SBIR-STTR Award

Chronic pain is a major disorder affecting millions of Americans and costing the health community billions of dollars annually. While opiates are the drug of choice in treating acute pain, they have limited effectiveness, and have abuse and side effects issues that limit their use in treating chronic pain, especially neuropathic pain. A number of studies have indicated that NMDA receptor antagonists can produce analgesia and are effective in neuropathic pain animal models. However, direct acting NMDA receptor antagonists, in general, have been found to cause cognitive impairment in humans as well as other side effects that limit their therapeutic utility. NMDA receptors can also be blocked by inhibitors of the "GlyB" co-agonist site of the NMDA receptor, and glycine antagonists reduce hyperalgesia and allodynia in neuropathic pain models. Importantly, GlyB antagonists have fewer side effects than classic NMDA receptor antagonists, making them a safer alternative as analgesics. 7-Chlorokynurenic acid (7-C1-KYNA) is one of the most potent and specific GlyB antagonists known, and it has powerful anticonvulsant and neuroprotective actions in brain. However, like other glycine antagonists, 7-CI-KYNA doesn't easily penetrate the blood brain barrier. However, its prodrug, L-4-chlorokynurenine (4-CI-KYN), readily gains access to the brain following systemic administration and is efficiently converted to therapeutically relevant concentrations of 7-CI-KYNA. Therefore, 4-CI-KYN has unique properties that make it desirable in treating neuropathic pain; oral availability, it is preferentially converted to 7-CI-KYNA in brain areas that suffer neuronal injury and the site of greatest therapeutic need, and likely to have fewer negative side effects. VistaGen would like to develop 4-CI-KYN for the treatment of chronic pain. The goal of this Phase I SBIR grant is to produce sufficient preclinical efficacy data on the utility of 4-CI-KYN as an analgesic to support an IND application. This will be done by testing the effectiveness of 4-CI-KYN in established models of pain, including neuropathic pain.

we proposed to develop a novel drug, 4-CI-KYN to treat neuropathic pain. 4-CI-KYN is a pro-drug of 7-Chlorokynurenic acid (7-Cl-KYNA), a chlorinated analogue of kynurenic acid, which is a natural neuromodulator and one of the most potent and specific GlyB antagonists known to man, which blocks glutamate transmission through the NMDA receptor. This receptor is important in mediating pain transmission, and drugs that block NMDA receptor produce analgesia. However, direct acting NMDA antagonists produce a number of side effects which have limited their therapeutic utility. In contrast, GlyB antagonists inhibit NMDA receptor function, reduce hyperalgesia and allodynia in neuropathic pain models, and have fewer side effects than classic NMDA receptor antagonists, making them a safer alternative as analgesics. 7-Cl-KYNA prevents excitotoxic and ischemic neuronal damage but like most GlyB antagonists does not cross the blood-brain barrier. 4-Cl-KYN, on the other hand, readily gains access to the brain following systemic administration and is efficiently converted to 7-Cl-KYNA specifically in brain areas with neuronal injury, and many believe that the hyperalgesia and allodynia associated with neuropathies originate from nerve damage or persistent activation and remodeling. Consequently, 4-Cl-KYN has a highly focused site of conversion in the CNS and spinal cord, and local concentrations of newly formed 7-Cl-KYNA are greatest at the site of therapeutic need. This reduces the level of systemic drug needed, and lowers the risk of side effects with long-term use of the drug. In our Phase I SBIR grant we showed that 4-Cl-KYN, which we refer to as AV-101, has potent antihyperalgesic actions in three models of peripheral tissue inflammation and nerve injury with no evidence of side effects. These preclinical studies support the efficacy of AV101 as an anti-hyperalgesic and its usefulness as a potential treatment of neuropathic pain. In subsequent studies, VistaGen developed an oral formulation of AV-101, conducted ADME analysis and subjected AV-101 to safety and toxicological assessments. Overall AV-101 is well tolerated, produces no safety or toxicity at doses that produce antihyperalgesic effects in animal models. Following on a positive pre-IND meeting with the FDA, we propose in this Phase II SBIR grant to conduct initial Phase 1 clinical safety evaluation of AV-101. The initial focus for our clinical development of AV-101 will be for the treatment of pain associated with human immunodeficiency virus-associated sensory neuropathy (HIV-SN). To begin the initial human testing of AV-101, we propose to conduct safety and pharmacokinetic studies in healthy human volunteers after single dose and repeated dosing of AV-101 to assess the maximum tolerated dose and the pharmacokinetic profiles of AV-101. AV-101 will also be tested in two pain models for efficacy in healthy human volunteers to gain an initial assessment of potential efficacy. These studies will provide the basis for Phase 2 clinical testing of AV-101 in treating neuropathic pain.

Public Health Relevance:
The goal of the proposed project is to test the safety of AV-101 in healthy human volunteers in Phase I clinical trials, and to also generate preliminary data on AV-101's potential efficacy. VistaGen is focused on developing AV-101 as a treatment for neuropathic pain and other neurodegenerative disorders. Positive results from this study will serve as a basis for further development of AV-101 in Phase II trials for treatment of neuropathic pain.

Thesaurus Terms:
2-Quinolinecarboxylic Acid, 4-Hydroxy-; 7-Chlorokynurenic Acid; Aids Virus; Absence Of Pain Sensation; Absence Of Sensibility To Pain; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Adverse Effects; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Animal Model; Animal Models And Related Studies; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Area; Blood - Brain Barrier Anatomy; Blood-Brain Barrier; Body Tissues; Brain; Clinical; Clinical Evaluation; Clinical Testing; Clinical Treatment; Clinical Trials, Phase I; Clinical Trials, Phase Ii; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Development; Dose; Drug Formulations; Drug Kinetics; Drug Precursors; Drug Usage; Drugs; Early-Stage Clinical Trials; Encephalon; Encephalons; Evaluation; Feels No Pain; Formulation; Formulations, Drug; Glutamates; Goals; Grant; Hiv; Htlv-Iii; Hand; Hemato-Encephalic Barrier; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Human Volunteers; Human, General; Hyperalgesia; Hyperalgesic Sensations; Inflm; Inflammation; Kynurenic Acid; L-Glutamate; Lav-Htlv-Iii; Lymphadenopathy-Associated Virus; Man (Taxonomy); Man, Modern; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Mediating; Medication; Medulla Spinalis; Modeling; N Methyl D Aspartic Acid; N Methyl D Aspartate; N-Methyl-D-Aspartate Receptors; N-Methyl-D-Aspartate; N-Methylaspartate; Nmda; Nmda Receptor-Ionophore Complex; Nmda Receptors; Nmda Receptor Antagonist; Nerve; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neuromodulator; Neuronal Injury; Neurons; Neuropathy; No Sensitivity To Pain; Oral; Pain; Painful; Peripheral; Peripheral Sensory Neuropathy; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase Ii Clinical Trials; Pro-Drugs; Prodrugs; Receptor Protein; Receptors, N-Methylaspartate; Risk; Sbir; Sbirs (R43/44); Safety; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Spinal Cord; Testing; Therapeutic; Tissues; Toxic Effect; Toxicities; Transmission; Treatment Side Effects; Virus-Hiv; Volunteers, Human; Allodynia; Analgesia; Analog; Base; Clinical Test; Drug Use; Drug/Agent; Hyperalgia; Man; Man's; Meetings; Model Organism; Nerve Injury; Neural Injury; Neurodegenerative Illness; Neuron Injury; Neuronal; Neuropathic; Neuropathic Pain; Novel; Painful Neuropathy; Phase 1 Study; Phase 1 Trial; Phase 2 Study; Phase 2 Trial; Phase I Trial; Phase Ii Trial; Preclinical Study; Prevent; Preventing; Protocol, Phase I; Protocol, Phase Ii; Public Health Relevance; Receptor; Receptor Function; Research Clinical Testing; Safety Testing; Sensory Neuropathy; Side Effect; Study, Phase Ii; Therapy Adverse Effect; Transmission Process; Treatment Adverse Effect; Trial Regimen; Trial Treatment