Cytokinetics Announces Publications Relating to Fast Skeletal Troponin Activation in Nemaline Myopathy
(Thomson Reuters ONE) -
Translational Research Suggests a New Therapeutic Approach to Rare Muscle
Disease
South San Francisco, CA, June 4, 2013 - Cytokinetics, Incorporated (Nasdaq:
CYTK) announced the publication of three peer-reviewed manuscripts co-authored
by company scientists with a group led by Dr. Henk Granzier, Professor of
Physiology, and Norville Endowed Chair, Molecular Cardiovascular Research
Program, University of Arizona. These publications relate to translational
research conducted by Dr. Granzier's laboratory in collaboration with
Cytokinetics in which the mechanistic effects of fast skeletal troponin
activation were explored in nemaline myopathy, a rare sarcomere-based disease.
Nemaline myopathy is an inherited disease that leads to skeletal muscle weakness
and decreased muscle tone (hypotonia) in the muscles of the face, neck and upper
limbs, and often affects the respiratory muscles. The preclinical studies
described in these publications provide support for the hypothesis that CK-
2066260, a fast skeletal troponin activator, may compensate in part for the
defect in sarcomere calcium sensitivity found in muscle derived both from mouse
models of nemaline myopathy as well as human muscle from patients with nemaline
myopathy. These findings suggest that fast skeletal troponin activators may
offer a promising therapeutic approach to improving muscle function in nemaline
myopathy and other inherited conditions in which the calcium sensitivity of the
sarcomere is abnormal.
"Our collaboration with Cytokinetics has revealed a potentially important new
opportunity in the treatment of nemaline myopathy," stated Dr. Granzier. "These
publications also underscore the possibility that fast skeletal troponin
activation may be useful to improve muscle function in a diversity of patients
with muscle disorders that relate to abnormal calcium sensitivity in the
sarcomere and in whom their disease manifests as debilitating muscle weakness
and persistent fatigue."
"We are very pleased to report the results of our collaboration with Dr.
Granzier's group that demonstrate that fast skeletal troponin activators may
have therapeutic application in primary skeletal muscle myopathies," stated Fady
I. Malik, MD, PhD, FACC, Cytokinetics' Senior Vice President, Research and Early
Development. "These findings suggest potential opportunities for broadening the
therapeutic application of fast skeletal troponin activators and may have
important implications for patients for whom treatment options are limited."
CK-2066260 is a structural analog of tirasemtiv, Cytokinetics' lead drug
candidate arising from the company's skeletal muscle contractility program
directed to neuromuscular diseases. Tirasemtiv selectively activates the fast
skeletal troponin complex by increasing its sensitivity to calcium, thereby
increasing skeletal muscle force in response to neuronal input and delaying the
onset and reducing the degree of muscle fatigue. Cytokinetics is evaluating
tirasemtiv as a potential treatment for amyotrophic lateral sclerosis (ALS) in
BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional
Improvement with Tirasemtiv in ALS), an ongoing international Phase IIb clinical
trial.
Publications Regarding Fast Skeletal Troponin Activation in Nemaline Myopathy
The publication titled, "Fast Skeletal Muscle Troponin Activation Increases
Force of Mouse Fast Skeletal Muscle and Ameliorates Weakness Due to Nebulin-
Deficiency," appeared in the February 2013 PLOS One journal and discusses the
effects on muscle strength of fast skeletal troponin activation in mice with a
complete deficiency of the sarcomeric protein, nebulin. The authors concluded
that CK-20660260 increased muscle force at submaximal activation in both wild-
type and nebulin deficient muscle fiber bundles and that fast skeletal troponin
activation is a potential therapeutic mechanism for increasing force in nemaline
myopathy and other skeletal muscle diseases characterized by diminished muscle
strength.
The publication titled, "Deleting Exon 55 from the Nebulin Gene Induces Severe
Muscle Weakness in a Mouse Model for Nemaline Myopathy," appeared in the May
2013 online publication of the journal Brain. The publication presents data
from a mouse model in which only part of the nebulin gene (exon 55) is deleted
in order to model a mutation frequently seen in patients with nemaline myopathy.
This model allowed, for the first time, a detailed and comprehensive
investigation of the impact on muscle function caused by a nebulin mutation.
The results indicate that the phenotype of this mouse model recapitulates
important features observed previously in patients harboring this particular
mutation. Severe muscle weakness and a reduction in the calcium sensitivity of
the sarcomere characterize the phenotype of both the mouse model and patients.
The authors concluded that these deficits in muscle function in part could be
mitigated by CK-2066260 as it augmented the response of muscle in this model to
calcium.
The publication titled "Troponin Activator Augments Muscle Force in Nemaline
Myopathy Patients with Nebulin Mutations," appears in the June 2013 issue of the
Journal of Medical Genetics and highlights the ability of CK-2066260 to augment
force generation at submaximal calcium levels in muscle tissue obtained from
biopsies of nemaline myopathy patients with nebulin mutations. The authors
found that nebulin protein concentrations were severely reduced in muscle cells
from these patients compared to controls, while myofibrillar ultrastructure was
largely preserved. Both maximal active tension and the calcium sensitivity of
force generation were lower in patients compared to controls. CK-2066260
increased the calcium-sensitivity of muscle force generation and at sub-maximal
calcium activation, the levels of force exceeded those observed in untreated
control muscles. The authors concluded that fast skeletal troponin activation
may be a therapeutic mechanism to augment contractile protein function in
nemaline myopathy patients with nebulin mutations and with other neuromuscular
diseases.
Background on Fast Skeletal Muscle Activators
Skeletal muscle contractility is driven by the sarcomere, the fundamental unit
of skeletal muscle contraction. It is a highly ordered cytoskeletal structure
composed of several key proteins. The first, skeletal muscle myosin, is the
cytoskeletal motor protein that converts chemical energy into mechanical force
through its interaction with a second protein, actin. A set of regulatory
proteins, which includes tropomyosin and several types of troponin, make the
actin-myosin interaction dependent on changes in intracellular calcium levels.
Cytokinetics' skeletal muscle contractility program is focused to the discovery
and development of small molecule skeletal sarcomere activators and leverages
Cytokinetics' expertise gained from its ongoing discovery and development of
cardiac sarcomere activators, including the cardiac myosin activator omecamtiv
mecarbil, now in Phase IIb clinical development as a potential treatment for
heart failure. In non-clinical models, skeletal sarcomere activators have
demonstrated pharmacological activity that may lead to new therapeutic options
for diseases associated with aging, muscle wasting, and neuromuscular
dysfunction. The clinical effects of muscle wasting, fatigue and loss of
mobility can range from decreased quality of life to, in some instances, life-
threatening complications. By directly improving skeletal muscle function, a
small molecule activator of the skeletal sarcomere may potentially enhance
physical performance and quality of life in patients with conditions marked by
muscle weakness, including neuromuscular diseases such as ALS, myasthenia
gravis, cachexia, sarcopenia and general frailty associated with aging.
Development Status of Tirasemtiv in ALS
Tirasemtiv (formerly CK-2017357) is currently being evaluated in BENEFIT-ALS, an
international, double-blind, randomized, placebo-controlled, Phase IIb clinical
trial designed to evaluate the safety, tolerability and potential efficacy of
this novel drug candidate in patients with ALS. BENEFIT-ALS is designed to
enroll approximately 500 patients who will first complete one week of treatment
with open-label tirasemtiv at 125 mg twice daily. Following completion of the
open-label period, patients will be randomized to receive 12 weeks of double-
blind treatment with twice-daily oral ascending doses of tirasemtiv beginning at
125 mg twice daily and increasing weekly up to 250 mg twice daily or a dummy
dose titration with placebo. Clinical assessments will take place monthly during
the course of treatment; patients will also participate in follow-up evaluations
one and four weeks after their final dose. The primary efficacy analysis of
BENEFIT-ALS will compare the mean change from baseline in the ALS Functional
Rating Scale in its revised form (ALSFRS-R) on tirasemtiv versus placebo.
Secondary endpoints will include Maximum Voluntary Ventilation (MVV) and other
measures of respiratory and skeletal muscle function. Patients taking riluzole
at the time of enrollment and who are randomized to receive tirasemtiv will
receive riluzole at a reduced dose of 50 mg daily.
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 (excluding Japan) to develop and commercialize omecamtiv
mecarbil and related compounds, subject to Cytokinetics' specified development
and commercialization participation rights. Cytokinetics is independently
developing tirasemtiv and CK-2127107, both fast skeletal muscle activators, as
potential treatments for diseases and medical conditions associated with aging,
muscle wasting or neuromuscular dysfunction. Tirasemtiv is currently 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, a debilitating disease of
neuromuscular impairment in which treatment with tirasemtiv produced potentially
clinically relevant pharmacodynamic effects in Phase II trials. 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 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 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 conduct, design, enrollment, progress and results of clinical
trials, the significance and utility of preclinical study and clinical trial
results; and the properties and potential benefits of Cytokinetics' skeletal
sarcomere activators, including tirasemtiv. 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: Cytokinetics
anticipates that it will be required to conduct at least one confirmatory Phase
III clinical trial of tirasemtiv in ALS patients which will require significant
additional funding, and it may be unable to obtain such additional funding on
acceptable terms, if at all; potential difficulties or delays in the
development, testing, regulatory approvals for trial commencement, progression
or product sale or manufacturing, or production of Cytokinetics' 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, 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; Amgen's decisions with respect to the
design, initiation, conduct, timing and continuation of development activities
for omecamtiv mecarbil; Cytokinetics may incur unanticipated research and
development and other costs or be unable to obtain additional financing
necessary to conduct development of its products; Cytokinetics may be unable to
enter into future collaboration agreements for its drug candidates and programs
on acceptable terms, if at all; standards of care may change, rendering
Cytokinetics' drug candidates obsolete; competitive products or alternative
therapies may be developed by others for the treatment of indications
Cytokinetics' drug candidates and potential drug candidates may target; and
risks and uncertainties relating to the timing and receipt of payments from its
partners, including milestones and royalties on future potential product sales
under Cytokinetics' 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.
Contact:
Cytokinetics, Inc.
Joanna L. Goldstein (Investors & Media)
(650) 624-3000
This announcement is distributed by Thomson Reuters on behalf of
Thomson Reuters clients. The owner of this announcement warrants that:
(i) the releases contained herein are protected by copyright and
other applicable laws; and
(ii) they are solely responsible for the content, accuracy and
originality of the information contained therein.
Source: Cytokinetics, Inc. via Thomson Reuters ONE
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Datum: 04.06.2013 - 13:30 Uhr
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