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Cytokinetics, Inc.: Cytokinetics Announces Three Publications Relating to Tirasemtiv and the Impact of Skeletal Muscle Activation on Respiratory Function and M

Manuscripts Support Rationale for

Potential Further Development of Tirasemtiv in Patients Living with ALS

South San Francisco, CA, May 21, 2014

Cytokinetics, Incorporated (Nasdaq: CYTK) announced the recent publication of
three peer-reviewed manuscripts relating totirasemtiv
and fast skeletal muscle troponin activation in the journalsPLOS ONE,
and theAmerican Journal of Respiratory and Critical Care Medicine
. These publications relate to pre-clinical and clinical studies conducted in
support of the development oftirasemtiv.
The reported data are consistent with results observed regarding certain
measures of respiratory function and muscle strength in BENEFIT-ALS (B
valuation ofN
ffects andF
mprovement withT

) in patients with amyotrophic lateral sclerosis (ALS). BENEFIT-ALS is the
first large Phase II clinical trial in patients with ALS to show a
statistically significant reduction in the decline of a clinically relevant
measure of respiratory function, slow vital capacity, and of a measure of
muscle strength.

"We are pleased to share additional scientific and clinical trial data that
elaborate on the mechanistic effects oftirasemtiv
and related compounds on muscle that we believe translate to demonstrable
effects on certain measures of respiratory function and muscle strength,"
stated Fady I. Malik, MD, PhD, Cytokinetics' Senior Vice President, Research
and Early Development. "We believe the results of these studies support the
rationale for further developingtirasemtiv
in patients with ALS."

Summary of Published Manuscripts

The first publication, titled "Fast Skeletal Muscle Troponin
Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse
Model," appeared in the May 7, 2014 edition ofPLOS ONE.
The objective of the study was to examine the effects oftirasemtiv
in a transgenic mouse model of ALS that expresses the mutant human superoxide
dismutase 1 (SOD1) gene responsible for an inherited form of ALS. The
B6SJL-SOD1G93Amouse develops progressive limb and body weakness eventually
culminating in full limb paralysis, morbidity and death at about 135-140 days
of life. The authors evaluated the effect of single doses oftirasemtiv
on several measures of skeletal muscle function and fatigability and of
respiratory performance. The authors concluded that a single dose
significantly increased submaximal isometric muscle force in the mouse leg,
forelimb grip strength, grid hang time, and the performance while
running/climbing on a rotating drum in mice that had developed substantial
weakness due to their disease progression. Additionally,tirasemtiv
significantly increased the force generation of isolated diaphragm muscle and
of tidal volume, a measure of how much air the mice exhale with each breath.
These effects oftirasemtiv
on measures of respiratory function in a mouse model of ALS are consistent
with the observed effects oftirasemtiv
on certain measures of respiratory function in patients with ALS.

The second publication, titled "Tirasemtiv
Amplifies Skeletal Muscle Response to Nerve Activation in Humans," appeared on
March 13, 2014 as an on-line publication in the journalMuscle&Nerve
. This paper describes findings from the Phase I first-time-in human clinical
trial oftirasemtiv
which was designed to assess the maximum tolerated dose (MTD) and the
pharmacodynamic effects oftirasemtiv
on skeletal muscle function in healthy volunteers. After completing the dose
escalation phase and determining the MTD, the study tested the hypothesis
could amplify the response of muscle to neuromuscular input in humans. Doses
(250, 500, and 1000 mg dosed orally) and placebo were administered in a
randomized, double-blind, 4-way crossover design to twelve healthy male
subjects; each dosing period was separated by at least a week. The deep
fibular nerve was stimulated transcutaneously at frequencies from 5 to 50
Hertz to activate the tibialis anterior muscle and produce dorsiflexion of
the foot. In this clinical trial,tirasemtiv
increased force produced by the tibialis anterior muscle in a dose-,
concentration-, and frequency-dependent manner with the largest increases
produced at sub-tetanic nerve stimulation frequencies. At plasma
concentrations oftirasemtiv
exceeding 12 µg/mL, the maximum placebo-corrected least-square mean percent
increase from baseline in peak muscle force was 24.5% ± 3.1 (mean ± standard
error, p<0.0001) at a stimulation frequency of 10 Hertz. These Phase I
clinical trial data support translation of the novel mechanism of action
from preclinical models to humans.

The third publication, titled "Diaphragm Fiber Strength is Reduced in
Critically Ill Patients and Restored by a Troponin Activator," appeared in
the April 2, 2014 edition of theAmerican Journal of Respiratory and Critical
Care Medicine
. The objective of the study was to understand whether contractile weakness
of diaphragm muscle fibers develops in mechanically ventilated critically ill
patients and whether fast skeletal troponin activation by a structural analog
, CK-2066260, could improve its contractile strength. The authors obtained
diaphragm biopsy samples from mechanically ventilated critically ill patients
who were undergoing laparotomy or thoracotomy. Similar samples from patients
undergoing elective lung surgery served as controls. The critically ill
patients were mechanically ventilated for an average of 210 hours compared to
only 1.6 hours for the control patients. The studies indicated that muscle
fibers from the critically ill patients were atrophied (smaller) and also
that the maximal contractile strength was substantially lower (weaker) than
muscle fibers from the control patients. The authors tested the effect of
the fast skeletal troponin activator, CK-2066260, on diaphragm muscle fiber
strength. The authors concluded that CK-2066260 increased the muscle fiber
response to calcium such that the force produced by the diaphragm fibers from
critically ill, mechanically ventilated patients was restored to the level of
force produced by the diaphragm fibers from control patients at physiological
calcium concentrations. These effects of CK-2066260 support the therapeutic
hypothesis fortirasemtiv
to potentially increase measures of pulmonary function in humans.


, a novel skeletal muscle activator, is the lead drug candidate from
Cytokinetics' skeletal muscle contractility program. Tirasemtiv
selectively activates the fast skeletal muscle troponin complex by increasing
its sensitivity to calcium and, in preclinical studies, demonstrated
increases in skeletal muscle force in response to neuronal input and delays
in the onset and reductions in the degree of muscle fatigue. BENEFIT-ALS was
a Phase IIb, multinational, double-blind, randomized, placebo-controlled
clinical trial designed to evaluate the safety, tolerability and potential
efficacy oftirasemtiv
in patients with amyotrophic lateral sclerosis (ALS). BENEFIT-ALS did not
achieve its primary efficacy endpoint, the mean change from baseline in the
ALS Functional Rating Scale in its revised form (ALSFRS-R). Treatment
resulted in a statistically significant and potentially clinically meaningful
reduction in the decline of Slow Vital Capacity (SVC), a measure of the
strength of the skeletal muscles responsible for breathing that has been
shown to be an important predictor of disease progression and survival in
prior trials of patients with ALS. The analyses of other pre-specified
secondary efficacy endpoints produced mixed results. Results from
BENEFIT-ALS were presented at the 66th Annual Meeting of the American Academy
of Neurology on April 29, 2014. Cytokinetics expects to continue to analyze
the data from BENEFIT-ALS to inform the potential further development
in patients living with ALS.

About Cytokinetics

Cytokinetics is a clinical-stage biopharmaceutical company focused on the
discovery and development of novel small molecule therapeutics that modulate
muscle function for the potential treatment of serious diseases and medical
conditions. Cytokinetics' lead drug candidate from its cardiac muscle
contractility program,omecamtiv mecarbil
, is in Phase II clinical development for the potential treatment of heart
failure. Amgen Inc. holds an exclusive license worldwide to develop and
commercializeomecamtiv mecarbil
and related compounds, subject to Cytokinetics' specified development and
commercialization participation rights. Cytokinetics is independently
, a fast skeletal muscle activator, as a potential treatment for diseases and
medical conditions associated with neuromuscular dysfunction.Tirasemtiv
is the subject of a Phase II clinical trials program and has been granted
orphan drug designation and fast track status by the U.S. Food and Drug
Administration and orphan medicinal product designation by the European
Medicines Agency for the potential treatment of amyotrophic lateral sclerosis
(ALS). Cytokinetics is collaborating with Astellas Pharma Inc. to develop
CK-2127107, a skeletal muscle activator structurally distinct fromtirasemtiv
, for non-neuromuscular indications. All of these drug candidates have arisen
from Cytokinetics' muscle biology focused 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

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
activities, including the potential significance and utility of the results
from preclinical studies and clinical trials of tirasemtiv; planned further
analyses of the results from BENEFIT-ALS and the potential outcomes of such
analyses; potential further development of tirasemtiv; and the properties and
potential benefits of skeletal muscle activators and of tirasemtiv and
Cytokinetics' other 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, the
results of BENEFIT-ALS may not support further clinical development of
tirasemtiv; further cli...

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