SOUTH SAN FRANCISCO, CA -- 09/05/08 --
Cytokinetics, Incorporated (NASDAQ: CYTK) announced today the initiation of its third Phase IIa clinical trial
evaluating CK-1827452, a novel cardiac myosin activator being developed by
the company for the potential treatment of patients with either acutely
decompensated or chronic heart failure. CK-1827452 is the subject of a
Collaboration and Option Agreement between Cytokinetics and Amgen Inc.
This open-label Phase IIa clinical trial is designed to evaluate an
intravenous formulation of CK-1827452 in patients with stable heart failure
undergoing clinically indicated coronary angiography in the cardiac
catheterization laboratory. The primary objective of this trial is to
evaluate the potential effects of CK-1827452 on myocardial efficiency,
defined as the ratio of ventricular performance to myocardial oxygen
consumption. The secondary objectives of this trial are to measure the
potential effects of CK-1827452 on ventricular performance, myocardial
oxygen consumption, hemodynamics, pressure-volume relationships and
systolic ejection time.
Preclinical studies have suggested that CK-1827452 increases ventricular
performance in the absence of substantial changes in myocardial oxygen
consumption, thereby increasing myocardial efficiency. This trial of
CK-1827452 is designed to investigate this finding further in patients with
stable heart failure. The protocol for this clinical trial provides for
the enrollment of two cohorts of patients. The first cohort, consisting of
six patients, will undergo a dose escalation phase, beginning with a target
plasma concentration of approximately 280 ng/mL. Based on the
tolerability and pharmacodynamic effects observed in this initial cohort,
the investigators will select a single dosing regimen to administer to the
second cohort, consisting of twelve patients.
"This clinical trial is a significant step towards a fuller understanding
of the effects of CK-1827452 in patients with heart failure," stated Andrew
A. Wolff, M.D., F.A.C.C., Cytokinetics' Senior Vice President of Clinical
Research and Development and Chief Medical Officer. "Because of its novel
mechanism, this drug candidate has the potential to demonstrate properties
in this trial that could differentiate it from existing inotropic drugs."
Development Status of CK-1827452
CK-1827452 is currently the subject of a clinical trials program comprised
of multiple Phase I and Phase IIa trials. This program is designed to
evaluate the safety, tolerability, pharmacodynamics and pharmacokinetic
profile of both intravenous and oral formulations of CK-1827452 in a
diversity of patients for the potential treatment of heart failure across
the continuum of care, in both hospital and outpatient settings.
In September 2008, Cytokinetics announced positive results from an interim
analysis of its first and ongoing Phase IIa clinical trial of CK-1827452 in
patients with stable heart failure. The interim analysis included eight
patients from each of Cohorts 1 and 2 and six patients from Cohort 3.
There were statistically significant correlations between CK-1827452
concentration and increases in systolic ejection time and stroke volume,
and between CK-1827452 concentration and increases in fractional shortening
and cardiac output. Changes in ejection fraction, left ventricular
end-diastolic volume and left ventricular end-systolic volume were not
statistically significant. Heart rate declined slightly at the higher
concentrations and there were no dose-related changes in blood pressure.
Treatments were well-tolerated at pre-specified dosages. CK-1827452
appeared to be well-tolerated in stable heart failure patients over a broad
range of plasma concentrations during continuous intravenous administration
and CK-1827452 appeared to increase stroke volume, cardiac output,
fractional shortening and systolic ejection time in a
concentration-dependent manner.
In April 2008, Cytokinetics initiated a Phase IIa trial that is designed to
evaluate an intravenous formulation together with an oral formulation of
CK-1827452 in patients with ischemic cardiomyopathy and angina. The
primary objective of this double-blind, randomized, placebo-controlled
Phase IIa clinical trial is to assess the effect of intravenous CK-1827452
on
symptom-limited treadmill exercise tolerance. The secondary objective of
this trial is to assess the tolerability and resulting plasma
concentrations of CK-1827452 administered as an oral formulation. The
trial is designed to evaluate two cohorts of 45 patients each with ischemic
cardiomyopathy and angina and an ejection fraction of less than or equal to
35 percent. In August 2008, Cytokinetics opened enrollment in Cohort 2 of
this trial, based on the Safety Review Committee's recommendation following
its review of safety data from Cohort 1.
Cytokinetics has conducted five Phase I clinical trials of CK-1827452 in
healthy subjects: a first-time-in-humans study evaluating an intravenous
formulation, an oral bioavailability study evaluating both intravenous and
oral formulations, and three studies of oral formulations: a drug-drug
interaction study, a dose proportionality study and a study evaluating
modified-release formulations. Data from each of these trials have been
reported previously.
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, a highly ordered cytoskeletal structure
composed of cardiac myosin, actin and a set of regulatory proteins, and is
the fundamental unit of muscle contraction in the heart. The sarcomere
represents one of the most thoroughly characterized protein machines in
human biology. Cytokinetics' cardiovascular 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 increasing intracellular calcium. Current inotropic agents, such
as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase
activity, increase cardiac cell contractility by increasing the
concentration of intracellular calcium, which further activates the cardiac
sarcomere. This effect on calcium levels, however, also has been linked to
potentially life-threatening side effects. The inotropic mechanism of
current drugs also increases the velocity of cardiac contraction and
shortens systolic ejection time. In contrast, cardiac myosin activators
have been shown to work in the absence of changes in intracellular calcium
by a novel mechanism that directly stimulates the activity of the cardiac
myosin motor protein. Cardiac myosin activators accelerate the
rate-limiting step of the myosin enzymatic cycle and shift the enzymatic
cycle in favor of the force-producing state. This inotropic mechanism
results not in an increase in the velocity of cardiac contraction, but
instead, in a lengthening of the systolic ejection time, which results in
increased cardiac contractility and cardiac output in a potentially more
oxygen-efficient manner.
About Cytokinetics
Cytokinetics is a biopharmaceutical company focused on the discovery,
development and commercialization of novel small molecule drugs that may
address areas of significant unmet clinical needs. Cytokinetics'
cardiovascular disease program is focused to cardiac myosin, a motor
protein essential to cardiac muscle contraction. Cytokinetics' lead
compound from this program, CK-1827452, a novel small molecule cardiac
myosin activator, entered Phase II clinical trials for the treatment of
heart failure in 2007. Under a strategic alliance established in 2006,
Cytokinetics and Amgen Inc. are performing joint research focused on
identifying and characterizing activators of cardiac myosin as back-up and
follow-on potential drug candidates to CK-1827452. Amgen has obtained an
option for an exclusive license to develop and commercialize CK-1827452,
subject to Cytokinetics' development and commercial participation rights.
Cytokinetics' cancer program is focused on mitotic kinesins, a family of
motor proteins essential to cell division. Under a strategic alliance
established in 2001, Cytokinetics and GlaxoSmithKline (GSK) are conducting
research and development activities focused on the potential treatment of
cancer. Cytokinetics is developing two novel drug candidates that have
arisen from this program, ispinesib and SB-743921, each a novel inhibitor
of kinesin spindle protein (KSP), a mitotic kinesin. Cytokinetics is
sponsoring a Phase I/II clinical trial of ispinesib as monotherapy as a
first-line treatment in chemotherapy-naïve patients with locally advanced
or metastatic breast cancer. In addition, Cytokinetics is conducting a
Phase I/II trial of SB-743921 in patients with non-Hodgkin or Hodgkin
lymphomas. GSK has obtained an option for the joint development and
commercialization of ispinesib and SB-743921. Cytokinetics and GSK are
conducting collaborative research activities directed to the mitotic
kinesin centromere-associated protein E (CENP-E). GSK-923295, a CENP-E
inhibitor, is being developed under the strategic alliance by GSK; GSK
began a Phase I clinical trial with GSK-923295 in 2007. In April 2008,
Cytokinetics announced the selection of a potential drug candidate directed
towards skeletal muscle contractility which may be developed as a potential
treatment for skeletal muscle weakness associated with neuromuscular
diseases or other conditions. All of these drug candidates and potential
drug candidates have arisen from Cytokinetics' research activities and are
directed towards the cytoskeleton. The cytoskeleton is a complex biological
infrastructure that plays a fundamental role within every human cell.
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
Cytokinetics' research and development programs, including the design,
enrollment, conduct and results of clinical trials, and the properties and
potential benefits of CK-1827452 and Cytokinetics' other drug candidates
and potential drug candidates. Such statements are based on management's
current expectations, but actual results may differ materially due to
various risks and uncertainties, including, but not limited to, potential
difficulties or delays in the development, testing, regulatory approval or
production of CK-1827452 or Cytokinetics' other drug candidates that could
slow or prevent clinical development, product approval, including risks
that current and past results of clinical trials or preclinical studies may
not be indicative of future clinical trials results, patient enrollment for
or conduct of clinical trials may be difficult or delayed, including
without limitation, due to political instability in countries where
clinical trials of CK-1827452 or Cytokinetics' other drug candidates are
being conducted, Cytokinetics' drug candidates may have adverse side
effects or inadequate therapeutic efficacy, the U.S. Food and Drug
Administration or foreign regulatory agencies may delay or limit
Cytokinetics' or its partners' ability to conduct clinical trials, and
Cytokinetics may be unable to obtain or maintain patent or trade secret
protection for its intellectual property; Cytokinetics may incur
unanticipated research and development and other costs or be unable to
obtain additional financing necessary to conduct development of its
products; standards of care may change; others may introduce products or
alternative therapies for the treatment of indications CK-1827452 or
Cytokinetics' other drug candidates and potential drug candidates may
target; and risks and uncertainties relating to the timing and receipt of
payments from Cytokinetics' partners, including milestones and royalties on
future potential product sales under its collaboration agreements with such
partners. For further information regarding these and other risks related
to Cytokinetics' business, investors should consult Cytokinetics' filings
with the Securities and Exchange Commission.
Contacts:
Scott R. Jordan (Media)
Director, Corporate Development
(650) 624-3000
Christopher S. Keenan (Investors)
Director, Investor Relations
(650) 624-3000
