AV-101 · program

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

DiscontinuedDiscontinuedVistagen Therapeutics, Inc. (VTGN)
  • FDA Fast Track (Adjunctive Treatment Of MDD; Granted December 2017)

Indications for AV-101: Levodopa-induced dyskinesia in Parkinson's disease · Phase 1 Neuropathic pain · Phase 1 Major depressive disorder · Discontinued

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.

Data current as of

Development timeline

DiscontinuedJun 2023
  1. INFERRED, not announced. The FY2022 10-K (2022-06-23) still listed AV-101 plus probenecid as a potential MDD treatment. The FY2023 10-K (2023-06-28) shifted to 'Phase 2A development ... as a treatment for one or more neurological disorders', and the FY2026 10-K names only LID and neuropathic pain and says no further development on its own. Vistagen has made no explicit discontinuation statement for MDD; the date is the first filing reflecting the pivot.↗
Phase 2Oct 2015 – Mar 2020
  1. missedNIMH crossover trial in treatment-resistant depression (n=19): 4-Cl-KYN 1080-1440 mg/day for 14 days had no antidepressant effect on HAM-D versus placebo (treatment-by-time P=.16); CSF 7-Cl-KYNA mostly below detection.↗
  2. missedELEVATE Phase 2 (adjunctive AV-101 1440 mg/day in MDD, n=199): AV-101 did not differentiate from placebo on change from baseline in MADRS-10; well tolerated, no psychotomimetic effects or SAEs.↗
  3. Vistagen's ELEVATE Phase 2 adjunctive MDD trial (NCT03078322) started.
  4. Trial startedELEVATE Phase 2 trial of adjunctive AV-101 in MDD starts
  5. Fast TrackFDA grants Fast Track designation to AV-101 for adjunctive treatment of major depressive disorder↗
  6. NIMH-sponsored Phase 2 crossover study of AV-101 monotherapy in treatment-resistant MDD (NCT02484456) started.

Readouts

  • 2020-03-31ReportedFull resultsmissedNCT02484456

    NIMH crossover trial in treatment-resistant depression (n=19): 4-Cl-KYN 1080-1440 mg/day for 14 days had no antidepressant effect on HAM-D versus placebo (treatment-by-time P=.16); CSF 7-Cl-KYNA mostly below detection. ↗

  • 2019-11-14ReportedTopline datamissedNCT03078322

    ELEVATE Phase 2 (adjunctive AV-101 1440 mg/day in MDD, n=199): AV-101 did not differentiate from placebo on change from baseline in MADRS-10; well tolerated, no psychotomimetic effects or SAEs. ↗

Clinical trials in Major depressive disorder

NCT03078322VSG-CL 003Phase 2Completedn=180

Double-Blind, Placebo-Controlled, Phase 2 Trial to Test Efficacy and Safety of AV-101 (L-4-chlorokynurenine) as Adjunct to Current Antidepressant Therapy in Patients With Major Depressive Disorder (the ELEVATE Study)

Started Mar 2018· Primary completion Oct 2019· 📍 22 sites across 1 country (United States)

NCT02484456150151Phase 2Completedn=22

An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder

Started Oct 2015· Primary completion Feb 2019· 📍 1 site across 1 country (United States)

Formulations

FormulationRouteRegimenPharmacokinetics
AV-101 oral capsule
Oral capsules. ELEVATE (adjunctive MDD): 1440 mg daily for 14 days. NIMH TRD crossover: 1080 mg/day for 7 days then 1440 mg/day for 7 days. Phase 1b healthy volunteers: 360, 1080 or 1440 mg daily for 14 days. Planned LID Phase 2: '1440 mg ... administered twice a day orally' per the registry arm text. Drug-interaction study: single 360 mg capsule alone or 2 h after 1000 mg probenecid.
OralOther—

Mechanism of action (compound-wide)

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.

TargetActionAffinity
NMDA receptorprimaryGRIN1Antagonist—ⓘ

← Full AV-101 compound page (identity, identifiers, all indications)

Sources

  1. NCT02484456 (NIMH 150151) — Antidepressant effects of the glycine receptor antagonist AV-101 (4-chlorokynurenine) in major depressive disorder — ClinicalTrials.gov (U.S. National Library of Medicine)
  2. NCT03078322 (VSG-CL 003, ELEVATE) — Phase 2 AV-101 as adjunct antidepressant therapy in MDD — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT05280054 (AV-101 CL005) — AV-101 alone and with probenecid in healthy subjects (drug-drug interaction) — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. Park LT, Kadriu B, Gould TD, ... Zarate CA Jr. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020;23(7):417-425 — International Journal of Neuropsychopharmacology (Oxford University Press) via PubMed Central
  5. VistaGen Reports Topline Phase 2 Results for AV-101 as an Adjunctive Treatment of Major Depressive Disorder (2019-11-14) — VistaGen Therapeutics, Inc. (PR Newswire via BioSpace)
  6. Vistagen Therapeutics Form 10-K for fiscal year ended 2023-03-31 (filed 2023-06-28) — AV-101 section and Fast Track designation dates — Vistagen Therapeutics, Inc. via SEC EDGAR
  7. Vistagen Therapeutics Form 10-K for fiscal year ended 2026-03-31 (filed 2026-06-15) — AV-101 section — Vistagen Therapeutics, Inc. via SEC EDGAR