Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that data
from two preclinical studies of reldesemtiv were presented at the
2019 Annual Cure SMA Conference in Anaheim, CA, showing that the
addition of reldesemtiv to treatment with SMN upregulators
(nusinersen and SMN-C1, an analogue to risdiplam) significantly
increased muscle force in a mouse model of spinal muscular atrophy
(SMA). In collaboration with Astellas, Cytokinetics is developing
reldesemtiv, a fast skeletal muscle troponin activator (FSTA), as a
potential treatment for people with SMA and certain other
debilitating diseases and conditions associated with skeletal
muscle weakness and/or fatigue.
“Advancements in the treatment landscape for SMA
have demonstrated positive effects to improve nerve and muscle
function and to extend lifespan for people with SMA; however,
substantial residual muscle weakness persists,” said Fady I. Malik,
M.D., Ph.D., Cytokinetics’ Executive Vice President, Research and
Development. “Data from these preclinical studies suggest that
reldesemtiv may complement SMN-directed therapies to further
improve muscle function, especially for routine activities that may
be fatiguing and don’t require maximum exertion.”
Preclinical Research
In one preclinical study, a cohort of Hung Li
SMA mice were treated with nusinersen alone or with nusinersen plus
reldesemtiv. In another preclinical study, a cohort of Hung Li SMA
mice were treated with either SMN-C1 alone or SMN-C1 plus
reldesemtiv. In both studies, the mice were evaluated using an in
vivo plantar flexor assay measuring isometric muscle force
production in response to sciatic nerve stimulation of 10 Hz-200
Hz.
Hung Li SMA mice treated with nusinersen (40, 80
and 160 µg/g) showed increased body weight, tail length and muscle
mass, confirming efficacy of treatment. In addition, nusinersen
produced dose-dependent increases in muscle force in response to
nerve stimulation. The administration of single doses of
reldesemtiv further increased muscle force in response to
sub-tetanic nerve stimulation in all groups of Hung Li SMA mice
treated with nusinersen. At a submaximal stimulation frequency of
50 Hz, treatment of Hung Li SMA mice with nusinersen (160 µg/g) and
reldesemtiv (30 mg/kg) significantly increased muscle force by 290%
(p<0.0001) relative to control Hung Li SMA mice in comparison to
100% (p<0.05) relative to control in Hung Li SMA mice treated
with nusinersen alone.
Hung Li SMA mice treated with SMN-C1 (10 mg/kg)
showed increased survival, body weight and muscle mass also
confirming the efficacy of treatment. In addition, treatment with
SMN-C1 increased muscle force in response to nerve stimulation. The
administration of single doses of reldesemtiv further increased
muscle force in response to sub-tetanic nerve stimulation in Hung
Li SMA mice treated with SMN-C1. At a submaximal stimulation
frequency of 50 Hz, treatment of Hung Li SMA mice with SMN-C1 (10
mg/kg) and reldesemtiv (30 mg/kg) significantly increased muscle
force by 320% (p<0.0001) relative to control Hung Li SMA mice in
comparison to 32% (p<0.05) relative to control in Hung Li SMA
mice treated with SMN-C1 alone.
In these studies, the addition of reldesemtiv to
either nusinersen or SMN-C1 resulted in a leftward shift of the
force-frequency curve, indicating an increase in calcium
sensitivity of the muscle at submaximal stimulation frequencies and
confirming the efficacy of fast skeletal muscle activation in
muscle in conjunction with SMN upregulators. Augmentation of muscle
force at submaximal stimulation frequencies may be relevant to
activities such as breathing and walking. These data suggest that
treatment with reldesemtiv in combination with an SMN upregulating
therapy such as nusinersen or SMN-C1, may complement and further
improve muscle function in SMA.
Nusinersen is an approved anti-sense
oligonucleotide therapy for SMA that increases production of
Survival Motor Neuron (SMN) protein. SMN-C1 is a small molecule
therapy that increases SMN protein expression, similar to
risdiplam, an investigational treatment in development for SMA.
About Reldesemtiv
Skeletal muscle contractility is driven by the
sarcomere, the fundamental unit of skeletal muscle contraction and
a highly ordered cytoskeletal structure composed of several key
proteins. Skeletal muscle myosin is the motor protein that converts
chemical energy into mechanical force through its interaction with
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. Reldesemtiv, a next-generation FSTA arising from
Cytokinetics’ skeletal muscle contractility program, slows the rate
of calcium release from the regulatory troponin complex of fast
skeletal muscle fibers, which sensitizes the sarcomere to calcium,
leading to an increase in skeletal muscle
contractility. Reldesemtiv has demonstrated
pharmacological activity that may lead to new therapeutic options
for diseases associated with skeletal muscle weakness and fatigue.
In non-clinical models of spinal muscular atrophy, a skeletal
muscle activator increased submaximal skeletal muscle force and
power in response to neuronal input and delayed the onset and
reduced the degree of skeletal muscle
fatigue. Reldesemtiv has been the subject of five
completed Phase 1 clinical trials in healthy volunteers, which
evaluated the safety, tolerability, bioavailability,
pharmacokinetics and pharmacodynamics of the drug candidate.
Mid-stage clinical trials in patients with SMA, ALS, COPD and
elderly adults with limited mobility have been completed. In the
Phase 2 hypothesis-generating clinical study in patients with SMA,
patients treated with reldesemtiv demonstrated increases
in measures of endurance and stamina consistent with the mechanism
of action.
About SMA
SMA is a severe, genetic neuromuscular disease
that leads to debilitating muscle function and progressive, often
fatal, muscle weakness. It occurs in 1 in 6,000 to 10,000 live
births each year and is one of the most common potentially fatal
genetic disorders. Spinal muscular atrophy manifests in various
degrees of severity as progressive muscle weakness resulting in
respiratory and mobility impairment. There are four types of SMA,
named for age of initial onset of muscle weakness and related
symptoms: Type 1 (Infantile), Type 2 (Intermediate), Type 3
(Juvenile) and Type 4 (Adult onset). Of the prevalent population,
approximately 80% of the patients are characterized as Type 2 and
Type 3. Life expectancy and disease severity vary by type of SMA.
Type 1 patients have the worst prognosis, with a life expectancy of
no more than two years unless treated with SMN-directed therapies;
Type 2 patients have delayed motor milestones with the most
advanced milestone normally achieved being sitting unsupported;
Type 3 patients can usually stand and walk but have increasingly
limited mobility as their abilities regress as they age; Type 4
patients may have a normal life span but eventually suffer gradual
weakness in the proximal muscles of the extremities, eventually
resulting in mobility issues. With the recent introduction of
SMN-directed therapies, it is expected that patients may live
longer, but will still have a significant need to address ongoing
disabilities related to respiration and mobility. Approximately 50%
of Type 3 patients with SMA are believed to maintain ambulatory
function today and an increasing number of Type 2 patients with SMA
are expected to remain ambulatory with the advent of complementary
new therapies that can enable motor milestones.1 Over the next 5
years, the prevalence of ambulatory adolescents and adults with SMA
may exceed 5-10,000 patients in the United States alone.2
About Cytokinetics and Astellas
Collaboration
In 2013, Cytokinetics and Astellas formed a
partnership focused on the research, development, and potential
commercialization of skeletal muscle activators. The primary
objective of the collaboration is to advance novel therapies for
diseases and medical conditions associated with muscle impairment
and weakness. Cytokinetics initially exclusively licensed to
Astellas rights to co-develop and potentially co-commercialize
reldesemtiv and other FSTAs in non-neuromuscular indications and to
develop and commercialize other novel mechanism, skeletal muscle
activators in all indications. Under the agreement as subsequently
expanded and amended, Astellas also has exclusive rights to
co-develop and commercialize reldesemtiv and other FSTAs in certain
neuromuscular indications (including SMA and ALS). Cytokinetics has
certain development and commercialization rights, including the
right to co-promote FSTAs for neuromuscular indications in the
U.S., Canada and Europe and to co-promote the other collaboration
products in the U.S. and Canada.
About Cytokinetics
Cytokinetics is a late-stage biopharmaceutical
company focused on discovering, developing and commercializing
first-in-class muscle activators and best-in-class muscle
inhibitors as potential treatments for debilitating diseases in
which muscle performance is compromised and/or declining. As a
leader in muscle biology and the mechanics of muscle performance,
the company is developing small molecule drug candidates
specifically engineered to impact muscle function and
contractility. Cytokinetics is collaborating with Amgen Inc.
(Amgen) to develop omecamtiv mecarbil, a novel cardiac muscle
activator. Omecamtiv mecarbil is the subject of an international
clinical trials program in patients with heart failure including
GALACTIC-HF and METEORIC-HF. Amgen holds an exclusive worldwide
license to develop and commercialize omecamtiv mecarbil with a
sublicense held by Servier for commercialization in Europe and
certain other countries. Cytokinetics is collaborating with
Astellas Pharma Inc. (Astellas) to develop reldesemtiv, a fast
skeletal muscle troponin activator (FSTA) for diseases of
neuromuscular dysfunction, including SMA and ALS. Astellas
holds an exclusive worldwide license to develop and commercialize
reldesemtiv. Licenses held by Amgen and Astellas are subject to
specified co-development and co-commercialization rights of
Cytokinetics. Cytokinetics is also developing CK-274, a novel
cardiac myosin inhibitor that company scientists discovered
independent of its collaborations, for the potential treatment of
hypertrophic cardiomyopathies. Cytokinetics continues its over
20-year history of pioneering innovation in muscle biology and
related pharmacology focused to diseases of muscle dysfunction and
conditions of muscle weakness.
For additional information
about Cytokinetics, visit www.cytokinetics.com and follow
us on Twitter, LinkedIn, Facebook and YouTube.
Forward-Looking Statements
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’ and
its partners’ research and development activities; the Phase 2
clinical study of reldesemtiv in patients with SMA,
including that such results may support progression
of reldesemtiv into a potentially pivotal Phase 3
clinical trial; the potentially beneficial effects
of reldesemtiv; and the properties and potential benefits of
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, 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; Astellas’ decisions with respect
to the design, initiation, conduct, timing and continuation of
development activities
for reldesemtiv; 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, 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:CytokineticsDiane WeiserVice President, Corporate
Communications, Investor Relations(415) 290-7757
1 Zeres er al. Journal of Neurological Sciences 146 (1997)
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