Next Generation Fast Skeletal Muscle
Activator Appears Promising Compared to Tirasemtiv in Studies of
Healthy Volunteers
Cytokinetics, Incorporated (Nasdaq:CYTK) today announced the
publication of results from three double-blind, randomized,
placebo-controlled Phase 1 clinical studies that evaluated safety,
tolerability, pharmacokinetics, and pharmacodynamics of CK-2127107,
an investigational next-generation fast skeletal muscle troponin
activator (FSTA). The results showed that CK-2127107 increased the
force generated by the tibialis anterior muscle versus placebo in
response to nerve stimulation in a dose, plasma concentration, and
frequency-dependent manner. Single doses of CK-2127107 were
well-tolerated in healthy volunteers at doses up to 4000 mg. No
serious adverse effects (SAEs) were reported and adverse effects
(AEs) were all mild or moderate. Additionally, the results showed
that CK-2127107 appeared more potent and produced a larger increase
in force than tirasemtiv which was evaluated in a comparable
study.1 The publication, titled “CK-2127107 Amplifies Skeletal
Muscle Response to Nerve Activation in Humans,” is published online
in Muscle & Nerve.2
“These published results reinforce CK-2127107 as
a promising drug candidate with potential advantages relative to
tirasemtiv that may include tolerability and potency,” said Fady I.
Malik, MD, PhD, Cytokinetics’ Executive Vice President of Research
& Development. “We look forward to the results from four
ongoing mid-stage clinical trials of CK-2127107 anticipated in
2018.”
CY 5011 was a single ascending dose crossover
clinical trial that evaluated the safety, tolerability and
pharmacokinetics of single doses of CK-2127107 in 35 healthy male
participants. Participants received two ascending, active doses and
one placebo dose, one in each of three treatment periods.
CK-2127107 was well tolerated at all dose levels ranging from 30 mg
to 4000 mg. A maximum tolerated dose was not achieved. All AEs were
mild or moderate, and no clinically meaningful changes from
baseline were observed in the neurological examination, walk test,
laboratory values, vital signs, ECG parameters or pulse oximetry.
Exposure to CK-2127107 increased approximately dose
proportionally.
CY 5012 was a multiple ascending dose, parallel
group clinical trial that evaluated the safety, tolerability and
pharmacokinetics of CK-2127107 in male and female healthy
volunteers. The clinical trial enrolled 59 young (aged 18-55) and
elderly (aged 65-85) participants. Three cohorts enrolled young
participants and two enrolled elderly participants; four cohorts
received 300 mg or 500 mg for 10 days and one cohort received 500
mg for 17 days. CK-2127107 was generally well-tolerated at all
doses administered, and all AEs were mild or moderate. No other
clinically meaningful changes from baseline were observed in other
laboratory values, neurological examination, vital signs, or ECG
parameters, and there were no clinically meaningful differences in
pharmacokinetics of CK-2127107 between young and elderly
participants. Steady state was achieved in elderly participants
dosed with 300 mg for 10 days and young participants taking 500 mg
for 17 days.
CY 5013 was a single-dose, four-period crossover
clinical trial of CK-2127107 in 16 healthy male participants that
evaluated the change in the force-frequency profile of the tibialis
anterior muscle during transcutaneous stimulation of the deep
fibular nerve and its relationship to dose and plasma
concentrations of CK-2127107. Participants received placebo, 300
mg, 1000 mg and 3000 mg single doses in random order administered
one week apart. Single doses were well-tolerated and all AEs were
mild or moderate. CK-2127107 increased the response of the tibialis
anterior muscle to neuronal input as dose and plasma concentration
increased. The overall largest increase from baseline in peak
force, compared to placebo, was 58.7 (10.2)% (least-squares mean
[SE]) occurring at a stimulation frequency of 10 Hz. For
comparison, the largest response tirasemtiv produced in a
comparable study was a 24.5 (3.1)% increase in peak force at 10
Hz.1 The effect of CK-2127107 on the force-frequency relationship
was also related to the stimulation frequency, being greatest at
approximately the rate that motor units typically discharge during
daily physical activity.
These results suggest that by directly
increasing skeletal muscle force production, with maximal effects
in the middle of the 5 to 15 Hz range where most normal daily human
muscle activity occurs3,4, CK-2127107 may have an effect on
physical performance in patients with neuromuscular and
non-neuromuscular diseases in which weakness and fatigue are the
result of reduced skeletal muscle force production. Furthermore,
the results show that compared to the first-generation FSTA
tirasemtiv, CK-2127107 may be more potent and produce larger
increases in force.
About CK-2127107
CK-2127107 is an investigational next-generation
FSTA arising 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 in comparable Phase 1 studies.
CK-2127107 has demonstrated pharmacological activity that 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 spinal muscular atrophy (SMA), amyotrophic lateral
sclerosis (ALS), or chronic obstructive pulmonary disease (COPD),
as well as a Phase 1b trial in elderly subjects with limited
mobility.
About Cytokinetics and
Astellas Collaboration
Cytokinetics and Astellas collaborate 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. Cytokinetics has licensed to Astellas exclusive
rights to develop and commercialize CK-2127107 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 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. 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.
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; 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.
References
- Hansen R, Saikali KG, Chou W, Russell AJ, Chen MM, Vijayakumar
V, Stoltz RR, Baudry S, Enoka RM, Morgans DJ, Wolff AA, Malik
FI. Tirasemtiv amplifies skeletal muscle response to nerve
activation in humans. Muscle & Nerve. 2014
Dec;50(6):925-31.
- Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng
L, Wolff AA, Malik FI. CK-2127107 amplifies skeletal muscle
response to nerve activation in humans. Muscle & Nerve. 2017
Nov 18.
- Person RS, Kudina LP. Discharge frequency and discharge pattern
of human motor units during voluntary contraction of muscle.
Electroencephalography and clinical neurophysiology.
1972;32(5):471-483.
- Tanji J, Kato M. Firing rate of individual motor units in
voluntary contraction of abductor digiti minimi muscle in man.
Experimental neurology. 1973;40(3):771-783.
Contact:CytokineticsDiane
WeiserVice President, Corporate Communications, Investor
Relations(415) 290-7757
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