Cytokinetics, Incorporated (Nasdaq: CYTK) today announced data from
the Phase 1 study of CK-3773274 (CK-274) were presented in a poster
session at the HFSA 23rd Annual Scientific Meeting in Philadelphia.
The study met its primary and secondary objectives to assess the
safety and tolerability of single and multiple oral doses of
CK-274, describe the pharmacokinetics (PK) of CK-274 and its
pharmacodynamic effects (PD) as measured by echocardiography, as
well as to characterize the PK/PD relationship with regards to
cardiac function. These data support the advancement of CK-274 into
a Phase 2 clinical trial in patients with obstructive hypertrophic
cardiomyopathy which is expected to begin in Q4 2019. CK-274 is a
novel selective cardiac myosin inhibitor, discovered by company
scientists, in development for the potential treatment of
hypertrophic cardiomyopathy (HCM).
Phase 1 Design and Key
Findings
The primary objective of this Phase 1
double-blind, randomized, placebo-controlled, multi-part, single
and multiple ascending dose study was to assess the safety and
tolerability of CK-274 in healthy volunteers. The study design
included single ascending dose cohorts and multiple ascending dose
cohorts, with eight healthy subjects per cohort. Additional
objectives included to describe the PK of CK-274 and its PD effects
as measured by echocardiography, as well as to characterize the
relationship between the two with regards to cardiac function. This
study was not designed to identify a maximum tolerated dose of
CK-274.
The study demonstrated that CK-274 was safe and
well tolerated in healthy participants. No serious adverse events
and no clinically meaningful changes in vital signs, ECGs or
laboratory tests were observed. Stopping criteria for continued
dose escalation were reached after a single dose of 75 mg and after
14 days of a daily of 10 mg dose. Decreases in ejection fraction
below 50% were readily reversible within six hours following single
doses and within 24-48 hours following 14 days of dosing. The
pharmacokinetics of CK-274 were generally dose linear, and
steady-state appeared evident within 14 days of dosing. Left
ventricular ejection fraction decreased in an exposure dependent
manner and the PK/PD relationship for CK-274 observed in humans was
similar to that observed preclinically when adjusted for
differences in protein binding. Specifically, the shallow
exposure-response relationship observed preclinically appears to
translate to humans and thereby may enable flexible dose
optimization in humans.
“Our scientists originally pioneered this
emerging area of muscle pharmacology and we have now advanced a
potential next-in-class drug candidate that was optimized for its
pharmacokinetic properties and therapeutic index, both of which are
evident in this study,” said Fady I. Malik, MD, PhD, Cytokinetics’
Executive Vice President, Research and Development. “Importantly,
steady state was achieved within two weeks of daily dosing and
reversibility of drug effect within 24-48 hours following 14 days
of dosing. These properties enable two-week dose titration in the
planned Phase 2 trial and may translate to rapid onset, ease of
titration and rapid symptom relief in the clinical setting.”
Planned Phase 2 Clinical Trial
Design
Cytokinetics expects to begin a randomized,
placebo-controlled Phase 2 trial of CK-274 in patients with
symptomatic obstructive HCM later this year. The primary objective
of the planned trial is to assess the safety and tolerability of
CK-274 in these patients. Secondary objectives are to assess the PK
and PD of CK-274 in these patents, guided by echocardiography, with
two-week dose titration. CK-274 will be added to stable background
medical therapy.
About CK-274
CK-274 is a novel, selective, 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
evaluated and optimized for potential rapid onset, ease of
titration, individualized dosing 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
hypercontractile ventricular function 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 ventricular
arrhythmias, atrial fibrillation, stroke, heart failure and sudden
cardiac death. 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 clinical 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: Diane Weiser Vice President, Corporate Communications,
Investor Relations (415) 290-7757
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/5a6efc9d-d14e-4a7b-9ffe-4ab4de674521
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