AV-101 (L-4-chlorokynurenine)

Mechanism of action#

AV-101 (4-Cl-KYN) is an oral prodrug that targets the NMDA receptor. Its active metabolite, 7-chloro-kynurenic acid (7-Cl-KYNA), is a potent and selective full antagonist of the glycine (co-agonist) binding site of the NMDA receptor and inhibits receptor function. Unlike ketamine and many other NMDA antagonists, 7-Cl-KYNA is not an ion-channel blocker. Vistagen reports that an extensive receptor screen found no off-target binding of AV-101 or 7-Cl-KYNA. Nonclinical results also indicate that chronic 4-Cl-KYN administration induces hippocampal neurogenesis and increases endogenous kynurenic acid, itself a functional glycine-site antagonist. A key clinical limitation is brain exposure: in the NIMH depression trial, CSF 7-Cl-KYNA was mostly below detection (<1.4 ng/mL) at 1080-1440 mg/day.

Formulations#

AV-101 (L-4-chlorokynurenine) for Levodopa-induced dyskinesia in Parkinson's disease#

Phase 1SuspendedLevodopa-induced dyskinesia in Parkinson's disease indication →

AV-101 (L-4-chlorokynurenine), an oral prodrug of the NMDA-receptor glycine-site antagonist 7-Cl-KYNA, for dyskinesia in Parkinson's disease patients on levodopa therapy (LID). The FDA cleared Vistagen's IND for a Phase 2 study in LID on 2020-01-30, supported by primate data: in MPTP-lesioned monkeys AV-101 250 mg/kg twice daily reduced levodopa-induced dyskinesia by about 25% while preserving levodopa's antiparkinsonian response. The planned Phase 2 trial (NCT04147949, a randomized, double-blind, placebo-controlled crossover proof-of-concept study in about 20 patients, primary endpoint Unified Dyskinesia Rating Scale) was registered in November 2019 but never opened; its last registry update (May 2021) lists it as not yet recruiting. Vistagen first ran a Phase 1B study of AV-101 with probenecid in healthy volunteers (NCT05280054) to explore raising brain exposure. As of the 10-K filed 2026-06-15, Vistagen names LID as a potential use but does not plan further development of AV-101 on its own and is looking for a third-party partner, so the program is recorded as suspended.

AV-101 (L-4-chlorokynurenine) for Neuropathic pain#

Phase 1SuspendedNeuropathic pain indication →

AV-101 (L-4-chlorokynurenine), an oral prodrug of the NMDA-receptor glycine-site antagonist 7-Cl-KYNA, as a potential non-opioid treatment for neuropathic pain. The only registered clinical study in this indication is a Phase 1b healthy-volunteer study (NCT01483846, completed September 2012, collaborators Cato Research and NIDA). It tested 360, 1080 and 1440 mg/day for 14 days for safety, pharmacokinetics and effect on capsaicin-induced hyperalgesia; the study is registered under neuropathic pain. The FDA granted Fast Track designation for neuropathic pain in September 2018. No neuropathic-pain patient trial has been registered. As of its 10-K filed 2026-06-15, Vistagen names neuropathic pain as a potential use but does not plan further development of AV-101 on its own and is looking for a third-party partner.

AV-101 (L-4-chlorokynurenine) for Major depressive disorder#

DiscontinuedDiscontinuedMajor depressive disorder indication →

AV-101 (L-4-chlorokynurenine), an oral prodrug of the NMDA-receptor glycine-site antagonist 7-Cl-KYNA, was developed as a fast-acting, non-dissociative antidepressant. Two Phase 2 trials were negative. ELEVATE (NCT03078322), Vistagen's adjunctive study in MDD patients with inadequate response to an SSRI or SNRI, randomized 199 patients at 25 US sites to AV-101 1440 mg/day or placebo using a sequential parallel comparison design. On 2019-11-14 Vistagen reported that AV-101 did not differentiate from placebo on MADRS-10 change from baseline. The drug was well tolerated, with no psychotomimetic effects or serious adverse events. An NIMH-sponsored crossover trial in treatment-resistant depression (NCT02484456; n=19) found no antidepressant effect on HAM-D at 1080-1440 mg/day, and 7-Cl-KYNA was mostly undetectable in cerebrospinal fluid. Vistagen attributed the failures to insufficient brain exposure and explored co-dosing with probenecid. From its FY2023 10-K onward it positioned AV-101 for neurological disorders (LID, neuropathic pain). It now does not plan further development on its own, so the depression program is recorded as discontinued.

Clinical trials#