Trial Did Not Meet Statistical
Significance for Primary Efficacy Analysis
Cytokinetics, Incorporated (Nasdaq: CYTK, “Cytokinetics”) announced
that results of FORTITUDE-ALS (
Functional
Outcomes in a
Randomized
Trial of
Investigational
Treatment with CK-2127107 to
Understand
Decline in
Endpoints – in
ALS) were
presented today by Jeremy Shefner, M.D., Ph.D., Lead Investigator
of FORTITUDE-ALS, Professor and Chair of Neurology at Barrow
Neurological Institute, and Professor and Executive Chair of
Neurology at the University of Arizona, Phoenix, at a podium
presentation at the American Academy of Neurology Annual Meeting in
Philadelphia.
FORTITUDE-ALS did not achieve statistical
significance for a pre-specified dose-response relationship in its
primary endpoint of change from baseline in slow vital capacity
(SVC) after 12 weeks of dosing (p=0.11). Similar analyses of
ALSFRS-R and slope of the Muscle Strength Mega-Score yielded
p-values of 0.09 and 0.31, respectively. However, patients on all
dose groups of reldesemtiv declined less than patients on placebo
for SVC and ALSFRS-R, with larger and clinically meaningful
differences emerging over time.
While the dose-response analyses for the primary
and secondary endpoints did not achieve statistical significance at
the level of 0.05, in a post-hoc analysis pooling the doses
together, patients who received reldesemtiv in FORTITUDE-ALS
declined less than patients who received placebo. The trial showed
effects favoring reldesemtiv across dose levels and timepoints with
clinically meaningful magnitudes of effect observed at 12 weeks for
the primary and secondary endpoints. The differences between
reldesemtiv and placebo in SVC and ALSFRS-R total score observed
after 12 weeks of treatment were still evident at follow-up, four
weeks after the last dose of study drug.
The incidence of early treatment
discontinuations, serious adverse events and clinical adverse
events in FORTITUDE-ALS were similar between placebo and active
treatment arms. The most common clinical adverse effects in the
trial included fatigue, nausea and headache. The leading cause for
early termination from FORTITUDE-ALS for patients who received
placebo was progressive disease; the leading cause for early
termination for patients who received reldesemtiv was a decline in
cystatin C based estimated glomerular filtration rate (eGFR), a
measure of renal function. Elevations in transaminases and declines
in cystatin C eGFR were dose-related.
“Results from FORTITUDE-ALS are among the most
impressive we have seen in a Phase 2 clinical trial in ALS,” said
Dr. Shefner. “Especially noteworthy are the consistency and
durability of effects observed across treatment arms on clinically
meaningful endpoints.”
In collaboration with Astellas, Cytokinetics is
developing reldesemtiv, a next-generation fast skeletal muscle
troponin activator (FSTA), as a potential treatment for people
living with debilitating diseases and conditions associated with
skeletal muscle weakness and/or fatigue.
Primary Efficacy Endpoint and Additional
Analyses
In FORTITUDE-ALS, the primary analysis of change
from baseline to Week 12 in percent predicted SVC was analyzed
using a mixed model for repeated measures (MMRM) with the contrast
(-5, -1, 3, 3) to reflect the assumed weighted dose-response
relationship for the placebo, 150 mg BID, 300 mg BID and 450 mg BID
dose groups of reldesemtiv, respectively. While all doses of
reldesemtiv demonstrated numerical reductions in SVC vs. placebo,
the mixed model analysis was not statistically significant (p=0.11)
(Figure 1). In a post-hoc analysis, when all active treatment
groups were combined and compared to placebo, the trial showed a
27% reduction in the decline of SVC (p=0.10) (Figure 2).
Photos accompanying this announcement are available
athttp://www.globenewswire.com/NewsRoom/AttachmentNg/673a83b5-81c7-4866-8e1a-df78cb617e44
http://www.globenewswire.com/NewsRoom/AttachmentNg/03bd19b6-e096-43df-95a6-1f8ed46b2f41
In FORTITUDE-ALS, the rate of decline in SVC in
the placebo group was slower than has been observed in previous
trials. FORTITUDE-ALS was powered with the expectation patients
receiving placebo would decline approximately 8.0 percentage points
during the 12-week trial. In FORTITUDE-ALS, patients receiving
placebo declined 6.5 percentage points over 12 weeks.
Secondary Efficacy Endpoints:
Additional Analyses
In a post-hoc analysis, FORTITUDE-ALS
demonstrated a decrease in the decline of the ALSFRS-R from
baseline to 12 weeks of 25% (p=0.01) when all active treatment
groups combined were compared to placebo (Figure 3). The ALSFRS-R
measures activities of daily living and has been deemed acceptable
by regulatory authorities for approval and marketing
authorization. According to a 2010 survey of ALS clinicians
conducted by the Northeast ALS Consortium (NEALS), respondents
deemed a therapy that resulted in a change of 20-25% or greater in
the slope of decline of ALSFRS-R to be a clinically meaningful
effect. 1
Photos accompanying this announcement are available
athttp://www.globenewswire.com/NewsRoom/AttachmentNg/14127d83-0ba5-422e-9d16-8660b8495241
http://www.globenewswire.com/NewsRoom/AttachmentNg/bd0d748c-d5d5-47cc-9342-e830f84eaec2
Within the ALSFRS-R domains, the largest effects
observed at 12 weeks in FORTITUDE-ALS were in the Gross Motor
Domain of the ALSFRS-R, which measures the ability of patients with
ALS to turn in bed, walk and climb stairs. The effect of
reldesemtiv for the Gross Motor Domain score was statistically
significant at each dose vs. placebo (p=0.0004 for 150 mg BID,
p=0.0158 for 300 mg BID, p=0.0065 for 450 mg BID) (Figure 4).
“While FORTITUDE-ALS did not meet the primary
endpoint, we are encouraged by the results of the trial as they
further validate the potential of skeletal muscle activation in
treating patients battling ALS,” said Fady I. Malik, M.D., Ph.D.,
Cytokinetics’ Executive Vice President, Research and Development.
“This Phase 2 trial of reldesemtiv demonstrated consistency of
effect for doses, endpoints and timepoints and we believe the
results support progression of reldesemtiv in further clinical
trials toward potential registration.”
Cytokinetics Event/Conference Call/Webcast
Cytokinetics will host an investor event and
conference call on May 6, 2019 at 7:30 a.m. Eastern Time including
members of management and members of the Steering Committee of
FORTITUDE-ALS. The event will be held at the Loews Philadelphia
Hotel in the Lescaze Room. 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 4284768. An archived
replay of the webcast will be available via Cytokinetics' website
until June 3, 2019. The replay will also be available via telephone
from May 6, 2019 at 11:00 a.m. Eastern Time until June 3, 2019 by
dialing (855) 859-2056 (United States and Canada) or (404) 537-3406
(International) and typing in the passcode 4284768.
FORTITUDE-ALS: Clinical Trial Design
FORTITUDE-ALS is a Phase 2, double-blind,
randomized, dose-ranging, placebo-controlled, parallel group study
of reldesemtiv in patients with ALS. 458 eligible ALS patients from
centers in the U.S., Canada, Europe and Australia were randomized
(1:1:1:1) to receive either 150 mg, 300 mg or 450 mg of reldesemtiv
or placebo dosed orally twice daily for 12 weeks. The primary
efficacy endpoint was the change from baseline in the percent
predicted SVC, a measure of respiratory function, at 12 weeks.
Secondary endpoints included change from baseline in the ALS
Functional Rating Scale – Revised (ALSFRS-R) and slope of the
change from baseline in the mega-score of muscle strength measured
by hand held dynamometry and handgrip dynamometry in patients on
reldesemtiv; incidence and severity of treatment-emergent adverse
events (TEAEs); and plasma concentrations of reldesemtiv at the
sampled time points during the clinical trial.
In addition, exploratory endpoints were measured
including the effect of reldesemtiv versus placebo on
self-assessments of respiratory function made at home by the
patient with assistance as needed by the caregiver; disease
progression through quantitative measurement of speech production
characteristics over time; disease progression through quantitative
measurement of handwriting abilities over time; and change from
baseline in quality of life (as measured by the ALSAQ-5) in
patients on reldesemtiv.
About ALS
Amyotrophic lateral sclerosis (ALS) is a
progressive neurodegenerative disease that afflicts approximately
20,000 people in the United States and a comparable number of
patients in Europe. Approximately 5,000 new cases of ALS are
diagnosed each year in the United States. The average life
expectancy of an ALS patient is approximately three to five years
after diagnosis and only approximately 10 percent of patients
survive for more than 10 years. Death is usually due to respiratory
failure because of diminished strength in the skeletal muscles
responsible for breathing. Few treatment options exist for these
patients, resulting in a high unmet need for new therapies to
address functional deficits and disease progression.
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 muscle weakness and fatigue. In
non-clinical models of spinal muscular atrophy (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. Mid-stage clinical trials
in patients with SMA, COPD and elderly adults with limited mobility
have been completed. In the Phase 2 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 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). 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 ALS, 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 Castrillo-Viguera, et al.
Clinical significance in the change of decline in ALSFRS-R.
Amyotrophic Lateral Sclerosis. 2010; 11: 178-180
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