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VistaGen Therapeutics, Inc. (VSTA) Partners with NIH in its Sponsored Phase 2 Study of Orally-Active AV-101 in MDD

VistaGen Therapeutics, a clinical-stage biopharmaceutical company focused on developing innovative medicine for depression and conditions associated with the central nervous system, has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institute of Mental Health (NIMH), a component of the U.S. National Institutes of Health (NIH). The CRADA enables VistaGen and the NIMH to partner on an NIH-sponsored Phase 2 clinical study of AV-101 in subjects with Major Depressive Disorder (MDD). MDD is a pervasive and debilitating mental disorder which affects millions of people worldwide. It has been noted that as many as 7% of all adults have some form of MDD.

Dr. Carlos Zarate, Chief of the Section on the Neurobiology and Treatment of Mood Disorders and Chief of the Experimental Therapeutics and Pathophysiology Branch at the NIMH, will be the Principal Investigator of the NIH-funded study, which will be a randomized, double-blind, placebo-controlled, crossover Phase 2 clinical trial designed to study the efficacy and safety of an oral dose of AV-101 taken once per day for two weeks. The study involves approximately 25 subjects with MDD. The main efficacy measure will be the Hamilton Depression Rating Scale (HDRS) – the subject standard for measuring the severity of MDD. The study is anticipated to be completed this year.

Mr. H. Ralph Snodgrass, VistaGen’s President and CSO, commented, “We are excited by the strong preclinical efficacy data supporting the ketamine-like antidepressant effects of AV-101, as well as the rapid and efficient oral-delivery and clinical safety range demonstrated by our successful Phase 1 clinical studies. Dr. Zarate and his team have deep experience with ketamine and other NMDA receptor antagonists. We look forward to collaborating closely with them to complete this important AV-101 Phase 2 study in MDD by year end.”

While the majority of people will experience moods of depression at some point during their lives, it should not be confused with clinically diagnosed MDD. MDD is the chronic, pervasive feeling of unhappiness and suffering, impairing how one functions. Symptoms of MDD include lower levels of pleasure in activities, insomnia or hypersomnia, weight changes, fatigue, feelings of worthlessness and guilt, poor concentration, suicidal thoughts and psychomotor agitation. It has been estimated that suicide is the cause of death in as much as 15% of individuals with MDD.

Current medications available in the multi-billion dollar global antidepressant market are known to have limited effectiveness. Because of this, their mechanism of action, SSRIs and SNRIs, must be taken for several weeks before patients experience any significant therapeutic benefit. Studies show that over 60% of depression sufferers do not benefit from first round treatments, and the likelihood of achieving remission of depressive symptoms declines with each successive treatment attempt.

In the placebo-controlled, double-blind clinical trials conducted by Dr. Zarate and others at the NIMH, ketamine produced expedient antidepressant effects in MDD patients who had not responded to approved antidepressants. Although the potential for widespread therapeutic use of ketamine is limited by its potential for abuse, dissociative and psychosis-like side effects, and practical challenges associated with its required intravenous administration in a medical center, the discovery of ketamine’s rapid onset antidepressant effects revolutionized thinking about the MDD treatment paradigm and mechanism of action of antidepressant medicines. The discovery also increased interest in the development of a new generation of antidepressants with a mechanism of action similar to ketamine’s, including a more rapid therapeutic benefit compared to existing agents.

AV-101’s fundamentally novel mechanism of action places it among a new generation of glutamatergic antidepressants with potential to address millions of MDD sufferers worldwide who are poorly served by SSRIs, SNRIs and other current depression therapies. Similar to ketamine, AV-101 down-regulates NMDA receptor channel activity. However, unlike ketamine’s antagonistic activity, which results from its blocking the NMDA receptor channel, AV-101’s antagonistic activity results from its selective binding to, and blocking of, the functionally-required glycine-binding co-agonist site of the NMDA receptor. Targeting the glycine-binding co-agonist site of the NMDA receptor may bypass potential adverse effects that occur with ketamine without affecting the robust efficacy observed in previous clinical studies. This may then result in the “glutamate surge” that has been associated with the rapid-acting antidepressant effects of ketamine.

To date, NIH has awarded VistaGen $8.8 million to advance its preclinical and Phase 1 clinical development of AV-101. In two randomized, double-blind, placebo-controlled Phase 1 safety studies, AV-101 was well tolerated and not associated with any severe adverse events. There were no signs of sedation, hallucinations or schizophrenia-like side effects often associated with ketamine and traditional NMDA receptor channel blockers.

VistaGen is a clinical-stage biopharmaceutical company developing innovative medicine for depression and conditions involving the central nervous system. VistaGen’s AV-101 is a new generation orally-available NMDA receptor glycine B-site antagonist now moving into Phase 2 clinical development for MDD. Preclinical studies to date have shown that AV-101 may also have potential as a treatment for other CNS-related conditions, including chronic neuropathic pain and epilepsy, Parkinson’s and Huntington’s disease. VistaGen is using its proprietary pluripotent stem cell technology and clinically-predictive bioassay systems, CardioSafe 3D™ and LiverSafe 3D™, for drug rescue applications focused on producing proprietary, novel new chemical entities (NCEs) that are safer versions of drug candidates previously optimized and tested for efficacy by pharmaceutical companies.

For more information on the company, visit

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