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Friday, April 28, 2017

AV-101 Shows Potential In Model of Neuropathic Pain

On April 27, 2017, VistaGen Therapeutics (NASDAQ: VTGN) announced the publication of preclinical data in the Journal of Pain highlighting the potential therapeutic effect of AV-101 for treating neuropathic pain. Scientists from the University of California, San Diego and the University of Maryland School of Medicine, in collaboration with VistaGen Therapeutics, demonstrated the utility of AV-101 in four well-established nonclinical rodent models of pain. The work was supported by VistaGen Therapeutics and research grants provided by the U.S. NIH.

Background On AV-101

VistaGen Therapeutics is currently developing AV-101 as an adjunct treatment for major depressive disorder (MDD). AV-101 is a prodrug candidate of 7-chlorokynurenic acid (7-Cl-KYNA). Upon oral delivery, the inactive AV-101 is transported into the brain by the large neutral amino acid transporter and converted into the active 7-Cl-KYNA form by aminotransferases in astrocytes. The drug is then readily released and acts as a  potent and specific antagonist of the GlyB co-agonist site of the NMDA receptor.

The U.S. NIMH is currently investigating AV-101 in a Phase 2a study (NCT02484456) as a monotherapy for the treatment of MDD under the principal investigation of Dr. Carlos Zarate, MD. Dr. Zarate is one of the nation's foremost experts in the field of depression and has authored over 100 papers on the subject, including paradigm-shifting work with ketamine recently published in Nature (1). Target enrollment for this study is 24 to 28 adult subjects with treatment-resistant MDD. Data are expected late 2017.

VistaGen is currently planning a company-sponsored Phase 2 study with AV-101 separate from the NIMH-sponsored study noted above. The Phase 2 study will be a randomized, double-blind, placebo-controlled study targeting enrollment of 200-250 patients with inadequate response to standard antidepressants. AV-101 will be studied as an adjunctive treatment to background antidepressants in a sequential parallel comparison design (SPCD). The primary endpoint is efficacy as assessed by the MADRS. Maurizio Fava, M.D. of the Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School, is the principal investigator of the study.

Preclinical Data In Neuropathic Pain

In the preclinical study, AV-101 (4-Cl-KYN) prodrug was systematically administered to examine its analgesic and behavioral profile. Two positive control drugs were used, the NMDA receptor antagonist MK-801 and GABA modulator gabapentin. Increasing concentrations of all three drugs were tested in four rat models of pain, assessing general behavioral observations, motor performance, thermal escape latency, evoked flinching, neuropathy, and safety/tolerability.

Researchers observed dose-dependent anti-hyperalgesia effects with AV-101 in all four models. Importantly, systemic delivery of AV-101 yielded brain concentrations of AV-101's active metabolite, 7-Cl-KYNA, that exceeded the IC50 level at the NMDA receptor GlyB binding site. Contrary to the control drugs tested (gabapentin and MK-801), AV-101 had no discernable negative side-effects. And, compared to the control drugs tested, AV-101 has robust anti-nociceptive effects with a better side effect profile, highlighting its potential for treating hyperpathic pain states

For example, MK-801 and gabapentin dose-dependently suppressed rotarod performance, whereas AV-101 has no discernable effect. The rotarod test is used to assess the safety of experimental drugs on motor control, including things like balance, grip strength, and motor coordination.


AV-101 demonstrated a statistically significant reduction in flinch count during both time phases (0-9, 10-60 min) in a formalin-evoked flinching model, whereas gabapentin was only statistically significant during Phase 2 and MK-801 was not statistically significant during either phase.


All three drugs demonstrated a reduction in hyperalgesia using the Carrageenan evoked thermal hyperalgesia model.


Similarly, all three drugs demonstrated improvement in tactile allodynia using a ligated nerve injury model.


Conclusion

The lead indication for AV-101 is as an adjunct for treatment-resistant major depressive disorder; however, the mechanism of action for the drug - NMDA receptor antagonism - has proven therapeutic effect in a number of other CNS disorders, including L-Dopa induced dyskinesia and neuropathic pain. Namenda® (memantine), a glutamatergic NMDA receptor antagonist, is approved for the treatment of Alzheimer's disease. Ketamine, perhaps the most widely used NMDA receptor blocker, is used off-label as a rescue medication for treatment resistant depression and suicidality. 

Gabapentin (Neurontin®) is perhaps the most commonly used drug for chronic neuropathic pain but confers significant sedation, dizziness, and mild cognitive impairment. Lyrica® (pregabalin), a next-generation GABA modulator, offers an improved tolerability profile vs. gabapentin but still carries significant side effects of somnolence and dizziness. Despite the side effects, Pfizer sold nearly $4.2 billion worth of Lyrica in 2016.

A drug that is equally effective on pain, but is better tolerated than gabapentin or pregabalin could be quite important for the management of chronic neuropathic pain. These preclinical data published in the Journal of Pain provide confidence to VistaGen to expand AV-101 development from the current path in treatment-resistant MDD into development as a next generation treatment alternative for patients suffering from neuropathic pain, a market forecasted to grow to $8.4 billion by 2024..

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3 comments:

  1. Is this the same as what Relmada is doing? I am not scientifically trained but I noticed lots of similarities with Vistagen's test product and Relmada's.

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    Replies
    1. RLMD's drug is an NMDA channel blocker, similar to ketamine. VTGN's drug hits a different part of the receptor, the GlyB side. Both have similar ultimate results, they just get there via different paths.

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  2. Is it possible they could now be waiting on the results of the NIMH Phase 2 trial in MDD before starting their own Phase 2.

    ReplyDelete