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Sage Therapeutics and Collaborators Publish New Pre-clinical Data in Neuropharmacology Demonstrating a Novel Metabotropic Mechanism of Sage Compounds Resulting in Enhanced Effects
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
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
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
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 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
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