Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that data
related to the optimization of CK-3773274 (CK-274), including the
first disclosure of its chemical structure, were presented at the
American Chemical Society Spring 2021 Virtual Meeting. The
presentation reviewed scientific activities that involved
evaluating CK-274 and precursor compounds for their
exposure-response relationship, projected human half-life, and
potential for meaningful cytochrome P450 (CYP450) interactions.
CK-274 is a next-in-class cardiac myosin inhibitor discovered by
company scientists, in development for the potential treatment of
hypertrophic cardiomyopathy (HCM).
“These preclinical data provide a first look at
the structure of our next-in-class cardiac myosin inhibitor,
CK-274, and its performance in certain preclinical assays,” said
Brad Morgan, Ph.D., Cytokinetics’ Senior Vice President, Research
and Non-Clinical Development. “CK-274 was synthesized from a newly
discovered and distinct chemical series following an optimization
program that was intentionally focused on key compound
physiochemical characteristics, such as a shallow dose-response
relationship and a half-life that may enable flexible and timely
dosing adjustments. We look forward to results from REDWOOD-HCM,
the Phase 2 clinical trial of CK-274, which is designed to
elaborate on how these differentiated properties may translate into
its potential use in patients with obstructive HCM.”
Data presented described the primary
optimization objectives, identification of an initial hit compound,
and its subsequent chemical optimization, including preclinical
characterization in biochemical assays, cardiac myocytes, and in
vivo models of cardiac function. In cardiac myofibrils, the
biochemical potency of CK-274 was 1.26 µM and it reduced cardiac
myocyte contractility to 33% of baseline at 5 µM. Echocardiographic
data from healthy rats showed that CK-274 reduced fractional
shortening, a measure of cardiac function, in a dose- and
exposure-dependent fashion. The pharmacodynamic window,
characterized by the ratio of plasma concentrations required to
achieve a 50% (IC50) and 10% (IC10) reduction in fractional
shortening (IC50/IC10) was 9.6 for CK-274. The exposure-response
relationship for CK-274 in healthy dogs was similar to that
observed in rats.
Preclinical pharmacokinetic characterization of
CK-274 suggested its predicted half-life in humans was 2.8 days1.
This projection was borne out in the first-in-human Phase 1 study
of CK-274 in healthy volunteers in which the single dose
administered half-life was observed to be 3.4 days2, and
steady-state was reached within 2 weeks following multiple doses.
Reaching steady state within two weeks may translate to ease of
dose titration and onset of action in patients with obstructive
HCM, as well as timely reversibility of effect if discontinuation
is necessary. CK-274 was designed to have a low potential to
inhibit representative human CYP450s in order to reduce the
potential for drug-drug interactions. CK-274 did not exhibit direct
or time dependent inhibition of seven human CYP isoforms (IC50 >
30 µM for 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4).
Comparison of CK-274 to mavacamten, a cardiac
myosin inhibitor, whose precursor was discovered by Cytokinetics’
scientists and subsequently optimized in collaboration with
Myokardia, Inc. and now being developed by Bristol-Myers Squibb
Company, was also performed in certain preclinical assays. The
presentation from the American Chemical Society Spring 2021 Virtual
Meeting can be found at
https://cytokinetics.com/publications-and-presentations.
Together, these data suggest that CK-274 may be
a next-in-class, cardiac myosin inhibitor with a shallow
pharmacokinetic/pharmacodynamic relationship and pharmacokinetics
that may provide for flexible dose titration. The efficacy and
safety of CK-274 are now being evaluated in patients with
obstructive HCM.
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 well suited 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. Previously presented data from the Phase 1
study of CK-274 demonstrated that it was well tolerated in healthy
participants and that the shallow exposure-response relationship
observed preclinically appeared to translate to
humans.1
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.
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.
Enrollment in Cohort 2 of REDWOOD-HCM completed
in Q1 2021 and full 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 www.clinicaltrials.gov.
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 conducting 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’ 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 WeiserSenior Vice President, Corporate
Communications, Investor Relations(415) 290-7757
References
- P Cremin, et al. Poster # 887215
presented at AAPS annual meeting, Atlanta, Georgia, October
28-November 5, 2020
- LA Robertson, et al. Poster #210
presented at the 23rd HFSA Annual Scientific Meeting, September
13–16, 2019, Philadelphia, PA, USA
Cytokinetics (NASDAQ:CYTK)
Historical Stock Chart
From Aug 2024 to Sep 2024
Cytokinetics (NASDAQ:CYTK)
Historical Stock Chart
From Sep 2023 to Sep 2024