Cytokinetics, Incorporated (Nasdaq: CYTK) today announced the
opening of enrollment in Cohort 3 of REDWOOD-HCM
(
Randomized
Evaluation of
Dosing
With CK-274 in
Obstructive
Outflow
Disease in
HCM), an ongoing Phase
2 clinical trial of CK-3773274 (CK-274), a next-generation cardiac
myosin inhibitor in development for the potential treatment of
hypertrophic cardiomyopathy (HCM). Cohort 3 will enroll patients
whose background therapy includes disopyramide.
“After completing enrollment in the first two
cohorts in REDWOOD-HCM, we are pleased to now begin Cohort 3, which
is enrolling patients who are being treated with disopyramide,”
said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice
President of Research & Development. “Given that disopyramide
is often prescribed in patients with more severe HCM, the data from
Cohort 3 may support the potential use of CK-274 in a broader
population of patients with obstructive HCM. Importantly, we do not
believe that Cohort 3 is required to refine the dosing strategy
that we expect to use in Phase 3 but it will help inform the
inclusion criteria for that potentially pivotal clinical trial
which we are planning to begin later this year.”
REDWOOD-HCM: Clinical Trial Design
REDWOOD-HCM is a multi-center, randomized,
placebo-controlled, double-blind, dose finding clinical trial of
CK-274 in patients with symptomatic obstructive HCM (oHCM). The
primary objective of the trial is to determine the safety and
tolerability of CK-274. The secondary objectives are to describe
the concentration-response relationship of CK-274 on the resting
and post-Valsalva left ventricular outflow tract gradient as
measured by echocardiography during 10 weeks of treatment, to
describe the dose response relationship of CK-274, and to evaluate
the plasma concentrations of CK-274 in patients with oHCM.
The trial previously completed enrollment in
Cohort 1 and Cohort 2, two sequential cohorts. Within each cohort,
approximately 20 patients were randomized 2:1 to active or placebo
treatment and received up to three escalating doses of CK-274 or
placebo based on echocardiographic guidance. Patients received an
echocardiogram after two weeks of treatment at each dose to
determine whether they would be up-titrated. Overall, the treatment
duration is 10 weeks with an echocardiogram to confirm
reversibility of effect 2 weeks after the last dose. In Cohorts 1
and 2, patients continued taking background medications exclusive
of disopyramide.
Cohort 3 will enroll, in an open label fashion,
8-12 patients whose background therapy includes disopyramide to
assess the safety, tolerability, pharmacokinetics, and
pharmacodynamic effects of CK-274 in patients taking disopyramide.
All patients will receive up to three escalating doses of CK-274,
titrated based on echocardiographic guidance. Overall treatment
duration will be 10 weeks with a 4-week follow up period after the
last dose.
Interim analysis of data from Cohort 1 of
REDWOOD-HCM showed patients experienced substantial reductions in
the average resting left ventricular outflow tract gradient
(LVOT-G) as well as the post-Valsalva LVOT-G (defined as resting
gradient <30 mmHg and post-Valsalva gradient <50 mmHg). These
clinically relevant decreases in pressure gradients were achieved
with only modest decreases in average left ventricular ejection
fraction (LVEF); there were no dose interruptions due to LVEF
falling below 50%, the prespecified safety threshold.
Pharmacokinetic data were similar to those observed in Phase 1 in
healthy subjects. In addition, the safety and tolerability data
were supportive of continued dose escalation with no serious
adverse events attributed to study treatment reported by the
investigators.
Results from REDWOOD-HCM, across both Cohort 1
and Cohort 2, are expected in mid-2021. Additional information
about REDWOOD-HCM can be found on
clinicaltrials.gov/.
About CK-274
CK-274 is a novel, oral, small molecule cardiac
myosin inhibitor arising 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 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.
In preclinical models of cardiac function,
CK-274 reduced cardiac contractility in a predictable dose and
exposure dependent fashion. In preclinical models of disease,
CK-274 reduced compensatory cardiac hypertrophy and cardiac
fibrosis. The preclinical pharmacokinetics of CK-274 were
characterized, evaluated and optimized for potential ease of
titration in the clinical setting.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease
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 FDA
approved 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 next-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 preparing for regulatory
interactions for omecamtiv mecarbil, its novel cardiac muscle
activator, following positive results from GALACTIC-HF, a large,
international Phase 3 clinical trial in patients with heart
failure. Cytokinetics is conducting METEORIC-HF, a second Phase 3
clinical trial of omecamtiv mecarbil. Cytokinetics is also
developing CK-274, a next-generation cardiac myosin inhibitor, for
the potential treatment of hypertrophic cardiomyopathies (HCM).
Cytokinetics is conducting REDWOOD-HCM, a Phase 2 clinical trial of
CK-274 in patients with obstructive HCM. Cytokinetics is also
developing reldesemtiv, a fast skeletal muscle troponin activator
for the potential treatment of ALS and other neuromuscular
indications following conduct of FORTITUDE-ALS and other Phase 2
clinical trials. The company is preparing for the potential
advancement of reldesemtiv to a Phase 3 clinical trial in ALS.
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 2 clinical trial of CK-274; the potential
benefits of CK-274; Cytokinetics’ research and development
activities; the timing of enrollment of patients in Cytokinetics’
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’
ability to conduct clinical trials; Cytokinetics may be unable to
obtain or maintain patent or trade secret protection for its
intellectual property; standards of care may change, rendering
Cytokinetics’ drug candidates obsolete; and competitive products or
alternative therapies may be developed by others for the treatment
of indications Cytokinetics’ drug candidates and potential drug
candidates may target. 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 WeiserSenior Vice President, Corporate
Communications, Investor Relations(415) 290-7757
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