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SOUTH SAN FRANCISCO, Calif.—VistaGen Therapeutics recently announced positive results of preclinical studies on 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 observed in PD patients treated with levodopa.
According to Shawn Singh, CEO of VistaGen Therapeutics, “AV-101 belongs to a new generation of investigational medicines in neuropsychiatry and neurology known as NMDA (N-methyl-D-aspartate) glutamate receptor modulators. AV-101 (4-Cl-KYN) is an orally available investigational prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and selective full antagonist of the glycine site of the NMDAR. AV-101’s mechanism of action is fundamentally different from all current oral antidepressants, oral pain medications and the standard oral treatments for LID [levodopa-induced dyskinesia].”
“AV-101 is actively transported across the blood-brain barrier and converted into 7-Cl-KYNA in the brain, primarily in astrocytes and predominantly by kynurenine aminotransferase II, the major enzyme responsible for the levels of kynurenic acid that can be rapidly mobilized in the brain. 7-Cl-KYNA, an allosteric antagonist, then binds to the glycine site of the NMDA receptor and inhibits NMDA receptor activity associated with a range of central nervous system (CNS) indications,” Singh continues.
“Although 7-Cl-KYNA is a full antagonist at the glycine site of the NMDAR, it does not block the ion channel of the NMDAR. Instead, 7-Cl-KYNA, an allosteric antagonist, down-regulates activity of the NMDAR, which in part is believed to account for AV-101’s exceptional safety profile and lack of psychological side effects and safety concerns often associated with classic NMDAR antagonists such as ketamine and amantadine. Because the NMDA receptor is a prevalent and pivotal receptor in the brain ... we believe AV-101 may have the potential to treat a wide range of diseases and disorders involving the CNS,” he adds.
In the MPTP primate model, AV-101’s antidyskinetic effects were similar to those generally observed with amantadine therapy, but AV-101 did not cause the adverse effects experienced with amantadine.
The MPTP primate model used in this study is the gold standard for animal modeling of PD and has been used extensively to study both antiparkinsonian therapies and LID. MPTP is a neurotoxin that kills dopaminergic neurons in the striatum, producing motor symptoms similar to those of PD. In 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.
The study demonstrated that AV-101 significantly reduced LID without affecting the timing, extent or duration of the therapeutic benefits of levodopa. This research was conducted by Dr. Thérèse Di Paolo, professor in the Faculty of Pharmacy at Laval University and among the world’s leading researchers focused on Parkinson’s disease and LID, pursuant to VistaGen’s research agreement with CHU de Québec–Université Laval Research Center in Canada. Summary results of the study will be presented at an upcoming scientific conference.
“The antidyskinetic activity of AV-101 that we measured compares favorably with our observation with amantadine in parkinsonian monkeys,” said Di Paolo. “Better than amantadine ... we observed no adverse effects with AV-101.”
Singh notes that “AV-101 was originally created with hope that it could positively impact a wide range of CNS diseases and disorders with high unmet therapeutic need, including LID, without causing the often debilitating side effects and safety concerns associated with many current CNS mediations. We believe AV-101 has potential to help individuals with PD who are suffering from the effects of extended levodopa treatment for PD, such as unwanted abnormal involuntary movements, including chorea and dystonia. These motor complications tend to become more severe as PD progresses and as the duration of levodopa treatment is extended, until the impact of LID may compromise the advantage of treatment with levodopa.”
“In all studies to date, there has been no evidence that AV-101 causes the psychological side effects and drug-related safety concerns associated with many current CNS medications, including amantadine therapy for LID,” he says. “[T]hese preclinical data and AV-101’s positive safety profile in all clinical studies to date support AV-101’s potential to treat LID, while both maintaining the antiparkinsonian benefits of levodopa and without causing hallucinations or other serious side effects that may be associated with current amantadine-based therapy for LID.”
“We believe that AV-101 has significant potential to treat numerous serious CNS-related conditions, including MDD [major depressive disorder], LID, CNP [chronic neuropathic pain], epilepsy and suicidal ideation,” Singh adds. “We are currently engaged in a first-step clinical study focused on U.S. veterans and suicidal ideation to facilitate progress toward a Phase 2 study. This study is being conducted in conjunction with Baylor and the U.S Department of Veterans Affairs.”
Singh points out that the next major milestones for the company will involve VistaGen’s Phase 2 ELEVATE study, which is testing AV-101 as an add-on treatment for MDD in individuals who have inadequate response to SSRIs or SNRIs. There will be a data read-out for ELEVATE later this year. The FDA has granted Fast Track designation for development of AV-101 as a potential adjunctive treatment for MDD.
“If ELEVATE demonstrates AV-101’s potential as an add-on treatment of MDD, we will advance development for that indication into pivotal Phase 3. In addition, building on recently reported positive preclinical data, we are also planning next steps for Phase 2a development of AV-101 as a new non-opioid, non-sedating treatment for CNP (for which we have Fast Track designation from the FDA) and as a new treatment for LID in individuals with PD, for which we hope to receive FTD from the FDA,” concludes Singh.