in the United States alone. The high and rapidly growing prevalence of congestive heart failure translates into significant hospitalization rates and associated societal costs.

The number of hospital discharges in the United States identified with a primary diagnosis of congestive heart failure rose from 550,000 in 1989 to 970,000 in 2002. Congestive heart failure is one of the most common primary discharge diagnoses identified in hospitalized patients over the age of 65 in the United States.

The annual costs of congestive heart failure in the United States are estimated to be $27.9 billion, including $18.3 billion for inpatient care. The market for congestive heart failure drugs was approximately $2.7 billion in 2001, according to industry reports. Despite currently available therapies, readmission rates for patients over the age of 65 remains high at 30 to 40 percent within six months of hospital discharge and mortality rates over an eight-year period range from 70% to 80% for patients under the age of 65.

The limited effectiveness of current therapies points to the need for next-generation agents with improved efficacy without increased adverse events.

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 congestive 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 or inhibiting phosphodiesterase activity, 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.

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