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Naurex Pipeline: Overview of R&D Programs
Naurex is developing a pipeline of molecules based on a new mechanism of action for modulating the NMDA receptor (NMDAR).
Naurex’s 1st-generation lead compound is GLYX-13, a novel partial agonist of the NMDA receptor that is in development as an adjunctive therapy for patients with depression who do not respond adequately to current therapy. GLYX-13 has shown promising results in Phase I and Phase II clinical trials and in preclinical studies. In a Phase II trial evaluating the use of GLYX-13 in subjects who had not achieved adequate responses to current antidepressant agents, subjects receiving a single dose of GLYX-13 had a rapid and long-lasting reduction in depression scores with good safety. Another Phase II trial is currently underway evaluating the effects of repeated dosing of GLYX-13.
Naurex's 2nd-generation compound, NRX-1074, is an orally bioavailable NMDAR partial agonist that will be developed as a therapy for major depressive disorder. NRX-1074 is currently in preclinical development and the company intends to file an IND in early 2013.
Naurex is also advancing 3rd-generation NMDAR partial agonists with a different activity profile that is potentially suited to the treatment of schizophrenia (including negative and cognitive symptoms). Additional 2nd- and 3rd-generation compounds from the company's novel NMDAR modulation platform are advancing in preclinical development.
Naurex’s research has shown that compounds generated from its NMDAR modulation platform have the potential for therapeutic utility in a number of CNS conditions, including:
- Mood and anxiety disorders
- Cognitive disorders
- Developmental disorders
- Neuropathic pain
NMDA Receptor Modulators as Potential CNS Drugs
The glutamate receptor subtype known as NMDA plays a central role in modulating aspects of brain activity in the central nervous system, including synaptic transmission, synaptic plasticity and excitotoxicity. Major pharmaceutical firms have been developing NMDAR modulators for over 20 years, and a few, including memantine, ketamine, D-cycloserine and dextromethorphan are marketed for non-depression CNS indications, generating annual sales of more than $1 billion.
The antidepressant potential of modulating the NMDA receptor has been confirmed by data from clinical studies with known NMDAR antagonists, such as ketamine, which produced significant reductions in depression scores in patients with treatment-resistant depression. In these studies, the potentantidepressant effects of ketamine were evident within hours of a single dose and lasted weeks from a single dose. This is in contrast to traditional antidepressants that can take multiple weeks to have an effect, require daily dosing to sustain the effect and fail to adequately improve symptoms in as many as half of patients. These data have confirmed the NMDA receptor as a target of high interest in depression, representing a potentially entirely new way to treat patients who do not respond adequately to current therapies. But, while the efficacy of these drugs is promising, they are also associated with significant toxicities at doses that are very close to the therapeutic dose. These toxicities include dissociative effects, such as hallucinations, as well as sedation and abuse and addiction potential. Until now, the narrow margin between therapeutic effects and adverse effects has limited the full therapeutic potential of these agents.
Given the central role played by the NMDA receptor in synaptic and CNS function, the receptor is a target of significant interest in the discovery of therapies for a variety of CNS disorders. NMDAR antagonists have demonstrated potential as therapies for neuropathic pain and other CNS conditions. Research with NMDAR agents with greater agonist activity has shed light on their potential for treating cognitive and developmental disorders, as well as neurodegenerative conditions. But the existing agents with this type of NMDAR modulation profile also have off-target effects that make them unsuitable for development as therapies for CNS disorders.
Partial Agonists of the NMDA Receptor: A Novel Approach with Encouraging Data
Naurex scientists designed the company’s novel partial agonists of the NMDA receptor to achieve the efficacy of previously known NMDAR modulators without their limiting side effects. In preclinical and clinical studies to date, the company’s compounds have demonstrated the therapeutic efficacy of classic NMDAR modulators with no evidence of these side effects. The novel chemistry underlying Naurex's NMDAR modulation platform is also generating a number of compounds with a rich variety of partial agonist/antagonist activity profiles profiles that may make them suitable as therapies for a variety of CNS disorders.