Intra-Cellular Therapies Announces the Results of a Phase I PET Study for ITI-007 for the Treatment of Schizophrenia and Other Psychiatric Disorders
Key Targets are Critical to Drug Treatment of Neuropsychiatric and Related Disorders
NEW YORK, Dec. 21 /PRNewswire/ -- Intra-Cellular Therapies, Inc.
(ITI) announced at a recent conference on neuropsychiatric diseases
the results from a recently completed Phase I clinical study
demonstrating ITI-007, the Company's lead antipsychotic drug,
interacts with important targets in the living human brain. These
key targets are critical to drug action in many neuropsychiatric
and related disorders. Using positron emission tomography (PET) to
image receptor interactions, ITI-007 produced dose-related and
long-lasting occupancy of three key targets of psychotropic drug
action: the serotonin 5-HT2A and dopamine D2 receptors, as well as
the serotonin reuptake transporter (SERT). At low doses, ITI-007
selectively occupies 5-HT2A receptors in the brains of normal
healthy volunteers. At a dose of 10 mg, neocortical 5-HT2A
receptors are fully occupied and the first evidence is seen of D2
receptor occupancy in the basal ganglia. This 10 mg dose has been
shown previously to be particularly effective in improving sleep in
patients with sleep maintenance problems.
As the dose of ITI-007 is increased, dose-dependent and
progressively increasing amounts of D2 occupancy are achieved,
reaching 40% peak occupancy in the basal ganglia at the 40 mg dose
(the highest dose tested in this study). At this dose, ITI-007 also
demonstrates significant occupancy of the SERT. Moreover, when
these targets are occupied in the presence of fully saturated
5-HT2A receptors, effects should be amplified.
"We are pleased to have demonstrated ITI-007's potent
interactions with key brain targets in humans," stated Sharon
Mates, Chief Executive Officer of Intra-Cellular Therapies. "The
simultaneous occupancy of these targeted receptors is unprecedented
for antipsychotic drugs. We believe that these results will
translate into a reduced need to impose high doses of drugs on
patients suffering from schizophrenia and other disorders."
ITI-007 rapidly penetrates the brain after oral administration
and interacts with molecular targets important in a variety of
central nervous system disorders. Taken together, these data
suggest that ITI-007 exhibits a unique and beneficial
pharmacological profile useful for the treatment of schizophrenia,
mood disorders and insomnia.
Summary of the Phase I Receptor Occupancy Results
This Phase I trial was a single-center, open-label study in
sequential groups of healthy volunteers (N = 2 to 4 at each dose).
At the lowest dose tested (10 mg), ITI-007 fully occupied cortical
5-HT2A receptors (up to 92% displacement of [11C]-MDL100907 in the
prefrontal cortex) with measurable occupancy of D2 receptors (up to
16% displacement of [11C]-raclopride) in the human basal ganglia.
This is consistent with the approximate 60-fold separation between
the 5-HT2A receptor and D2 receptor binding affinities previously
measured in vitro. Moreover, at the highest dose evaluated, 40 mg,
ITI-007 showed similar occupancy for D2 receptors (up to 39%
occupancy) and for SERTs (up to 31% occupancy) in the human basal
Given the unique pharmacological profile of ITI-007 that
includes potent 5-HT2A receptor antagonism, pre-synaptic partial
agonism and post-synaptic antagonism of D2 receptors, and
functional mesolimbic/mesocortical selectivity of dopaminergic and
glutamatergic interactions, ITI-007 is predicted to exhibit
antipsychotic efficacy at low levels of D2 receptor occupancy.
However, the positive safety profile of ITI-007 allows for the
exploration of higher doses and higher levels of receptor
occupancies. Further, the ability of ITI-007 to interact with
SERTs, an important target of antidepressant drug action, expands
the therapeutic utility of this unique drug.
ITI-007 was safe and well-tolerated in healthy volunteers at all
doses evaluated. No serious adverse events were reported.
Pharmacokinetic analyses confirmed good exposure to ITI-007. There
was a significant correlation between ITI-007 receptor occupancy
and ITI-007 plasma levels. Important for a centrally mediated drug,
the brain residency time for ITI-007 far outlasted its plasma
half-life confirming rapid and long-lasting effects in brain.
ITI-007 is the Company's first-in-class 5-HT2A receptor
antagonist/dopamine receptor phosphoprotein modulator
(DPPM)/serotonin reuptake inhibitor for the treatment of
schizophrenia. As a DPPM, ITI-007 has dual properties; it acts as a
post-synaptic antagonist and as a pre-synaptic partial agonist.
ITI-007 also exhibits mesocortical and mesolimbic selectivity as
evidenced by regionally selective increases in dopamine release and
phosphorylation of glutamatergic NMDA NR2B receptors in response to
dopamine D1 receptor activation. The combination of ITI-007's
high-potency blockade of 5-HT2A receptors and unique dopamine
receptor activity should allow a personalized approach to patient
treatment for schizophrenia by making it possible for the first
time to select a clinical dose capable of saturating 5-HT2A
receptors while permitting the "dialing in" of an optimal amount of
dopamine receptor modulation by simple dose adjustments using a
single drug. The ability to optimize the level of dopamine receptor
modulation holds promise for the reduction of psychotic symptoms
without incurring high levels of dopamine antagonism that cause
motor disturbances and other deleterious side effects. In addition,
the wide separation of affinity at 5-HT2A and D2 receptors may
allow for administration of the appropriate amount of dopamine
modulation for antipsychotic maintenance therapy and the treatment
of bipolar disorders. The additional serotonin reuptake inhibition
allows the potential for antidepressant efficacy.
ITI-007 has a low propensity to interact with receptors that
mediate deleterious cardiovascular events, sedation and rapid and
significant weight gain.
At low doses, ITI-007 is sleep promoting without having sedative
properties and should not exhibit adverse effects during the night
(e.g. falls, amnesia) or next day hangover effects that are
commonly associated with other sleep medications. In a Phase II
clinical trial, ITI-007 showed robust, dose-related and
statistically significant increases in deep, slow wave sleep and
decreases in the duration of wake time after sleep onset in
patients with insomnia. ITI-007 is expected to have a strong safety
profile with no addiction liability. This compound is being
evaluated for the treatment of sleep disorders in various patient
populations with sleep maintenance problems and in other sleep
disorders such as sleep disorders in depression, other mood
disorders, Alzheimer's disease and schizophrenia.
ABOUT INTRA-CELLULAR THERAPIES
Intra-Cellular Therapies, Inc. (ITI) is a biopharmaceutical
company developing novel drugs for the treatment of diseases and
disorders of the Central Nervous System (CNS). Building on the
science generated from the Nobel Prize winning laboratory of Dr.
Paul Greengard at The Rockefeller University, the Company develops
compounds that have the potential to treat a wide range of diseases
associated with the CNS, including schizophrenia, sleep disorders,
Parkinson's and Alzheimer's disease, cognitive deficits in
schizophrenia, depression and female sexual dysfunction, and other
disorders pertaining to Women's Health. To aid in the development
process, ITI incorporates its CNSProfile(TM), a state-of-the-art
platform that allows the Company to choose compounds with the
strongest potential to succeed in these difficult to treat
Intra-Cellular Therapies has developed a state-of-the-art
technology platform, CNSProfileTM, capable of generating a unique
molecular signature for drug compounds. Specifically, CNSProfile
measures the levels of phosphoproteins, proteins chemically linked
at specific sites to phosphates. This profile provides the Company
with a proprietary and unique window into the intracellular action
of CNS drugs or drug candidates. Intra-Cellular Therapies uses this
platform in its drug discovery and development efforts of
proprietary compounds and also to evaluate in-licensing
Source: Intra-Cellular Therapies, Inc.
CONTACT: Allen A. Fienberg, Ph.D., Vice President, Business
of Intra-Cellular Therapies, Inc., +1-212-923-3344; or Kathy L. Nugent, Ph.D.
of Burns McClellan, Inc., +1-212-213-0006
Web Site: http://www.intracellulartherapies.com/
Posted: December 2009