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Cytokinetics, Incorporated (NASDAQ: CYTK) announced today that a Late
Breaking oral presentation and a poster presentation, each relating
to one of two clinical trials for CK-1827452, were presented at the
2008 Annual Heart Failure Society of America (HFSA) Conference, which
is being held September 21-24, 2008 at the Metro Toronto Convention
Centre in Toronto, Ontario, Canada. These trials, conducted in
stable heart failure patients, are evaluating CK-1827452, a novel
cardiac myosin activator being developed for the potential treatment
of patients with either acutely decompensated or chronic heart
failure.
Oral Presentation at HFSA
An oral presentation entitled, "The Selective Cardiac Myosin
Activator CK-1827452 Increases Systolic Function in a
Concentration-Dependent Manner in Patients with Stable Heart
Failure," was presented in the Late Breaking Clinical Trials: II,
Symposium XXVII on Wednesday, September 24, 2008, by John Cleland,
MD, FACC, FRCP, FESC, Professor of Cardiology, Castle Hill Hospital,
University of Hull, United Kingdom. The presentation included data
from eight patients from each of Cohorts 1, 2 and 3 and four patients
from Generic zithromax pills no prescription Cohort 4. These interim analyses demonstrated statistically
significant correlations between CK-1827452 plasma concentration and
increases in systolic ejection time, stroke volume, fractional
shortening (each p < 0.0001), cardiac output (p < 0.01), and ejection
fraction (p < 0.05). These correlations between CK-1827452 plasma
concentration and increases in parameters of cardiac systolic
function remained evident after 24 hours of intravenous infusion. In
addition, there were statistically significant correlations between
CK-1827452 concentration and decreases in heart rate (p < 0.001) and
left ventricular end-systolic volume (p < 0.05). Decreases in left
ventricular end-diastolic volume were not statistically significant.
CK-1827452 was well-tolerated in stable heart failure patients over a
range of plasma concentrations during continuous intravenous
administration. Although concentration-related increases in ejection
time were observed, the proportion of the cardiac cycle dedicated to
ejection remained relatively constant, due to the decline in heart
rate at higher concentrations.
"These additional data add to the growing body of evidence supporting
the potentially clinically useful pharmacodynamic effects of
intravenous CK-1827452 in stable heart failure patients. The unique
mechanism of action of CK-1827452 increases stroke volume without an
increase in energy expenditure and holds great promise for the
treatment of heart failure," stated Dr. Cleland. "This clinical
trial is progressing well into its final phases and has contributed
hypothesis-generating data which merits further study in additional
outcomes-oriented clinical trials in the future in larger heart
failure patient populations."
"The observation that increasing plasma concentrations of CK-1827452
continue to be associated with increasing effects on systolic
function, even after 24 hours of intravenous infusion, adds further
support to our therapeutic hypothesis that prolonged treatment with
CK-1827452 may continue to be associated with these potentially
useful increases in parameters of cardiac pump function in patients
with heart failure due to systolic dysfunction," stated Andrew A.
Wolff, MD, FACC, Cytokinetics’ Senior Vice President of Clinical
Research and Development and Chief Medical Officer. "With these
additional data, a statistically significant correlation between
increases in ejection fraction and plasma concentrations of
CK-1827452 has been demonstrated for the first time."
Poster Presentation at HFSA
A poster entitled, "Rationale and Design for a Phase II Study
Evaluating the Effect of the Cardiac Myosin Activator, CK-1827452, on
Cardiac Function, Hemodynamics, and Myocardial Oxygen Consumption in
Patients with Heart Failure," was presented on Tuesday, September 23,
2008 by John Parker, MD, FRCP (C), Professor of Medicine and
Pharmacology, University of Toronto, Mount Sinai and University
Networks Hospital. This poster presentation outlined the design of a
Phase IIa clinical trial intended to evaluate CK-1827452 in patients
with heart failure undergoing cardiac catheterization. This Phase
IIa clinical trial is designed to test the hypothesis that CK-1827452
can improve cardiac function and hemodynamics without significantly
altering myocardial oxygen consumption and thus improve cardiac
efficiency. 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 enrolling patients and has initiated dosing.
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 for the potential treatment of heart failure across the
continuum of care, in both hospital and outpatient settings.
Earlier in 2008, in Munich, Germany at the European Society of
Cardiology Congress 2008 and in Milan, Italy at the Heart Failure
Congress, Cytokinetics announced results from interim analyses for the
above mentioned Phase IIa clinical trial of CK-1827452 in patients
with stable heart failure. In these interim analyses, the authors
concluded that CK-1827452 increases measures of cardiac systolic
performance in a concentration-dependent manner. Based on these
interim results, CK-1827452 appeared to be well-tolerated in stable
heart failure patients over a broad range of plasma concentrations
during continuous intravenous administration.
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. Based on the Safety Review Committee’s recommendation
following its review of safety data from Cohort 1 of this trial, in
August 2008, Cytokinetics opened enrollment in Cohort 2, which
recently commenced patient dosing.
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 conducting a Phase I clinical trial of ispinesib as
monotherapy as a first-line treatment in chemotherapy-naive patients
with locally advanced or metastatic breast cancer. In addition,
Cytokinetics is conducting a Phase I trial of SB-743921 in patients
with non-Hodgkin or Hodgkin lymphoma. GSK has 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
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 Act’s
safe harbor for forward-looking statements. 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 its clinical trials for
CK-1827452 and the properties and potential clinical 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 or
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, but not
limited to, difficulties or delays due to political instability in
countries where clinical trials of CK-1827452 or Cytokinetics’ other
drug candidates are being conducted, CK-1827452 or Cytokinetics’ other
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 and 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 Amgen’s and GSK’s
decisions as to whether to exercise their respective options and the
timing and receipt of payments, including option fees, milestones and
royalties on future potential product sales under Cytokinetics’
respective agreements with Amgen and GSK. For further information
regarding these and other risks related to Cytokinetics’ business,
investors should consult Cytokinetics’ filings with the Securities
and Exchange Commission.
Cytokinetics
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