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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