L-4-chlorokynurenine (AV-101) / VistaGen - LARVOL DELTA

Vistagen Receives U.S. Patent for AV-101 to Treat Neuropathic Pain (Businesswire) - "Vistagen (Nasdaq: VTGN)...today announced that the U.S. Patent and Trademark Office (USPTO) granted a patent to the Company for its oral non-opioid product candidate, AV-101, for the treatment of neuropathic pain. The patent will not expire until at least 2034 and is part of Vistagen’s global patent portfolio on manufacturing methods and therapeutic uses for AV-101 to treat various disorders involving the NMDA receptor."

Patent • Pain

Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101). (PubMed, Mol Pharm) - "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 • SLC7A5

Vistagen Receives Notice from European Patent Office of Intention to Grant Patent for AV-101 to Treat Neuropathic Pain (Businesswire) - "Vistagen...today announced that the European Patent Office (EPO) issued a Notice of Intention to Grant a patent related to the use of AV-101 for the treatment of neuropathic pain. The patent, once granted, will not expire until at least 2034 and will become part of Vistagen’s global patent portfolio on therapeutic uses and manufacturing techniques for AV-101."

Patent • CNS Disorders • Neuralgia • Pain

Vistagen Receives Notice of Allowance for AV-101 Canadian Patent for Treatment of Dyskinesia Related to Levodopa Therapy for Parkinson’s Disease (Businesswire) - "Vistagen...announced that the Canadian Intellectual Property Office (CIPO) issued a Notice of Allowance for a patent related to the use of AV-101 for reduction of dyskinesia (sudden uncontrolled movements) induced by the administration of levodopa (L-Dopa), the most commonly prescribed medication for treatment of Parkinson's disease (PD)."

Patent • CNS Disorders • Parkinson's Disease

Clinical specificity profile for novel rapid acting antidepressant drugs. (PubMed, Int Clin Psychopharmacol) - "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."

Journal • CNS Disorders • Cognitive Disorders • Insomnia • Mood Disorders • Psychiatry • Sexual Disorders • Sleep Disorder • Suicidal Ideation

Vistagen Receives New European Patent for AV-101 (Businesswire) - "Vistagen...today announced that the European Patent Office (EPO) has granted the Company a patent for AV-101, its oral NMDAR (N-methyl-D-aspartate receptor) glycine site antagonist. The patent relates to the synthesis of AV-101 and certain chemical intermediaries, which synthesis yields AV-101 in commercial quantities and has the scalability for commercial manufacture. The new European patent is a counterpart to previously granted U.S. patent 11,427,530 and will be in effect until at least 2039. Based on observations and findings from preclinical animal models translatable to human conditions targeting the NMDAR, AV-101 has the potential to become a new oral treatment alternative for multiple CNS disorders involving the NMDAR, such as dyskinesia associated with levodopa therapy for Parkinson’s disease, major depressive disorder and neuropathic pain."

Patent • CNS Disorders • Major Depressive Disorder • Pain • Parkinson's Disease

Diversity-Oriented Biosynthesis Yields l-Kynurenine Derivative-Based Neurological Drug Candidate Collection. (PubMed, ACS Synth Biol) - "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."

Journal • CNS Disorders • Developmental Disorders • TDO2

AV-101, a Pro-Drug Antagonist at the NMDA Receptor Glycine Site, Reduces L-Dopa Induced Dyskinesias in MPTP Monkeys. (PubMed, Cells) - "L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. 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."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

"$VTGN InvestorNewsBreaks — VistaGen Therapeutics Inc. (NASDAQ: VTGN) Publishes Positive Preclinical Findings Related to AV-101 https://t.co/TNm4q33Aat" (@otcdynamics)

Preclinical

Vistagen Announces Publication in Cells Demonstrating AV-101’s Potential for Treating Levodopa-Induced Dyskinesia in Patients with Parkinson's Disease (Businesswire) - "Vistagen...announced the publication of positive results from a preclinical study of the effects of AV-101, its oral NMDA receptor glycine site antagonist, in a widely used MPTP non-human primate model for reproducing motor complications of Parkinson's disease (PD), including dyskinesia (sudden uncontrolled movements) observed in PD patients treated with levodopa (L-Dopa). Findings from the preclinical study were published in the international, peer-reviewed journal, Cells. In the preclinical study, AV-101 reduced L-Dopa-induced dyskinesias (LID) by about 25% while maintaining the antiparkinsonian response to L-Dopa....n this study, AV-101's efficacy against LID was measured through behavioral scores on a dyskinesia scale, and a Parkinsonian disability scale was used to measure levodopa antiparkinsonian efficacy. This study demonstrated that AV-101 significantly (p = 0.01) reduced LID without affecting the timing, extent, or duration of the therapeutic benefits of levodopa."

Preclinical • CNS Disorders • Parkinson's Disease

AV-101 Alone and in Combination With Probenecid in Healthy Subjects (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: VistaGen Therapeutics, Inc.

Combination therapy • New P1 trial

Electrophysiological Biomarkers of AV-101 (clinicaltrials.gov) - P1/2 | N=18 | Completed | Sponsor: Marijn Lijffijt, PhD | N=12 ➔ 18

Biomarker • Enrollment change

Levodopa-induced dyskinesia: a brief review of the ongoing clinical trials. (PubMed, Neurodegener Dis Manag) - No abstract available

Clinical • Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

IMPAHCT: A Study of AV-101 (Dry Powder Inhaled Imatinib) in Patients With Pulmonary Arterial Hypertension (PAH) (clinicaltrials.gov) - P2b; N=462; Recruiting; Sponsor: Aerovate Therapeutics; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Novel antidepressant drugs: Beyond monoamine targets. (PubMed, CNS Spectr) - "The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. 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..."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

IMPAHCT: A Study of AV-101 (Dry Powder Inhaled Imatinib) in Patients With Pulmonary Arterial Hypertension (PAH) (clinicaltrials.gov) - P2b; N=462; Not yet recruiting; Sponsor: Aerovate Therapeutics

Clinical • New P2b trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

VistaGen Therapeutics Reports Fiscal Year 2022 First Quarter Financial Results and Provides Corporate Update (GlobeNewswire) - "PH10 Nasal Spray: Exploratory Phase 2A clinical development of PH10 as a potential rapid-onset treatment of major depressive disorder (MDD) has been completed. VistaGen is preparing to initiate a U.S. Phase 2B multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety and tolerability of PH10 as a potential rapid-onset, stand-alone treatment for MDD in mid-2022....AV-101: VistaGen is currently preparing to initiate a Phase 1B clinical study to evaluate AV-101 in combination with probenecid during the second half of calendar 2021."

New P1 trial • New P2b trial • Trial completion • CNS Disorders • Depression • Major Depressive Disorder

Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders. (PubMed, Chronic Stress (Thousand Oaks)) - "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."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

AV-101 (L-4-chlorokynurenine) in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesia (clinicaltrials.gov) - P2; N=20; Not yet recruiting; Sponsor: VistaGen Therapeutics, Inc.; Trial completion date: Apr 2022 ➔ Apr 2024; Trial primary completion date: Dec 2021 ➔ Dec 2023

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Gastrointestinal Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

[VIRTUAL] The Impact of NMDA Antagonists Ketamine and Prodrug 4-Chlorokynunerine (AV-101) in Subjects With Treatment-Resistant Mood Disorders (SOBP 2021) - No abstract available

Clinical • CNS Disorders • Mood Disorders • Psychiatry

Does mismatch negativity have utility for NMDA receptor drug development in depression? (PubMed, Braz J Psychiatry) - P1, P1/2, P3 | "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."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VistaGen Therapeutics Reports Fiscal 2021 Third Quarter Financial Results and Provides Update on Expected Clinical Studies in Calendar 2021 (VistaGen Press Release) - " 'This year, we will also complete preparations to launch Phase 2B clinical development of PH10 as a potential rapid-onset stand-alone treatment for major depressive disorder in early 2022. Finally, later this year, based on successful preclinical studies involving AV-101 alone and in combination with probenecid, we will launch Phase 1B'...PH10 development expenses increased by approximately $1.5 million in the quarter ended December 31, 2020...AV-101-related expenses decreased primarily due to the completion of the Company’s multi-center Phase 2 study of AV-101 for the adjunctive treatment of major depressive disorder in the quarter ended December 31, 2019....At December 31, 2020, the Company had cash and cash equivalents of approximately $104.3 million....Sufficient to advance an important stream of potential clinical and regulatory catalysts, including...Phase 2B clinical development of PH10..."

Commercial • New P1 trial • New P2b trial • CNS Disorders • Depression • Major Depressive Disorder

VistaGen: Patience Could Lead To Significant Upside (SeekingAlpha) - "AV-101 initiated a Phase 2 study...in Parkinson's disease subjects with levodopa-induced dyskinesia estimated to have a primary completion date in Dec. 2021."

Trial primary completion date • CNS Disorders • Parkinson's Disease

VistaGen Therapeutics Announces Pricing of Underwritten Public Offering (GlobeNewswire) - "VistaGen Therapeutics, Inc....today announced the pricing of its underwritten public offering consisting of 63,000,000 shares of its common stock at an offering price of $0.92 per share...All of the securities in the offering are being sold by VistaGen....VistaGen intends to use the net proceeds from the offering for research, development and manufacturing and regulatory expenses associated with continuing development of PH94B, PH10, AV-101, and potential drug candidates to expand its CNS pipeline and for other working capital and general corporate purposes."

Financing • CNS Disorders • Depression • General Anxiety Disorder • Parkinson's Disease