Cytokinetics Announces Preclinical Data for CK-3773274 Presented at the American Heart Association’s Basic Cardiovascular...
July 31 2019 - 7:30AM
Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that
preclinical data for CK-3773274 (CK-274) were presented at the
American Heart Association’s Basic Cardiovascular Sciences (BCVS)
Scientific Sessions in Boston, showing that CK-274 decreased
cardiac contractility in vitro, in vivo in healthy animals, and in
vivo in a mouse model of hypertrophic cardiomyopathy (HCM). CK-274
is a novel cardiac myosin inhibitor, discovered by company
scientists, in development for the potential treatment of HCM which
may result from increased cardiac contractility.
“We are pleased to share these important
findings demonstrating that CK-274 decreases cardiac contractility
in a dose- and concentration-related fashion, without changes to
calcium transient. We further confirmed this effect in a mouse
model of HCM and observed its effect appears reversible within 24
hours after administration with CK-274,” said Brad Morgan, Ph.D.,
Cytokinetics’ Senior Vice President, Research and Non-Clinical
Development. “We are encouraged by the emerging pharmacologic
profile for this drug candidate and look forward to presenting data
from its first-in-human Phase 1 study and beginning a Phase 2 trial
later this year.”
Preclinical Research
In vitro studies demonstrated that CK-274
selectively inhibited cardiac myosin activity, as it reduced the
cardiac myosin ATPase activity in a concentration-dependent manner,
with an IC50 of 1.3 µM. Additionally, in adult rat cardiomyocytes,
CK-274 reduced fractional shortening (FS), a measure of cardiac
contractility, without any effect on the calcium transient.
Two in vivo studies in healthy animals also
demonstrated that CK-274 decreased cardiac contractility. In
healthy rats, single doses of CK-274 ranging from 0.5 to 4.0 mg/kg
significantly reduced FS in a dose-related fashion relative to
control treatment. Similarly, in healthy dogs, single doses of
CK-274 ranging from 0.75-3.0 mg/kg decreased left ventricular
ejection fraction (LVEF) in a dose-related fashion relative to
control treatment.
CK-274 also was evaluated in the genetic R403Q
mouse model of HCM. Single doses of CK-274 ranging from 0.25-1.5
mg/kg significantly reduced FS in a dose-related fashion relative
to baseline values. At all dose levels, FS returned to baseline
values by 24 hours. In both the genetic R403Q mouse model of HCM
and wild-type mice, CK-274 achieved a 10% reduction (IC10) in
contractility at nanomolar concentrations with a >7-fold
difference between the IC50 and IC10 which may translate into a
measured, gradual on-target effect in patients with HCM (see Figure
below).
These data indicate that CK-274 reduced cardiac
contractility in vitro and in vivo and reduced fractional
shortening in a dose- and concentration-dependent manner in a mouse
model of HCM, suggesting that cardiac myosin inhibition may address
the underlying hypercontractility of the cardiac sarcomere in
hypertrophic cardiomyopathies.
About CK-274
CK-274 is a novel, oral, small molecule cardiac
myosin inhibitor that company scientists discovered independent of
its collaborations. CK-274 arose from an extensive chemical
optimization program conducted with careful attention to
therapeutic index and pharmacokinetic properties that may translate
into next-in-class potential in clinical development. CK-274 was
purposely designed to reduce the hypercontractility that is
associated with hypertrophic cardiomyopathy (HCM). In preclinical
models, CK-274 reduces myocardial contractility by binding directly
to cardiac myosin at a distinct and selective allosteric binding
site, thereby preventing myosin from entering a force producing
state. CK-274 reduces the number of active actin-myosin cross
bridges during each cardiac cycle and consequently reduces
myocardial contractility. This mechanism of action may be
therapeutically effective in conditions characterized by excessive
hypercontractility, such as HCM.
The preclinical pharmacokinetics of CK-274 were
characterized evaluated and optimized for potential rapid onset,
ease of titration and rapid symptom relief in the clinical setting.
The initial focus of the development program for CK-274 will
include an extensive characterization of its PK/PD relationship as
has been a hallmark of Cytokinetics’ industry-leading development
programs in muscle pharmacology. The overall development program
will assess the potential of CK‑274 to improve exercise capacity
and relieve symptoms in patients with hyperdynamic ventricular
contraction due to HCM.
About Hypertrophic
Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an
inherited cardiovascular disorder in which the heart muscle
(myocardium) becomes abnormally thick (hypertrophied). The
thickening of cardiac muscle leads to the inside of the left
ventricle becoming smaller and stiffer, and thus the ventricle
becomes less able to relax and fill with blood. This ultimately
limits the heart’s pumping function, resulting in symptoms
including chest pain, dizziness, shortness of breath, or fainting
during physical activity. A subset of patients with HCM are at high
risk of progressive disease which can lead to atrial fibrillation,
stroke and death due to arrhythmias. There are no current medical
treatments that directly address the hypercontractility that
underlies HCM. 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 the timing, design
and results of Cytokinetics’ Phase 1 study and Phase 2 trial of
CK-274; the potential benefits of CK-274; Cytokinetics’ and its
partners’ research and development activities; the timing of
enrollment of patients in Cytokinetics’ and its partners’ clinical
trials; the design, timing, results, significance and utility of
preclinical and clinical results; 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; 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; Cytokinetics may be unable to obtain or maintain
patent or trade secret protection for its intellectual property;
Cytokinetics’ partners decisions with respect to research and
development activities; 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
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/19d5ef4f-6875-4c9b-a80b-c90a5ca3a427
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