VistaGen Therapeutics announced positive new data from the Company's second preclinical study of its oral investigational drug, AV-101, in combination with probenecid. Probenecid has extensive data supporting its safe oral delivery and ability to increase the therapeutic benefit of various antibacterial, anticancer and antiviral drugs.

The results of this new study complement previous preclinical data demonstrating the combination's potential to substantially increase the brain concentration of AV-101's active metabolite, 7-Cl-KYN, a potent and selective full antagonist of the NMDA receptor glycine co-agonist site, thereby reducing, rather than blocking, NMDA receptor signaling.

"These new positive results amplify our message that AV-101, when administered in combination with probenecid, has exciting therapeutic potential across a wide range of CNS indications," said Shawn Singh, Chief Executive Officer of VistaGen. "The studies completed to date are promising and will help us determine the best next step in our overall development plan for the combination."

The second preclinical pharmacokinetic (PK) study of AV-101 and probenecid involved four groups: AV-101 (10 mg/kg and 50 mg/kg) with and without probenecid (30 mg/kg). Plasma and cerebral spinal fluid (CSF), as an indicator of brain concentration of 7-Cl-KYNA in dogs, were collected. A single oral gavage administration of AV-101 at both dose levels alone or in combination with intravenous probenecid was well-tolerated. CSF levels of both AV-101 and 7-Cl-KYNA increased roughly dose proportionally. AV-101 administered with probenecid increased the CSF 7-Cl-KYNA AUC (total drug exposure across time) by approximately 4.6 times, compared to AV-101 alone.

This PK study data are significant for three reasons: (i) CSF levels of AV-101, and especially 7-Cl-KYNA, rose dramatically, while there was only a modest increase in blood levels of AV–101; (ii) the AV–101-probenecid combination appeared safe and well-tolerated; and (iii) the significant increase in level and duration of 7-Cl-KYNA continues to suggest that adding probenecid could achieve therapeutic 7-Cl-KYNA brain levels that may not be achieved by AV-101 alone.

AV-101 (4-Cl-KYN) targets the NMDAR (N-methyl-D-aspartate receptor), an ionotropic glutamate receptor in the brain. Abnormal NMDAR function is associated with numerous CNS diseases and disorders. AV-101 is an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), which is a potent and selective full antagonist of the glycine co-agonist site of the NMDAR that inhibits the function of the NMDAR. Unlike ketamine and many other NMDAR antagonists, 7-Cl-KYNA is not an ion channel blocker.

In all studies to date, AV-101 has exhibited no dissociative or hallucinogenic psychological side effects or safety concerns similar to those that may be caused by NMDAR antagonists that block the ion channel of the NMDAR, such as amantadine, esketamine and ketamine. With its exceptionally few side effects and excellent safety profile in all clinical studies to date, AV-101, in combination with probenecid, has potential to be an oral new generation treatment for multiple large-market CNS indications where current standard of care is inadequate.