Cytokinetics, Incorporated (Nasdaq:CYTK) today announced data from
the Phase 2 clinical study of reldesemtiv in patients with spinal
muscular atrophy (SMA) were presented in an oral presentation by
John W. Day, M.D., Ph.D., Professor of Neurology and Pediatrics
(Genetics), Stanford University, at the 2018 Annual Cure SMA
Conference in Dallas. This hypothesis-generating study met its
primary objective to determine potential pharmacodynamic effects of
reldesemtiv after multiple oral doses in patients with SMA, and
secondary objectives to evaluate the safety, tolerability and
pharmacokinetics of reldesemtiv. In collaboration with Astellas,
Cytokinetics is developing reldesemtiv as a potential treatment for
people with SMA and certain other debilitating diseases and
conditions associated with skeletal muscle weakness and/or fatigue.
The study showed dose- and
concentration-dependent increases in time to muscle fatigue as
measured by changes from baseline in Six Minute Walk Distance
(6MWD), a sub-maximal exercise test of aerobic capacity and
endurance, and Maximal Expiratory Pressure (MEP), a measure of
strength of respiratory muscles, after eight weeks of treatment
with reldesemtiv.
The study, which examined two dose levels of
reldesemtiv, 150 mg or 450 mg twice daily, demonstrated
dose-dependent increases in 6MWD in ambulatory patients as measured
at both post-baseline time points, week four and week eight. In the
150 mg twice daily group, the increase vs. placebo was 10.86 meters
(p=0.2531) after four weeks of treatment with reldesemtiv and 7.72
meters (p=0.4684) after eight weeks of treatment. In the 450 mg
twice daily group, the increase vs. placebo was 35.63 meters (p=
0.0037) at week four and 24.89 meters (p= 0.0584) at week eight.
There was also a statistically significant correlation between
Cmax, or peak concentration of reldesemtiv, and change from
baseline in 6MWD, with a slope estimate of 9.53 meters/(µg/mL).
(p=0.0086).
The study also showed increases vs. placebo in
MEP. In the 150 mg twice daily group, the increase in MEP was 5.95
cm H2O (p=0.2276) after four weeks of treatment with reldesemtiv
and 11.69 cm H2O (p=0.0378) after eight weeks of treatment. In the
450 mg twice daily group, the increase in MEP compared to placebo
was 9.17 cm H2O (p=0.0855) after four weeks of treatment
with reldesemtiv and 13.15 cm H2O (p=0.0298) after
eight weeks of treatment. Other assessments in the study, including
the Hammersmith Functional Motor Score - Extended, Revised Upper
Limb Module, Timed Up-and-Go and Forced Vital Capacity did not
demonstrate meaningful differences between reldesemtiv versus
placebo.
Adverse events were similar between groups
receiving reldesemtiv and placebo. The most commonly observed
adverse effects were headache, constipation and nausea. Four
patients had serious adverse events reported that resulted in early
termination of study drug treatment, all considered to be unrelated
to reldesemtiv.
“This hypothesis-generating study provides the
first data indicating that a muscle-directed therapy, namely a fast
skeletal muscle troponin activator, may be clinically beneficial in
patients with SMA,” said Dr. Day. “These data are especially
encouraging given the unmet need among those adolescent and adult
individuals with SMA who have persistent muscle weakness, fatigue
and functional impairment.”
“We are pleased that treatment with reldesemtiv
showed potentially clinically beneficial effects in adolescent and
adult patients with SMA as evidenced by dose-dependent increases
vs. placebo in Six Minute Walk and Maximal Expiratory Pressure,”
said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice
President of Research and Development. “We believe that these data
support the evaluation of higher doses of reldesemtiv in
future clinical trials in SMA given the absence of an efficacy
plateau and no dose-limiting safety or tolerability issues. We look
forward to working with Astellas, investigators and regulatory
authorities to further review the data and consider a potential
path forward.”
Clinical Study Design
The primary objective of this Phase 2,
double-blind, randomized, placebo-controlled clinical study was to
determine the potential pharmacodynamic effects of a suspension
formulation of reldesemtiv following multiple oral doses in
patients with Type II, Type III, or Type IV SMA. Secondary
objectives were to evaluate the safety, tolerability and
pharmacokinetics of reldesemtiv. There was no single primary
endpoint in this early, Phase 2, hypothesis-generating study.
The study enrolled 70 patients, 39 in Cohort 1
and 31 in Cohort 2. Ambulatory and non-ambulatory (Type II or Type
III) patients 12 years of age and older were randomized 2:1,
stratified by ambulatory ability, to receive reldesemtiv or placebo
dosed twice daily for eight weeks. The first cohort of patients
received 150 mg of reldesemtiv or placebo and the second cohort
received 450 mg of reldesemtiv or placebo twice daily. Enrollment
in this study was stopped short of the targeted 72 patients after
blinded analyses of the variability around the changes from
baseline of several efficacy measures demonstrated that the study
had sufficient statistical power to detect clinically relevant
differences versus placebo in efficacy endpoints with the 70
patients already enrolled.
Multiple assessments of skeletal muscle function
and fatigability were performed in the study, including respiratory
assessments, upper limb strength and functionality for
non-ambulatory patients, as well as Six Minute Walk Distance and
Timed Up-and-Go for ambulatory patients. In this
hypothesis-generating study, all endpoints were evaluated using
nominal p-values without adjusting for multiple comparisons.
Patients enrolled in the second cohort were also assessed with the
SMA Health Index, a patient reported outcome measure. Additional
information regarding the study can be found
at www.clinicaltrials.gov.
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 fast skeletal muscle troponin activator (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 muscle weakness and fatigue. In non-clinical models
of SMA, a skeletal muscle activator has demonstrated increases in
submaximal skeletal muscle force and power in response to neuronal
input and delays in the onset and reductions in the degree of
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. In addition to the Phase 2
clinical study in patients with SMA, Cytokinetics is
collaborating with Astellas on the conduct of Phase 2 clinical
trials in patients with amyotrophic lateral sclerosis (ALS) and
chronic obstructive pulmonary disease (COPD) as well as a Phase 1b
clinical trial of reldesemtiv in elderly adults with limited
mobility.
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 I patients have the worst prognosis, with a
life expectancy of no more than two years; 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 gene modifying
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. 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.
Cytokinetics Conference Call /
Webcast
Cytokinetics will host a conference call on June
18, 2018 at 8:30 a.m. Eastern Time including members of management
and Dr. Day. The conference call will be simultaneously webcast and
will be accessible in the Investors & Media section of
Cytokinetics' website. The live audio of the conference call is
also accessible via telephone to investors, members of the news
media and the general public by dialing either (866) 999-2985
(CYTK) (United States and Canada) or (706) 679-3078 (International)
and typing in the passcode 2491748. An archived replay of the
webcast will be available via Cytokinetics' website until June 25,
2018. The replay will also be available via telephone from June 18,
2018 at 11:30 a.m. Eastern Time until June 25, 2018 by dialing
(855) 859-2056 (United States and Canada) or (404) 537-3406
(International) and typing in the passcode 2491748.
About Cytokinetics and
Astellas Collaboration
In 2013, Astellas
and Cytokinetics formed a partnership focused on the
research, development, and 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. Under the
collaboration, Cytokinetics exclusively licensed to
Astellas rights to co-develop and potentially co-commercialize
reldesemtiv, a fast skeletal muscle troponin activator (FSTA), in
non-neuromuscular indications. In 2014, Astellas
and Cytokinetics agreed to expand the collaboration to
include certain neuromuscular indications, including SMA, and to
advance reldesemtiv into Phase 2 clinical development, initially in
SMA. Under the agreement as further amended in 2016, Astellas has
exclusive rights to co-develop and commercialize reldesemtiv and
other FSTAs in non-neuromuscular indications and certain
neuromuscular indications (including SMA and ALS) and other novel
mechanism skeletal muscle activators in all indications, subject to
certain Cytokinetics’ development and commercialization
rights; Cytokinetics may co-promote and conduct certain
commercial activities in North
America and Europe under agreed scenarios.
About Cytokinetics
Cytokinetics is a late-stage biopharmaceutical
company focused on discovering, developing and commercializing
first-in-class muscle activators 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 increase 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 GALACTIC-HF, an
international Phase 3 clinical trial in patients with heart
failure. 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 next-generation FSTA.
Reldesemtiv has been granted orphan drug designation by the FDA for
the potential treatment of spinal muscular atrophy. Reldesemtiv is
the subject of three Phase 2 clinical trials in patients with
spinal muscular atrophy, chronic obstructive pulmonary disease and
amyotrophic lateral sclerosis. Astellas is also conducting a Phase
1b clinical trial of reldesemtiv in elderly adults with limited
mobility. Astellas holds an exclusive worldwide license to develop
and commercialize reldesemtiv. Licenses held by Amgen and Astellas
are subject to Cytokinetics' specified co-development and
co-commercialization rights. Cytokinetics continues its 20-year
history of innovation with three new muscle biology directed
compounds advancing from research to development in 2018. For
additional information about Cytokinetics, visit
www.cytokinetics.com.
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, including the Phase 2 clinical
study of reldesemtiv in patients with SMA and its potentially
beneficial effects; and the properties and potential benefits of
Cytokinetics’ 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
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