Sage Therapeutics & Collaborators Publish New Pre-clinical Data in Neuropharmacology Demonstrating a Novel Metabotropic Mecha...
20 October 2016 - 10:00PM
Business Wire
In vitro data show short exposure to certain
neuroactive steroids, including allopregnanolone and novel Sage
tool compound SGE-516, can have sustained effects through
enhancement of extrasynaptic GABAA receptor surface expression
SAGE-547, Sage’s proprietary intravenous
formulation of allopregnanolone, is in late-stage clinical
development for super-refractory status epilepticus, and is being
developed for postpartum depression
SGE-516 was designed with similar pharmacology
to SAGE-217, Sage’s lead oral compound entering Phase 2
development
Sage Therapeutics (NASDAQ: SAGE), a clinical-stage
biopharmaceutical company developing novel medicines to treat
life-altering central nervous system (CNS) disorders, today
announced the publication in the journal Neuropharmacology of
pre-clinical data demonstrating new findings relevant to Sage’s
GABA product candidate portfolio. The paper, titled “Endogenous and
synthetic neuroactive steroids evoke sustained increases in the
efficacy of GABAergic inhibition via a protein kinase C-dependent
mechanism” (Modgil et al., doi: 10.1016/j.neuropharm.2016.10.010),
documents in vitro data on a novel mechanism of action that enables
certain neuroactive steroids to have sustained effects on
extrasynaptic GABAA receptors, in particular by increasing the
number of extrasynaptic receptors on the membrane surface by means
of receptor trafficking.
The change in the number of receptors is achieved by inducing a
metabotropic mechanism, and the impact of this effect may exert
long term enhancement of GABAergic tonic currents. Both
allopregnanolone, a naturally occurring neuroactive steroid, and
SGE-516, a synthetic next generation neuroactive steroid, were
found to induce these changes in vitro, while another synthetic
neuroactive steroid, ganaxolone, did not induce this sustained
enhancement. While neuroactive steroids are known to possess
extrasynaptic activities that may be qualitatively similar, the
metabotropic mechanism and related sustained enhancement exhibited
in this study are distinct from other well-known activities of the
class. Interestingly, not all neuroactive steroids tested produced
this increase in receptor trafficking. GABA is the major inhibitory
neurotransmitter in the CNS, and mediates downstream neurologic and
bodily function via activation of GABAA receptors.
“Whereas neuroactive steroids are known to allosterically
modulate GABAA receptors, our research findings suggest the ability
of neuroactive steroids, specifically allopregnanolone and SGE-516,
a synthetic compound designed with an improved pharmacokinetic
profile, to exert sustained effects on GABAergic inhibition in
vitro by selectively enhancing the trafficking of GABAA receptors
that mediate tonic inhibition,” said Stephen Moss, PhD, Professor
of Neuroscience, Tufts University School of Medicine. “These
findings, which build on our prior research, demonstrate a novel
metabotropic pathway that may contribute to the profound effects
these neurotransmitters have in animal models on neuronal
excitability and behavior. Furthermore, these results indicate that
trafficking is not universally stimulated by all GABAA modulators,
such as ganaxolone as demonstrated in this study or propofol as
shown in a prior study, which did not demonstrate the ability to
metabotropically enhance extrasynaptic receptors in this
study.”
The research highlighted in this article sought to examine the
allosteric and metabotropic properties of allopregnanolone and
synthetic neuroactive steroids, SGE-516 and ganaxolone.
Allopregnanolone and SGE-516 increased the phosphorylation and
surface expression of the β3 subunit-containing extrasynaptic GABAA
receptors in vitro, resulting in increased tonic current. While the
allosteric modulation only exists while the neuroactive steroid is
present, the PKC-mediated metabotropic enhancement can cause a
prolonged increase in inhibitory tone.
“These pre-clinical findings are profoundly relevant for Sage
and our portfolio of novel GABA compounds, particularly as reduced
expression of extrasynaptic GABAA receptors has been demonstrated
in human and rodent models of status epilepticus, postpartum
depression and forms of epilepsy,” said Jim Doherty, PhD, Senior
Vice President of Research at Sage. “We believe the potential
ability of neuroactive steroids, and Sage’s compounds in
particular, to restore tonic inhibition by increasing the surface
expression and trafficking of extrasynaptic GABAA receptors may
provide new ways to approach the treatment of CNS disorders
associated with GABAergic disruption. SGE-516, our novel orally
active GABAA modulator tool compound, used in this study, was
designed with similar pharmacology to SAGE-217, our lead oral
program entering Phase 2 development, and is an example of Sage’s
ability to create novel GABA-targeted compounds with improved
pharmacokinetic profiles compared to first generation
therapies.”
Sage is developing a series of novel positive allosteric
modulators of synaptic and extrasynaptic GABAA receptors. Its lead
product candidate, SAGE-547 (a proprietary formulation of
allopregnanolone), is currently in late-stage development as a
treatment for super-refractory status epilepticus (SRSE), and is
being developed for postpartum depression (PPD). Sage’s lead orally
active compound, SAGE-217, is planned to enter Phase 2 clinical
development for essential tremor and PPD, as well as
proof-of-concept Phase 2 clinical trials in Parkinson’s disease and
major depressive disorder. Sage is also developing a portfolio of
additional novel compounds that target the GABAA receptors,
including SAGE-105, SAGE-324 and SAGE-689.
About Sage TherapeuticsSage Therapeutics is a
clinical-stage biopharmaceutical company committed to developing
novel medicines to transform the lives of patients with
life-altering central nervous system (CNS) disorders. Sage has a
portfolio of novel product candidates targeting critical CNS
receptor systems, GABA and NMDA. Sage's lead program, SAGE-547, is
in Phase 3 clinical development for super-refractory status
epilepticus, a rare and severe seizure disorder, and is being
developed for postpartum depression. Sage is developing its next
generation modulators, including SAGE-217 and SAGE-718, with a
focus on acute and chronic CNS disorders. For more information,
please visit www.sagerx.com.
Forward-Looking Statements
Various statements in this release concern Sage's future
expectations, plans and prospects, including without limitation:
statements about the potential for the findings from the study
described in this release and the likely mechanism of action of
Sage’s compounds to be relevant to future development or clinical
results; our plans with respect to clinical development of our
product candidates; and our other statements regarding the
potential of Sage's product candidates. These forward-looking
statements are neither promises nor guarantees of future
performance, and are subject to a variety of risks and
uncertainties, many of which are beyond our control, which could
cause actual results to differ materially from those contemplated
in these forward-looking statements, including the risks that: the
scientific findings described in this release may not prove to have
relevance in humans or to the efficacy and safety of our product
candidates in any indication or to our ability to successfully
develop our product candidates; we may not be able to successfully
demonstrate the efficacy and safety of our product candidates at
each stage of development; success in early stage clinical trials
and preclinical studies may not be repeated or observed in ongoing
or future studies involving the same compound or other product
candidates; and ongoing and future pre-clinical and clinical
results may not support further development of a product candidate
or be sufficient to gain regulatory approval to market any product;
we may decide that a development pathway for one of our product
candidates in one or more indications is no longer feasible or
advisable; and we may encounter technical and other unexpected
hurdles in the development and manufacture of our product
candidates; as well as those risks more fully discussed in the
section entitled "Risk Factors" in our most recent Quarterly Report
on Form 10-Q, as well as discussions of potential risks,
uncertainties, and other important factors in our subsequent
filings with the Securities and Exchange Commission. In addition,
any forward-looking statements represent our views only as of
today, and should not be relied upon as representing our views as
of any subsequent date. We explicitly disclaim any obligation to
update any forward-looking statements.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20161020005302/en/
Investor Contact:Sage TherapeuticsPaul Cox,
617-299-8377paul.cox@sagerx.comorMedia Contact:Suda Communications
LLCMaureen L. Suda, 585-387-9248maureen.suda@sagerx.com
Sage Therapeutics (NASDAQ:SAGE)
Historical Stock Chart
From Apr 2024 to May 2024
Sage Therapeutics (NASDAQ:SAGE)
Historical Stock Chart
From May 2023 to May 2024