US-based VistaGen Therapeutics has received clearance from the US Food and Drug Administration (FDA) and the US National Institutes of Health (NIH) to begin a Phase II clinical trial of its orally active AV-101 in patients with treatment-resistant major depressive disorder (MDD).

AV-101 is an orally active, clinical-stage prodrug candidate that readily gains access to the central nervous system (CNS) after systemic administration and is rapidly converted in vivo to its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA)

The US National Institutes of Mental Health (NIMH) Neurobiology and Treatment of Mood Disorders chief and Experimental Therapeutics and Pathophysiology Branch chief Dr Carlos Zarate will be the principal investigator of the NIH-funded trial.

Around 25 patients with MDD will be included in the randomised, double-blind, placebo-controlled, crossover Phase II trial, which will be conducted at the NIMH to evaluate the efficacy and safety of a single oral dose of AV-101 administered once per day for 14 days.

NIMH and the company expect to begin patient enrolment in the trial in the third quarter of this year.

7-Cl-KYNA is a well-characterised, potent and highly-selective antagonist of the glycine-binding co-agonist (GlyB) site of the N-methyl-D-aspartate receptor (NMDAR).

According to the company, current evidence shows that AV-101’s antagonism of NMDAR signalling may provide fast-acting antidepressant effects in MDD treatment.

VistaGen Therapeutics president and chief scientific officer Ralph Snodgrass said: "The NIMH and several key leaders in the field with clinical experience using ketamine to treat MDD provided valuable expert advice on the design of our Phase II MDD study.

"We are grateful for their assistance. With their help, we have now achieved an important regulatory milestone for our AV-101 clinical development program.

"The pharmacology and existing clinical safety data and preclinical efficacy data point to AV-101’s potential to provide a transformative advancement in the treatment of MDD, in a manner fundamentally different from all currently approved antidepressants."

Additionally, as confirmed in two Phase I clinical trials, using AV-101 to target the GlyB site of the NMDAR may bypass potential adverse effects that occur with ketamine, while activating similar pathways resulting in the ‘glutamate surge’ that has been related with increased neurogenesis and the rapid-acting antidepressant effects of ketamine observed in previous clinical trials.