Depression affects nearly 7% of all adults in the U.S. and over 350M people worldwide according to the World Health Organization, and it is a major contributor to overall disease statistics. GBI Research forecasts the global antidepressant market as growing to around $13.4B by 2018 with a CAGR of approximately 1.8%, even though the primary market component, serotonin re-uptake inhibitors (SSRIs), has continued to produce red flags like ill-served patients and a variety of dangerous side effects.
The FDA-approved anaesthetic ketamine is currently used for starting and maintaining anesthesia, with the chief applications being to induce sedation during intensive care or as a serious pain killer. However, ketamine has also more recently been shown to have significant effect as a fast-acting antidepressant in depression patients that don’t respond well to the typical depression medicine available on the market today, such as Prozac, which mostly target monoamine neurotransmitters. Pharmacologically classified as an NMDA (N-methyl-D-aspartate) receptor antagonist, ketamine induces a trance-like state and, in addition to pain relief and sedation, causes memory loss. Ketamine is classified as a dissociative agent alongside other drugs in its class, like PCP (phencyclidine), with side psychotomimetic effects like confusion, seeing flashing lights and bright color, things that make it popular as a club drug of abuse. The clinical and therapeutic emergence of ketamine in major depressive disorder (MDD) has naturally been significantly slowed down, despite its efficacy in placebo-controlled studies at the NIH, due to these acute psychosis-like side effects (and the potential for abuse, despite having to be administered intravenously), opening up a massive opportunity for a new generation of safe and effective, fast-acting drugs giving the benefits of ketamine while minimizing or eliminating these psychotomimetic side effects.
The rush is now officially on to bring such fast-acting antidepressant agents to market, but to gain widespread approval and clinical acceptance, such agents would ideally need to have comparably robust efficacy and rapidity of onset to intravenously (IV) administered ketamine, according to the Global Therapeutic Head of Neuroscience at Johnson & Johnson (NYSE:JNJ), Husseini K. Manji, MD, FRCPC. Dr. Manji has also noted that to truly gain widespread acceptance, such agents really need vital characteristics that further distinguish them from ketamine, like oral availability and a toxicology profile that would make the agent viable for daily or even chronic use.
One such promising new generation agent, GLYX-13, is an IV-administered partial NMDA receptor agonist being developed by a private company, Naurex, Inc. which raised $18M during its launch of Phase 2 efficacy testing for GLYX-13 back in 2011, and that was without any prior clinical efficacy data. To date, based mostly on the potential of GLYX-13, which is currently Phase 3-ready, Naurex has raised over $160M from a broad array of sector heavy-hitters, including Baxter Ventures, the venture capital arm of Baxter International (NYSE:BAX). Naurex’s latest raise brought in $80M this December 3, largely due to positive Phase 2 data showing robust and sustained antidepressant effect in major depressive disorder patients, again with giants like Baxter and Genesys (NSE:GENESYS) on board.
Another promising new generation antidepressant agent, currently entering Phase 2 development, the same pipeline stage as GLYX-13 was in when Naurex raised that first $18M chunk of their development war chest, is AV-101 from VistaGen Therapeutics (OTCQB: VSTA). VistaGen’s share price is highly accessible to investors and the company is currently poised to launch an important Phase 2 clinical efficacy study of AV-101 in early 2015. The company is planning to collaborate with the National Institute of Mental Health (NIMH) under a Cooperative Research and Development Agreement (CRADA) expected to provide NIH sponsorship of the study.
AV-101, a prodrug which is rapidly and enzymatically converted into the established and highly potent NMDAR antagonist, 7-chlorokynurenic acid (7-Cl-KYNA), after crossing the blood-brain barrier, is novel, orally available (in a capsule), non-sedating, and non-hallucinogenic, with no signs of the schizophrenia-like side effects associated with other NMDA channel blockers, such as ketamine. VistaGen’s focus on the glycine binding site (GlyB) within the NMDAR could prove to be one of the best approaches in the new generation antidepressant space to date, potentially offering compelling advantages over competitors like oral-availability and a highly selective method of action.
VistaGen also has an ace up their sleeve, a highly-respected NIH physician with considerable clinical experience using ketamine in major depression, Dr. Carlos Zarate, Chief of the Experimental Therapeutics & Pathophysiology Branch (ETPB) and Section on the Neurobiology and Treatment of Mood Disorders at the NIMH. Dr. Zarate will be conducting the NIH-sponsored Phase 2 efficacy study of AV-101 for major depression early next year. They should have the CRADA hammered out sometime early next month. Savvy investors will want to keep an ear to the ground for developments on AV-101, as this candidate could emerge as one of the leading new generation antidepressants, with therapeutic potential in a variety of central nervous system (CNS) disorders as well, including chronic neuropathic pain, epilepsy and even neurodegenerative diseases like Parkinson’s disease and Huntington’s disease.
For more information on VistaGen Therapeutics, visit: www.vistagen.com
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