Current evidence suggests that AV-101’s antagonism of NMDA signaling may provide rapid-onset antidepressant effects in the treatment of Major Depressive Disorder. In addition, as confirmed in Phase 1 clinical studies, targeting the glycineB coagonist site of the NMDA receptor does not have the adverse effects typically associated with classic NMDA receptor antagonists, such as ketamine and other NMDA channel blockers. The fact that AV-101 is a safe, well-tolerated, oral drug, with strong preclinical data in three animal models of depression, suggests that AV-101 has the potential of a breakthrough treatment for Major Depressive Disorder.  We have completed preclinical studies and Phase 1 clinical safety studies supporting the Phase 2 clinical development of AV-101 in Major Depressive Disorder.

Depression is a global public health concern. The World Health Organization estimates that “depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease,” affecting 350 million people globally, including nearly 7% of adults in the United States.

Although approved treatments are available, many of such treatments require several weeks before therapeutic benefits are achieved, and, ultimately, millions of patients remain symptomatic following such treatments.

Classic NMDA receptor channel blockers, such as ketamine, have been shown in clinical trials to act rapidly to alleviate symptoms of depression. These clinical studies, many of which were conducted by the U.S. National Institutes of Health (NIH), introduced a new paradigm for the research and development of antidepressants with rapid-onset action, in stark contrast to existing FDA-approved antidepressants. However, their potential for widespread clinical use has been severely limited by their high risk for abuse and behavioral impairment, including schizophrenia-like side effects, and required i.v. administration.

VistaGen’s AV-101 is a novel potent oral NMDA receptor glycineB-site antagonist with demonstrated potential to achieve the well-documented efficacy of classic NMDA receptor channel blockers, such as ketamine, without causing their serious side effects. AV-101 is a pro-drug that efficiently crosses the blood-brain barrier and is rapidly converted into 7-chlorokynurenic acid (7-Cl-KYNA) by astrocytes, which is released into the synaptic spaces. 7-Cl-KYNA is a well-characterized, potent and highly selective antagonist of N-methyl-D-aspartate (NMDA) receptors due to its antagonistic binding to the glycineB site of the NMDA receptor.

In preclinical studies, AV-101 has demonstrated the robust antidepressant-like activity of ketamine, including its rapid onset and long duration of effect, without ketamine’s serious side effects. In two Phase I clinical trials in the U.S., AV-101 was well tolerated, with adverse events for the groups receiving AV-101 no different than placebo controls. There were no signs of sedation, hallucinations or the schizophrenia-like side effects often associated with ketamine and other drugs that modulate the NMDA receptor.

To date, the U.S. National Institutes of Health (NIH) has awarded us $8.8 million of grant funding for our successful preclinical and Phase 1 clinical development of AV-101. We are now in discussions with the NIH regarding a collaborative Phase 2 clinical study of AV-101 in Major Depressive Disorder to address the high unmet medical need for faster, more effective and safe antidepressant therapy for patients who have had an inadequate response to existing FDA-approved antidepressant therapies.

Depression statistics infographic