Intra-Cellular Therapies, Inc. (Nasdaq:ITCI) today announced
topline results from Study ITI-214-104, a Phase I/II translational
study of single ascending doses of ITI-214, a novel, selective
phosphodiesterase-1 (PDE1) inhibitor, in patients with chronic
systolic heart failure with reduced ejection fraction
(HFrEF). ITI-214 is the first PDE1 inhibitor to be tested in
patients with HFrEF.
In this study, ITI-214 improved cardiac output by
increasing heart contractility and decreasing vascular resistance.
Agents that both increase heart contractility (inotropism) and
decrease vascular resistance (vasodilation) are called inodilators.
Inodilators in current clinical use are associated with the
development of arrhythmias, which are abnormal heart rhythms that
when serious can impair heart function and lead to mortality.
ITI-214, which acts through a novel mechanism of action, was not
associated with arrhythmias in this study and was generally well
tolerated in all patients.
The results of Study ITI-214-104 are consistent with our prior
findings in preclinical models of heart failure and indicate that
single-dose administration of ITI-214 can improve heart function in
patients with HFrEF. These findings warrant further investigation
of acute and chronic PDE-1 inhibition with ITI-214 in this patient
population.
“ITI-214 improved the strength of heart contraction on top of
lowering blood pressure stress on the heart. This occurred
without impacting arrhythmia in patients with heart failure.
These exciting results support a novel mechanism of action, and
suggest that inhibition of the PDE-1 enzyme concurrent with
standard-of-care may benefit heart failure patients without
incurring the risks associated with inodilators in current clinical
use,” said David Kass, M.D., the Abraham and Virginia Weiss
Professor of Cardiology at Johns Hopkins University School of
Medicine, who was involved in the study.
“Based on these findings, ITI-214 has the potential to be a
safe, once-a-day oral inodilator with a novel mechanism of action
that could have utility in clinical situations where there is great
unmet medical need, ranging from the treatment of acute heart
failure to the maintenance of patients with stable chronic HFrEF,”
said Sharon Mates, Ph.D., Chairman and CEO of Intra-Cellular
Therapies, Inc.
The initiation of Study ITI-214-104 followed findings in
preclinical models that ITI-214 had improved cardiac output through
a mechanism of action different from those of available heart
failure therapies. These findings in preclinical models of
heart failure were published by researchers at Johns Hopkins
University and Intra-Cellular Therapies scientists in the
journal Circulation1. Currently available heart failure
drugs that strengthen heart contractions, such as PDE3 inhibitors
(amrinone and milrinone) and ß-adrenergic agonists (dobutamine),
are associated with potentially dangerous complications, such as
arrhythmias. ITI-214 does not interact with the ß-adrenergic
signaling pathway and does not stimulate abnormal rhythms in an
animal model of heart failure. These experimental results
demonstrated that ITI-214 may exert its effects via distinct
pathways, one of which involves adenosine A2B receptor
signaling, and suggest that ITI-214 may represent a mechanistically
novel and potentially safe approach for the treatment of human
heart failure.
About Study ITI-214-104
Study ITI-214-104 was a randomized, double-blind,
placebo-controlled study of escalating single oral doses of ITI-214
(10, 30, and 90 mg) in patients with HFrEF NYHA class II-III.
The primary objective of the study was to determine the effects of
ITI-214 on cardiac function, using echocardiography with Doppler
imaging, in patients with reduced ejection fraction (≤35%) who were
already maintained on standard-of-care treatment. Safety was
evaluated by monitoring for hemodynamic effects and changes in
cardiac rhythm.
Thirty-five patients were enrolled in this study, 9 in each of
three dose cohorts and 8 in the placebo arm. The mean age of the
patients was 54; 57% were male, and 57% were black. The etiology of
the heart failure was ischemic heart disease in 31% of the
patients. The mean left ventricular ejection fraction at screening
was 25%.
In this study, compared to placebo, single doses of ITI-214
increased mean left ventricular (LV) power index and cardiac output
while systemic vascular resistance and mean arterial blood pressure
decreased. Reported adverse events were all mild to moderate and
consisted of three occurrences of orthostatic hypotension and three
episodes of non-postural hypotension. Patients were monitored by
continuous telemetry, and no changes in heart rhythms were noted.
No serious adverse events were reported. Further details of these
results will be presented at upcoming medical conferences.
About Heart Failure According to the U.S.
Centers for Disease Control and Prevention, heart failure affects
about 6.5 million adults in the United States and contributes to an
estimated one in eight deaths. Heart failure is a chronic
condition marked by weakening of the heart muscle that leads to
shortness of breath and general body weakness that worsens with
physical exertion. There is no cure for heart failure, and there is
significant unmet need, particularly for safe agents that can both
increase the strength of the heart as well as reduce vascular
afterload.
Currently available heart failure drugs that can
improve the contractile strength of the heart muscle, such as the
PDE3 inhibitors amrinone and milrinone, and the β-adrenergic
agonist dobutamine, increase cyclic AMP and thereby increase
intracellular calcium in cardiac muscle cells. Both
approaches are associated with safety risks, most notably
arrhythmia.
PDE1 inhibition also modifies cyclic AMP, but it does so in a
different manner linked with a novel intracellular pathway that
involves adenosine A2B receptor signaling but not ß-adrenergic
signaling to stimulate heart contractility. ITI-214 did not cause
calcium levels to rise in cardiomyocyte cells. In all of the
studies to date, activation of the PDE1-regulated pathway has not
triggered arrhythmia.
About ITI-214
ITI-214 is a potent and selective phosphodiesterase type 1
(PDE1) inhibitor. ITI-214 is the lead compound in the Company’s
PDE1 portfolio and is in development for the treatment of symptoms
associated with Parkinson's disease and for the treatment of heart
failure. ITI-214 has been generally well tolerated with a favorable
safety profile in six Phase 1 clinical trials. ITI-214 works by
slowing the breakdown of cyclic nucleotides (cAMP, cGMP), thus
allowing these molecules to build up in the cells and to exert
important functions. The PDE1 enzyme is highly active in
pathological or disease states, and our PDE1 molecules are designed
to reestablish normal function in these disease states through the
inhibition of the PDE1 enzyme.
In heart disease, excessive PDE1 activity may limit the
beneficial effects of cAMP or cGMP, so inhibitors like ITI-214 have
the potential to act as a therapy. ITI-214 is an inodilator that
can improve cardiac function by both increasing the force of heart
contractions and reducing the resistance to pushing blood through
the vascular system. Preclinical research has shown that
ITI-214 increases cardiac contractility and decreases vascular
resistance without increasing abnormal heart rhythms, and the
clinical results announced herein indicate that similar,
potentially therapeutic physiologic effects can be attained in
heart failure patients. ITI-214 is being developed for the
potential treatment of heart failure with reduced ejection fraction
(HFrEF).
Previous studies have described the mechanism of action of
ITI-214 in the brain. The mechanism of action of ITI-214 and our
other PDE1 inhibitors suggests therapeutic potential across a
variety of diseases including neurological and cardiovascular
diseases.
1. Bui AL, et al. Nat Rev Cardiol. 2011;8: 30-41. 2. Hashimoto
et al., Circulation 138:1974-1987 (2018)
About Intra-Cellular Therapies
Intra-Cellular Therapies is a biopharmaceutical company
founded on Nobel prize-winning research that allows us to
understand how therapies affect the inner-workings of cells in the
body. The company leverages this intracellular approach to develop
innovative treatments for people living with complex psychiatric
and neurologic diseases. For more information, please
visit www.intracellulartherapies.com.
Forward-Looking Statements
This news release contains "forward-looking statements" within
the meaning of the Private Securities Litigation Reform Act of 1995
that involve risks and uncertainties that could cause actual
results to be materially different from historical results or from
any future results expressed or implied by such forward-looking
statements. Such forward-looking statements include statements
regarding, among other things, the therapeutic value, clinical and
non-clinical development plans and commercial potential of our drug
product candidates; the progress, timing and results of our
clinical trials and preclinical studies; our beliefs about the
extent to which the results of our clinical trials and preclinical
studies to date support new drug application filings for product
candidates; the safety and efficacy of our product development
candidates; our beliefs about the potential uses and benefits of
our drug product candidates; the potential for ITI-214 to represent
a novel approach for the treatment of human heart failure; that
ITI-214 offers a potential new treatment for heart failure with a
novel mechanism of action that may provide an effective and safer
alternative to existing therapies and development efforts and plans
under the caption "About Intra-Cellular Therapies." All such
forward-looking statements are based on management's present
expectations and are subject to certain factors, risks and
uncertainties that may cause actual results, outcome of events,
timing and performance to differ materially from those expressed or
implied by such statements. These risks and uncertainties include
but are not limited to the following: our current and planned
clinical trials, other studies for our product candidates may not
be successful or may take longer and be more costly than
anticipated; product candidates that appeared promising in earlier
research and clinical trials may not demonstrate safety and/or
efficacy in larger-scale or later clinical trials; our proposals
with respect to the regulatory path for our product candidates may
not be acceptable to the FDA; our reliance on collaborative
partners and other third parties for development of our product
candidates; the COVID-19 pandemic may negatively impact the conduct
of, and the timing of enrollment, completion and reporting with
respect to, our clinical trials; any other impacts on our business
as a result of or related to the COVID-19 pandemic; and the other
risk factors detailed in our public filings with
the Securities and Exchange Commission. All statements
contained in this press release are made only as of the date of
this press release, and we do not intend to update this information
unless required by law.
CONTACT:
Intra-Cellular Therapies, Inc. Juan Sanchez, M.D. Vice
President, Corporate Communications and Investor Relations
646-440-9333
Burns McClellan, Inc. Lisa Burns jgrimaldi@burnsmc.com
212-213-0006
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