Previously Announced Results from Phase 3
Clinical Trial of Tirasemtiv Shared with ALS
Community
Cytokinetics, Incorporated (Nasdaq:CYTK) today announced the
presentation of results from VITALITY-ALS
(
Ventilatory
Investigation of
Tirasemtiv and
Assessment of
Longitudinal
Indices after
Treatment for a
Year in
ALS), the international Phase 3 clinical trial of
tirasemtiv in patients with amyotrophic lateral sclerosis (ALS), at
the 28th International Symposium on ALS and Motor Neurone Disease
(MND) in Boston. This presentation follows a prior announcement
that the trial did not meet the primary endpoint of change from
baseline in slow vital capacity (SVC) which was evaluated at 24
weeks following randomization or any of the secondary endpoints in
the trial which were evaluated at 48 weeks. The results were
presented by Jeremy Shefner, M.D., Ph.D., Lead Investigator of
VITALITY-ALS, Professor and Chair of Neurology at Barrow
Neurological Institute, and Professor and Executive Chair of
Neurology at University of Arizona, Phoenix.
“Although we are profoundly disappointed with
these results, we believe that data from VITALITY-ALS provide
validation for the mechanism of action of fast skeletal muscle
troponin activation. The effects of tirasemtiv observed in
patients with ALS support the future development of CK-2127107, our
next-generation fast skeletal muscle troponin activator which is
the subject of FORTITUDE-ALS, our ongoing Phase 2 clinical trial in
patients with ALS,” said Robert I. Blum, Cytokinetics’ President
and CEO. “As recently published Phase 1 studies demonstrate,
CK-2127107 may be more effective and better tolerated than
tirasemtiv. We are humbled by the outpouring of support we have
received from the ALS community and will continue our search for a
potential therapy to slow the progressive respiratory decline and
muscle weakness which characterize this dreadful disease.”
“VITALITY-ALS did not achieve our pre-specified
objectives which included improving tolerability in ALS patients by
altering the dosing of tirasemtiv,” said Dr. Shefner. “The
increased numbers of non-serious adverse effects and drop-outs in
patients who received tirasemtiv confound our ability to evaluate
efficacy and safety in the primary analyses of VITALITY-ALS.
Additional analyses of patients able to tolerate tirasemtiv suggest
slowing of the decline in SVC, providing support for the continued
investigation of fast skeletal muscle troponin activators in
patients with ALS.”
VITALITY-ALS randomized patients to placebo and
three target doses of tirasemtiv (250, 375, and 500 mg/day) in a
3:2:2:2 ratio. The primary analysis was an intent to treat analysis
of the dose groups of tirasemtiv pooled together and compared to
placebo. The least squares mean change from baseline in percent
predicted SVC was ‑13.4 percentage points in the patients
randomized to tirasemtiv compared to -14.4 percentage points in
those randomized to placebo. The least squares mean difference from
baseline to 24 weeks between tirasemtiv and placebo was 0.92
percentage points (p=0.5552). In a pre-specified analysis of the
average daily maintenance dose of tirasemtiv actually taken (rather
than as randomized), patients who completed VITALITY-ALS at the
highest average daily dose of tirasemtiv (> 437.5 mg/day),
experienced the largest difference from placebo in change from
baseline to 24 weeks in percent predicted SVC, although the
difference was not statistically significant (least squares mean
difference from placebo: 4.57, p=0.107). VITALITY-ALS did not meet
any of the pre-specified secondary endpoints which were evaluated
at 48 weeks.
Of the 565 randomized patients who received
double-blind treatment in the trial, 188 received placebo and 377
received tirasemtiv. 165 (87.8 percent) of patients on placebo
completed 24 weeks of treatment, while 248 (65.8 percent) of
patients on tirasemtiv completed 24 weeks of treatment.
Serious adverse events in patients receiving
tirasemtiv were consistent with disease progression of ALS with no
meaningful differences from placebo. Mortality was also similar in
patients receiving tirasemtiv and placebo. No new safety or
tolerability findings related to tirasemtiv were identified in
VITALITY-ALS. The adverse events with the greatest differences in
frequency between patients receiving tirasemtiv and those on
placebo were dizziness, weight decrease, insomnia, fatigue and
nausea, consistent with the adverse event profile of tirasemtiv
observed in Phase 2.
About VITALITY-ALS and
VIGOR-ALS
VITALITY-ALS was a multi-national, randomized,
double-blind, placebo-controlled trial in patients with possible,
probable or definite ALS, diagnosed within 24 months, and with SVC
at baseline ≥ 70 percent predicted. The primary endpoint of the
trial assessed change from baseline in SVC after 24 weeks of
double-blind, placebo-controlled treatment. Secondary endpoints,
assessed at 48 weeks, included change from baseline in the score of
the three respiratory items of the ALSFRS-R (i.e., the sum of items
10, 11 and 12) at 48 weeks; slope of the mega-score of muscle
strength at 48 weeks; time to the first occurrence of a decline
from baseline in percent predicted SVC ≥20 percentage points or the
onset of respiratory insufficiency or death through 48 weeks; time
to the first occurrence of a decline in SVC to ≤50 percent
predicted or the onset of respiratory insufficiency or death
through 48 weeks; change from baseline in the ALSFRS-R total score
at 48 weeks; and time to the first use of mechanical ventilatory
assistance or death through 48 weeks. Patients enrolled in
VITALITY-ALS received two-weeks of open-label treatment with
tirasemtiv administered at 250 mg/day. Patients were then
randomized into a double-blind treatment phase to placebo or one of
three target tirasemtiv dose levels (250 mg/day, 375 mg/day, 500
mg/day) in a 3:2:2:2 ratio. After 48 weeks of randomized,
double-blind, placebo-controlled treatment, patients who received
tirasemtiv during those 48 weeks of double-blind treatment were
randomized to continue the dose of tirasemtiv at which they
completed the 48 weeks of double-blind treatment or to placebo for
a four-week double-blind, tirasemtiv withdrawal phase.
Patients who received placebo during the 48 weeks of
double-blind treatment continued to receive placebo during the
double-blind, tirasemtiv withdrawal phase.
Following their participation in VITALITY-ALS,
patients were eligible to participate in an open-label extension
study of tirasemtiv, VIGOR-ALS (Ventilatory
Investigations in Global
Open-label Research in
ALS), designed to assess the long-term safety and
tolerability of tirasemtiv in patients with ALS. Cytokinetics will
seek advice from the academic leadership of VITALITY-ALS and its
clinical investigators, regulatory authorities and other
consultants before making decisions about continuing treatment with
tirasemtiv in VIGOR-ALS.
About ALS
Amyotrophic lateral sclerosis (ALS) is a
progressive neurodegenerative disease that afflicts approximately
30,000 people in the United States and a comparable number of
patients in Europe. Approximately 6,000 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 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 Tirasemtiv and
CK-2127107
Tirasemtiv is a fast skeletal muscle troponin
activator (FSTA) that selectively activates the fast skeletal
muscle troponin complex by increasing its sensitivity to calcium
and, in preclinical studies and early clinical trials, demonstrated
increases in skeletal muscle force in response to neuronal input
and delays in the onset and reductions in the degree of muscle
fatigue. Tirasemtiv has been studied in clinical trials that have
enrolled over 1500 people internationally.
CK-2127107 is a next-generation FSTA from
Cytokinetics' skeletal muscle contractility program. CK-2127107 was
derived from a different chemical structural class and was designed
to have certain advantages relative to tirasemtiv. CK-2127107
appears to be more potent than tirasemtiv in preclinical models and
in humans and appears better tolerated compared to tirasemtiv.
CK-2127107 has demonstrated pharmacological activity that may lead
to new therapeutic options for diseases associated with muscle
weakness and fatigue. CK-2127107 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.
CK-2127107 is the subject of an ongoing clinical development
program in neuromuscular and non-neuromuscular diseases and
conditions associated with muscle dysfunction and weakness,
including three Phase 2 trials currently underway in patients with
each of SMA, ALS, or COPD, as well as a Phase 1b trial in elderly
subjects with limited mobility.
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 CK-2127107, a next-generation FSTA.
CK-2127107 has been granted orphan drug designation by the FDA for
the potential treatment of SMA. CK-2127107 is the subject of three
ongoing Phase 2 clinical trials enrolling patients with spinal
muscular atrophy, chronic obstructive pulmonary disease and ALS.
Astellas is also conducting a Phase 1b clinical trial of CK-2127107
in elderly adults with limited mobility. Astellas holds an
exclusive worldwide license to develop and commercialize
CK-2127107. Licenses held by Amgen and Astellas are subject to
Cytokinetics' specified co-development and co-commercialization
rights. 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 our continuing
review and assessment related to the results from VITALITY-ALS, our
evaluation, in consultation with the FDA and other regulatory
authorities of future development plans for tirasemtiv and the
process and timing of anticipated future development of tirasemtiv;
the design, results, significance and utility of preclinical study
results; and the properties and potential benefits of CK-2127107
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, 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 trial 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 FDA 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; Astellas’ decisions with respect to
the design, initiation, conduct, timing and continuation of
development activities for CK-2127107 including FORTITUDE-ALS;
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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