Cytokinetics, Incorporated (Nasdaq: CYTK) today announced the
progression of REDWOOD-HCM following the conduct of an interim
analysis of data from Cohort 1. REDWOOD-HCM
(
Randomized
Evaluation of
Dosing
With CK-274 in
Obstructive
Outflow
Disease in
HCM) is 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).
The 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
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.
Based on these results from Cohort 1, the
Steering Committee and the Data Monitoring Committee of REDWOOD-HCM
have recommended that the trial proceed to Cohort 2. The second
cohort is open for enrollment in centers in North America and
Europe. Enrollment in Cohort 2 of REDWOOD-HCM is expected to
complete in Q1 2021 and full results from REDWOOD-HCM across both
Cohort 1 and Cohort 2 are expected in mid-2021.
“We are encouraged that clinically relevant
reductions in the LVOT gradient were achieved within four to six
weeks in the majority of patients of Cohort 1 in this interim
analysis,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive
Vice President of Research & Development. “Given the observed
safety profile and opportunity to achieve further reductions of the
LVOT-G in some patients, we are pleased to dose escalate in Cohort
2. We hope to rapidly enroll Cohort 2 with the goal of sharing
results from REDWOOD-HCM in the middle of 2021 as may support
progression of CK-274 to a planned Phase 3 by the end of next
year.”
REDWOOD-HCM: Interim
Analysis
In Cohort 1, 21 patients were randomized 2:1 in
double-blind fashion to escalating doses of CK-274 (5, 10, and 15
mg. once daily) or placebo. Two weeks after initiation of treatment
in each patient at the starting dose of 5 mg (or placebo), an
echocardiogram was performed and, if escalation criteria were met
(LVEF >50% and resting LVOT-G >30 mmHg or post-Valsalva
LVOT-G >50 mmHg), the patient was up-titrated to receive 10 mg
(or placebo) for two weeks; similarly, if escalation criteria were
met at four weeks, the patient up-titrated again to receive 15 mg
(or placebo) and continued study drug until 10 weeks. If escalation
criteria were not met at Week 2 or 4, the patient continued at the
same dose for the rest of the trial.
At the cut-off date for this interim analysis,
echocardiographic core lab data were available from 11 patients
through Week 6 for review while all 21 patients contributed safety
data. Following a review of the aggregate, unblinded dataset, the
Data Monitoring Committee of REDWOOD-HCM endorsed the
recommendation jointly made by Cytokinetics and the Steering
Committee of REDWOOD-HCM to proceed to Cohort 2 with doses of 10
mg, 20 mg, and 30 mg, once-daily. Screening of patients for Cohort
2 of REDWOOD-HCM has commenced.
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 will enroll two sequential cohorts,
with an option for a third cohort. Within each cohort,
approximately 18 patients will be randomized 2:1 to active or
placebo treatment and receive up to three escalating doses of
CK-274 or placebo based on echocardiographic guidance. Patients
receive an echocardiogram after two weeks of treatment at each dose
to determine whether they will be up-titrated. Overall, the
treatment duration will be 10 weeks with an echocardiogram to
confirm reversibility of effect 2-weeks after the last dose.
REDWOOD-HCM is expected to enroll patients in approximately 20
investigative sites in North America and Europe. Additional
information can be found on www.clinicaltrials.gov.
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 best-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-use in
the clinical setting.
A Phase 1 study demonstrated that CK-274 was
safe and well tolerated in healthy participants. 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.
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 the most
common inherited cardiovascular disorder, affecting approximately 1
in 500 individuals worldwide. 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 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 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 considering potential advancement
of reldesemtiv to Phase 3 pending ongoing regulatory interactions.
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; the ability to complete enrollment of Cohort 2
of REDWOOD-HCM in Q1 2021 and the impact of the COVID-19 pandemic
on such enrollment (for further information regarding the
historical and potential prospective impact of the COVID-19
pandemic on our business operations and clinical trials, please
refer to Cytokinetics’ Form 10-Q for the quarterly period ended
September 30, 2020); 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 WeiserSenior Vice President, Corporate
Communications, Investor Relations(415) 290-7757
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