Naurex Inc., a company developing innovative treatments to address unmet needs in psychiatry and neurology, reported that data presented at Neuroscience 2010 show that GLYX-13, its clinical-stage candidate for the treatment of depression, shares key mechanistic features associated with the antidepressant efficacy of the NMDA receptor antagonist ketamine. Numerous studies have shown that ketamine has a markedly faster onset of action than other antidepressants (within hours, instead of weeks) and alleviates depression symptoms in a greater proportion of patients, but its clinical utility has been limited by the high incidence of addictive, dissociative and sedative side effects seen at dose levels close to the therapeutic dose.
GLYX-13 is Naurex’s lead glycine-site functional partial agonist (GFPA) selective modulator of the NMDA receptor (NMDAR). The novel GFPA class of compounds has been specifically designed by Naurex to achieve the well-documented efficacy of classic NMDAR-modulating drugs such as ketamine, while avoiding the serious side effects that have limited their clinical utility.
In previous studies in preclinical models of depression, GLYX-13 demonstrated antidepressant-like effects consistent with those of ketamine. In the preclinical studies presented at Neuroscience 2010, researchers found that three key features associated with the molecular mechanism underlying ketamine’s antidepressant efficacy are also seen with GLYX-13. Similar to ketamine, GLYX-13 appears to exert its antidepressant-like effects, at least in part, through AMPA receptor-dependent activity, shown by an increase in AMPA throughput and blocking of antidepressant effects when an AMPA antagonist is administered. In these studies, antidepressant-like efficacy was demonstrated within minutes of administering a single dose of GLYX-13, and it lasted more than two weeks post-dosing. No ketamine-like side effects were observed.
“Our GFPA modulators are designed to achieve ketamine-like efficacy without ketamine’s side effects,” said Joseph Moskal, Ph.D., founder, president and chief scientist of Naurex. “These new preclinical data confirm that the efficacy mechanism of GLYX-13 is similar to that of ketamine. Since ketamine’s preclinical efficacy has been shown to be predictive of its antidepressant efficacy in humans, these data give us additional confidence that the strong antidepressant efficacy observed in preclinical studies of GLYX-13 will also be predictive of the antidepressant efficacy we will be evaluating in our upcoming Phase 2 trial in treatment-resistant patients.”
The clean safety profile of GLYX-13 has been confirmed in a Phase I clinical trial in healthy volunteers. No psychotomimetic or cardiac side effects were observed at therapeutic doses. In preclinical studies, GLYX-13 has demonstrated the widest therapeutic ratio between efficacy and side effects (>500:1) of any known NMDAR modulator.
“As envisioned by our founding scientists who discovered the GFPA modulators, it appears that the GFPA mechanism of GLYX-13 results in ‘just right’ modulation of the NMDA receptor, achieving efficacy consistent with that of NMDAR blockers such as ketamine, but without the prohibitive side effects that plague those agents,” said Derek Small, acting CEO of Naurex. “We are eager to assess GLYX-13 in our upcoming Phase 2 trial in treatment-resistant depression, testing whether it can help some of the millions of patients who are poorly served by existing therapies, and provide relief within hours—rather than weeks—of receiving a single dose.”
Naurex will initiate a Phase II proof-of-concept trial early next year to evaluate GLYX-13 in patients who are not achieving an adequate response to their current antidepressant agents.
In addition to GLYX-13, Naurex is developing the NRX-1050 series of GFPAs, including numerous second-generation, orally available molecules with structures and mechanisms of action similar to GLYX-13.
Date: November 17, 2010
Source: Naurex Inc.