L-4-chlorokynurenine (AV-101) News

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101). (Pubmed Central) - Jan 23, 2024
Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

|||||||||| Journal: Clinical specificity profile for novel rapid acting antidepressant drugs. (Pubmed Central) - Jun 29, 2023
This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.

|||||||||| Review, Journal: Novel antidepressant drugs: Beyond monoamine targets. (Pubmed Central) - Feb 27, 2023
The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: Diversity-Oriented Biosynthesis Yields l-Kynurenine Derivative-Based Neurological Drug Candidate Collection. (Pubmed Central) - Feb 7, 2023
Our work highlights the great potential of existing enzymes in addressing long-standing synthetic challenges for facilitating the development or discovery of new drug candidates. Furthermore, our approach enables translating the reaction parameters from Eppendorf tubes to 1 L scale, affording l-4-Cl-Kyn and l-5-Cl-Kyn both on a gram scale with more than 80% isolated yields, and provides a promising alternative to further industrial applications.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: AV-101, a Pro-Drug Antagonist at the NMDA Receptor Glycine Site, Reduces L-Dopa Induced Dyskinesias in MPTP Monkeys. (Pubmed Central) - Nov 27, 2022
Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Preclinical: $VTGN InvestorNewsBreaks — VistaGen Therapeutics Inc. (NASDAQ: VTGN) Publishes Positive Preclinical Findings Related to AV-101 https://t.co/TNm4q33Aat (Twitter) - Nov 17, 2022

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
New P1 trial, Combination therapy:  AV-101 Alone and in Combination With Probenecid in Healthy Subjects (clinicaltrials.gov) -  Mar 15, 2022
P1, N=24, Recruiting,  Sponsor: VistaGen Therapeutics, Inc.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: Does mismatch negativity have utility for NMDA receptor drug development in depression? (Pubmed Central) - Feb 19, 2022
P1, P1/2,
We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Biomarker, Enrollment change:  Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) -  Feb 17, 2022
P1/2, N=18, Completed,  Sponsor: Marijn Lijffijt, PhD
This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606. N=12 --> 18

|||||||||| Review, Journal: Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (Pubmed Central) - Jan 7, 2022
Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: Probenecid Increases the Concentration of 7-Chlorokynurenic Acid Derived from the Prodrug 4-Chlorokynurenine within the Prefrontal Cortex. (Pubmed Central) - Oct 7, 2021
In summary, our data show that 4-Cl-KYN crosses the BBB using LAT1, while its active metabolite, 7-Cl-KYNA, is rapidly transported out of the brain via OAT1/3 and MRP4. We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Clinical, Journal: A Randomized Trial of the N-methyl-d-aspartate Receptor Glycine Site Antagonist Prodrug 4-chlorokynurenine in Treatment-Resistant Depression. (Pubmed Central) - Sep 24, 2021
P2
We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect. In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Clinical, Journal: A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans. (Pubmed Central) - Jun 24, 2021
Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

|||||||||| ganaxolone oral (CCD-1042) / Marinus
Review, Journal: Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders. (Pubmed Central) - Jun 16, 2021
We cover both glutamate-targeting drugs such as: esketamine, AVP-786, REL-1017, AXS-05, rapastinel (GLYX-13), AV-101, NRX-101; as well as GABA-targeting drugs such as: brexanolone (SAGE-547), ganaxolone, zuranolone (SAGE-217), and PRAX-114. We focus the review on phase-II and phase-III clinical trials and evaluate the extant data and progress of these compounds.

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial completion date, Trial primary completion date:  AV-101 (L-4-chlorokynurenine) in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesia (clinicaltrials.gov) -  May 26, 2021
P2, N=20, Not yet recruiting,  Sponsor: VistaGen Therapeutics, Inc.
We focus the review on phase-II and phase-III clinical trials and evaluate the extant data and progress of these compounds. Trial completion date: Apr 2022 --> Apr 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
[VIRTUAL] The Impact of NMDA Antagonists Ketamine and Prodrug 4-Chlorokynunerine (AV-101) in Subjects With Treatment-Resistant Mood Disorders () - Apr 10, 2021 - Abstract #SOBP2021SOBP_1963;

|||||||||| ketamine / Generic mfg.
Journal: Progress in the development of kynurenine and quinoline-3-carboxamide derived drugs. (Pubmed Central) - Mar 5, 2021
4-Cl-KYN has completed clinical trials in depression without success...Quinoline-3-carboxamide derivatives laquinimod, paquinimod, and tasquinimod show structural similarities to kynurenines...Further clarification may emerge from studies involving higher drug concentration, and/or from identification of ketamine targets. Clinical application trials in very diverse indications of structurally related quinoline-3-carboxamides and the wide range of their mode of action warrant further studies permitting direct comparison of effects and better target identification.

|||||||||| galantamine hydrobromide / Generic mfg.
Journal: Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task. (Pubmed Central) - Oct 1, 2020
These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.

|||||||||| memantine / Generic mfg.
[VIRTUAL] Auditory Mismatch Negativity as Event-Related Potential (ERP) Biomarkers for NMDA Receptor Antagonist Medications () - Sep 30, 2020 - Abstract #ACNP2020ACNP_362;
(Rosburg et al., 2016). This effect is sustained for at least 30 min after end of infusion (Umbricht D 2000).

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen, amantadine / Generic mfg.
[VIRTUAL] 4-Chlorokynurenine inhibits L-Dopa-induced dyskinesias in non-human parkinsonian primates () - Sep 20, 2020 - Abstract #MDSCongress2020MDS Congress_332;
Presented at the 7th Int. Conf.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Journal: Biosynthesis of L-4-Chlorokynurenine, a Lipopeptide Antibiotic Non-Proteinogenic Amino Acid and Antidepressant Prodrug. (Pubmed Central) - Sep 17, 2020
This work revealed the first tryptophan 2,3-dioxygenase (Tar13) and kynurenine formamidase (Tar16) enzymes that are selective for chlorinated substrates. The substrate scope of Tar13, 14, and 16 was examined revealing intriguing promiscuity, thereby opening doors for the targeted engineering of these enzymes as useful biocatalysts.

|||||||||| ketamine / Generic mfg., L-4-chlorokynurenine (AV-101) / VistaGen
The Impact of Ketamine and AV-101 on the Kynurenine Pathway in Subjects With Treatment-Resistant Unipolar or Bipolar Depression () - Apr 17, 2020 - Abstract #SOBP2020SOBP_1137;
P2
Unlike ketamine, AV-101 had no significant treatment efficacy in subjects with treatment-resistant MDD and no significant effects on the KYN pathway or related peripheral and central measures. Funding Source: National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857; NCT02484456)

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Cortical Gamma as a Marker of Kynurenine Pathway Engagement in Healthy Veterans Receiving L-4-Chloro-Kynurenine (AV-101) (Americas Hall I & II) - Apr 17, 2020 - Abstract #SOBP2020SOBP_990;
More broadly, combining EEG and KP metabolites could be used to inform multimodal biomarkers of NMDAR target engagement. Future studies could examine the effect of AV-101 dose on suicide risk, which has been associated with KP dysregulation and increased activation of NMDARs.

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial completion date, Trial initiation date, Trial primary completion date:  AV-101 (L-4-chlorokynurenine) in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesia (clinicaltrials.gov) -  Jan 13, 2020
P2, N=20, Not yet recruiting,  Sponsor: VistaGen Therapeutics, Inc.
Future studies could examine the effect of AV-101 dose on suicide risk, which has been associated with KP dysregulation and increased activation of NMDARs. Trial completion date: Jul 2021 --> Apr 2022 | Initiation date: Jul 2020 --> Dec 2020 | Trial primary completion date: Jul 2021 --> Dec 2021

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial primary completion date:  Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder (clinicaltrials.gov) -  Dec 6, 2019
P2, N=22, Completed,  Sponsor: National Institute of Mental Health (NIMH)
Trial completion date: Jul 2021 --> Apr 2022 | Initiation date: Jul 2020 --> Dec 2020 | Trial primary completion date: Jul 2021 --> Dec 2021 Trial primary completion date: Dec 2019 --> Feb 2019

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial completion:  Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder (clinicaltrials.gov) -  Dec 5, 2019
P2, N=22, Completed,  Sponsor: National Institute of Mental Health (NIMH)
Trial primary completion date: Dec 2019 --> Feb 2019 Recruiting --> Completed

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Biomarker, Trial completion:  Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) -  Nov 15, 2019
P1/2, N=12, Completed,  Sponsor: Marijn Lijffijt, PhD
Recruiting --> Completed Recruiting --> Completed

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
P2 data: $VTGN Reports Topline Phase 2 Results for AV-101 as an Adjunctive Treatment of Major Depressive Disorder. #Fail (Twitter) - Nov 14, 2019

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
New P2 trial:  AV-101 (L-4-chlorokynurenine) in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesia (clinicaltrials.gov) -  Nov 3, 2019
P2, N=20, Not yet recruiting,  Sponsor: VistaGen Therapeutics, Inc.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Evoked and Resting State Gamma Mechanics to Test NMDA Receptor Engagement of Kynurenine Pathway Modulator AV-101 in Healthy Veterans (Floridian Ballroom) - Oct 17, 2019 - Abstract #ACNP2019ACNP_1240;
High dose AV-101 is associated with increased gamma ITPC, indicating stronger event-related interneuron firing. These findings are consistent with NMDAR blockade by AV-101.

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
A Randomized Trial of the NMDAR Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression (Floridian Ballroom) - Oct 17, 2019 - Abstract #ACNP2019ACNP_730;
In this small cross-over trial, 4-Cl-KYN monotherapy had no antidepressant effect or anti-anxiety efficacy in this sample of subjects with treatment-resistant MDD subjects. Furthermore, 4-Cl-KYN appeared to have no biochemical effects, as no significant changes were observed in glutamate brain levels measured by 7T 1H-MRS, rs-fMRI connectivity, or peripheral and central measures (including tryptophan/kynurenine metabolites).

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial completion, Trial completion date:  ELEVATE: AV-101 as Adjunct Antidepressant Therapy in Patients With Major Depression (clinicaltrials.gov) -  Oct 9, 2019
P2, N=180, Completed,  Sponsor: VistaGen Therapeutics, Inc.
Furthermore, 4-Cl-KYN appeared to have no biochemical effects, as no significant changes were observed in glutamate brain levels measured by 7T 1H-MRS, rs-fMRI connectivity, or peripheral and central measures (including tryptophan/kynurenine metabolites). Active, not recruiting --> Completed | Trial completion date: Dec 2019 --> Oct 2019

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Enrollment closed, Trial completion date, Trial primary completion date:  ELEVATE: AV-101 as Adjunct Antidepressant Therapy in Patients With Major Depression (clinicaltrials.gov) -  Aug 15, 2019
P2, N=180, Active, not recruiting,  Sponsor: VistaGen Therapeutics, Inc.
Active, not recruiting --> Completed | Trial completion date: Dec 2019 --> Oct 2019 Recruiting --> Active, not recruiting | Trial completion date: Jun 2019 --> Dec 2019 | Trial primary completion date: May 2019 --> Nov 2019

|||||||||| L-4-chlorokynurenine (AV-101) / VistaGen
Clinical: $VTGN Achieves Target Patient Enrollment in the ELEVATE Study of AV-101 as an Adjunctive Treatment for MDD. Topline Data Before EOY'19. (Twitter) - Aug 15, 2019

|||||||||| ganaxolone oral (CCD-1042) / Marinus
Review, Journal: A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (Pubmed Central) - Aug 3, 2019
Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Biomarker, Trial completion date, Trial primary completion date:  Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) -  Jul 9, 2019
P1/2, N=12, Recruiting,  Sponsor: Marijn Lijffijt, PhD
We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217. Trial completion date: Mar 2019 --> Oct 2019 | Trial primary completion date: Mar 2019 --> Oct 2019

|||||||||| Journal: Glutamatergic Modulators in Depression. (Pubmed Central) - Jun 7, 2019
These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Biomarker, Enrollment open, Trial completion date, Trial primary completion date:  Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) -  Oct 30, 2018
P1/2, N=12, Recruiting,  Sponsor: Marijn Lijffijt, PhD
Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]). Not yet recruiting --> Recruiting | Trial completion date: Sep 2018 --> Mar 2019 | Trial primary completion date: Sep 2018 --> Mar 2019

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Biomarker, New P1/2 trial:  Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) -  Jul 15, 2018
P1/2, N=12, Not yet recruiting,  Sponsor: Marijn Lijffijt, PhD

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Enrollment open, Trial completion date, Trial primary completion date:  ELEVATE: AV-101 as Adjunct Antidepressant Therapy in Patients With Major Depression (clinicaltrials.gov) -  Mar 9, 2018
P2, N=180, Recruiting,  Sponsor: VistaGen Therapeutics, Inc.
Not yet recruiting --> Recruiting | Trial completion date: Sep 2018 --> Mar 2019 | Trial primary completion date: Sep 2018 --> Mar 2019 Not yet recruiting --> Recruiting | Trial completion date: Mar 2019 --> Jun 2019 | Trial primary completion date: Jan 2019 --> Apr 2019

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial initiation date:  ELEVATE: AV-101 as Adjunct Antidepressant Therapy in Patients With Major Depression (clinicaltrials.gov) -  Aug 3, 2017
P2, N=180, Not yet recruiting,  Sponsor: VistaGen Therapeutics, Inc.
Not yet recruiting --> Recruiting | Trial completion date: Mar 2019 --> Jun 2019 | Trial primary completion date: Jan 2019 --> Apr 2019 Initiation date: Jun 2017 --> Jan 2018

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
New P2 trial:  ELEVATE: AV-101 as Adjunct Antidepressant Therapy in Patients With Major Depression (clinicaltrials.gov) -  Mar 12, 2017
P2, N=180, Not yet recruiting,  Sponsor: VistaGen Therapeutics, Inc.

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
New P2 trial:  Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder (clinicaltrials.gov) -  Jun 29, 2015
P2, N=25, Recruiting,  Sponsor: National Institute of Mental Health (NIMH)

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
Trial completion:  Safety, Tolerability and Pharmacokinetics of Multiple Doses of AV-101 in Healthy Volunteers (clinicaltrials.gov) -  Oct 22, 2012
P1, N=50, Completed,  Sponsor: VistaGen Therapeutics, Inc.
Initiation date: Jun 2017 --> Jan 2018 Not yet recruiting --> Completed

||||||||||  L-4-chlorokynurenine (AV-101) / VistaGen
New P1 trial:  Safety, Tolerability and Pharmacokinetics of Multiple Doses of AV-101 in Healthy Volunteers (clinicaltrials.gov) -  Nov 29, 2011
P1, N=50, Completed,  Sponsor: VistaGen Therapeutics, Inc.



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