What is GRX-917?2019-09-22T19:26:44+00:00

GRX-917 is a proprietary (patent-protected until 2036), improved version of Etifoxine, an anxiety drug first approved in France 39 years ago. GRX-917 is a deuterated version of Etifoxine (specific hydrogen atoms were replaced by isotopic deuterium (heavy hydrogen) atoms). Like the vast majority of deuterated drug analogs, GRX-917 retains the same mechanism of action and pharmacological properties as etifoxine, because their biological properties are identical.

Clinically, GRX-917’s speed of onset, efficacy and side effects profile will be identical to the original drug. However, the pharmacokinetic profile is significantly improved as a result of reduced metabolism due to deuterium stabilization.  Critically, GRX-917’s metabolism remains identical to etifoxine, but with a reduced rate. This is expected to lead to lower and/or less frequent dosing and more consistent exposure, leading to better efficacy and less potential side effects/adverse effects than the original drug.

What is GRX-917’s Mechanism of Action?2019-09-22T19:26:54+00:00

GRX-917’s main mechanism of action increases the amount of naturally occurring neurosteroids (like allopregnanolone) by activation of TSPO on mitochondria. This increase of endogenous neurosteroids occurs in areas in the brain where they are used to activate GABA receptors, slowing dysregulated brain activity in diseases like anxiety and depression, but minimizing the typical side effects of GABA drugs, like benzodiazepines. Additionally, increases of neurosteroids acting at other receptors have been found to minimize neuroinflammation, affect neuroregeneration and modulate the activation of microglia – potentially key elements in therapeutics for Alzheimer’s Disease, Multiple Sclerosis and Parkinson’s Disease.

How Effective is GRX-917 for Anxiety?2019-09-22T19:33:53+00:00

Etifoxine (and therefore GRX-917) has been shown through multiple published, peer reviewed clinical studies, to have comparable rapid onset and efficacy to leading benzodiazepines, including like alprazolam (Xanax™) and lorazepam (Ativan™).

What are the Side Effects of GRX-917?2019-09-22T19:29:01+00:00

Over 40 years of research and clinical data on etifoxine (and therefore GRX-917) has shown that the drug has little to no side effects:

  • No Sedation (some people say slight sedation on day one which quickly remits)
  • No Cognitive Impairment
  • No Ataxia

What is the Safety Profile of GRX-917?2019-09-22T19:29:11+00:00

Etifoxine (and therefore GRX-917) has an excellent safety/pharmacological profile, based on a safety profile review by ANSM in France (2000-2012) which analyzed over 14 million prescriptions of etifoxine.

  • Non addictive (no cases of abuse, misuse or pharmacodependence)
  • No tolerance, withdrawal or rebound
  • Low ADRs (21 per million) based on +14 million prescriptions analyzed in France (2000-2012)
  • SAEs are very rare and occur less frequently than with both first line and second-line anxiolytics

Why Was Etifoxine Never Introduced into the United States?2019-09-22T19:29:45+00:00

Early Beginnings

The original, non-deuterated drug (etifoxine) was originally developed to compete with tranquilizing and sedative BZs of the 1960’s, such as Valium and Librium. But it was mischaracterized as a mild benzodiazepine, because of its lack of typical benzodiazepine side effects, like sedation and ataxia. Hoechst sold the rights to the drug, without knowing its true efficacy and unaware of its mechanism of action. A small pharmaceutical distributor has been producing and distributing the drug off-patent since 1979, in limited markets. The drug was never developed in the U.S. or broader European markets.

Discovering the Extraordinary Mechanism of Action

Contrary to what was originally believed, French researchers in the 2000’s discovered that etifoxine did not interact at the benzodiazepine site on GABA receptors! It took sophisticated modern research techniques to reveal a truly significant discovery: The drug increases the levels of natural neurosteroids, like allopregnanolone (ALLO), a highly potent and effective modulator of GABA channels, and that the clinically observed effects could be reversed in pre-clinical experiments by blocking the natural synthesis of these steroids. Scientists quickly took notice of this unique biological action and began to explore etifoxine in models of other indications where neurosteroids (like ALLO) had shown efficacy: Alzheimer’s Disease, Multiple Sclerosis, Parkinson’s Disease and traumatic brain injury, to name a few.

Etifoxine – No Patent Protection – Not Viable

The stage was set for an old drug to be rejuvenated, but the original patents had expired and most of the therapeutic indications had already been disclosed (or patented). Without patent protection, there was no business rationale to re-develop the drug in any new markets, which explains why etifoxine was never introduced into the United States. This is the rationale behind the discovery and development of GRX-917: a vastly improved variant of etifoxine, with patent protection.

What’s Wrong with Current Anxiety Medications?2019-09-22T19:29:55+00:00

The first-line anxiety medications (SSRIs/SNRIs) take 4-6 weeks to take effect and work in less than 50% of anxiety patients.

The second line anxiety medications (benzodiazepines) are highly addictive, have serious side effects and historically have been involved in approximately 1/3 of fatal prescription overdoses in the United States.

What Are Neurosteroids and How Do They Benefit CNS Disorders?2019-09-22T19:30:10+00:00

Neurosteroids, like allopregnanolone (ALLO), are natural signaling molecules made in the brain from cholesterol and are essential for normal brain biochemistry. They can induce potent anxiolytic, antidepressant, anticonvulsant, and analgesic effects, mainly through interaction with the GABA channel, the main inhibitory system in the brain.

In addition to these psychopharmacological effects, neurosteroids also demonstrate neuroprotective, neurotrophic, and anti-inflammatory effects in several animal models of neurodegenerative diseases, mainly by shutting down overactive immune cells (like microglia). Chronic activation of the brain’s resident immune cells results in neuroinflammation, a common feature of many neurodegenerative diseases which is implicated in their onset and progression.

Altered levels of neurosteroids such as ALLO have been measured in many neuropsychiatric and neurological disorders (anxiety, depression, post-partum, post-traumatic stress disorder, schizophrenia, alcohol dependence, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann-Pick type C disease, diabetic neuropathy, traumatic brain injury, stroke and retinal degenerative disorders) both in humans and animal models.

Both preclinical and clinical studies demonstrate a therapeutic potential for neuroactive steroids to both alleviate symptomology, and/or modify the disease state in a variety of CNS disorders.

Why is increasing Endogenous Neurosteroids a Better Therapeutics Approach than dosing Exogenous Neurosteroids?2019-09-22T19:30:19+00:00

The human brain is a complex network of billions of interconnected cells, organized in many networks communicating with one another. Some CNS disorders arise from dysregulation in the modulation of these networks, either by altered levels of signaling molecules like neurosteroids or the receptors they target.

Boosting the brain’s natural production of neurosteroids to restore normal neurosteroid tone represents a better and potentially more natural therapeutic approach for the treatment of these complex CNS disorders.

Drugs that naturally enhance the brain’s concentration of neurosteroids produce a full spectrum of pharmacological actions, unlike unnatural synthetic versions, which only target specific receptors. Key to natural enhancement of neurosteroids is the preservation of the spatial and temporal nature of neurotransmission. This results in less side effects, because the brain controls, with exquisite precision, what, where and when neurosteroids are being produced, unlike drugs that are given exogenously.

Is GRX-917 Patent Protected?2019-09-22T19:30:37+00:00

The Company has used deuteration technology to create a new and improved version of etifoxine, deuterated etifoxine (GRX-917), that has composition of matter patent protection, until 2036.

How Are GABA Therapeutics Inc. and Atai Life Sciences AG Related?2019-09-23T17:02:55+00:00

On August 29, 2019 GABA Therapeutics Inc. secured up to $15.5 million of Series A investment from Atai Life Science AG, which will take the GRX-917 program through Phase 2a.

ATAI Life Sciences AG is a global biotech platform and company builder, based in Berlin, London and New York, focused on curing mental health disorders. Clearly there are synergies between GABA Therapeutics and Atai Life Sciences, and both companies aim to collaborate and share resources where commercially viable.

What is Being Studied in Phase 1?2019-09-22T19:31:14+00:00

GABA Therapeutics will be conducting the following Phase 1 studies:

  1. Initially etifoxine will be studied to measure its ability to increase endogenous neurosteroids in man.
  2. Secondly, GRX-917 (deuterated etifoxine) will be studied for toxicology, safety, dosing and its ability to increase endogenous neurosteroids in man.

Where Will Phase 1 be Conducted and Why?2019-09-22T19:31:23+00:00

GABA Therapeutics is conducting Phase 1 studies in Australia for the following reasons:

  1. Australian law allows clinical studies to commence before an IND is submitted, substantially expediting the program, and
  2. Current Australian tax law provides for a 43.5% tax rebate on eligible clinical related costs.

What Indications Have Been Shown to Benefit from Increased Neurosteroids (from etifoxine/GRX-917)?2019-09-22T19:31:37+00:00

Neurosteroids could benefit the following neuropsychiatric and neurologic disorders:

  • Green (1-11) – preclinical studies using Etifoxine which have demonstrated efficacy
  • Blue (12) – Etifoxine is prescribed for depression in France (off-label), and clinical data demonstrates ALLO efficacy
  • Purple (13-20) – preclinical and clinical studies suggest increasing biosynthesis of neurosteroids, like ALLO, could benefit these conditions