While psychedelics are an important component of the dawning mental healthcare revolution, it is critical to recognize that a comprehensive response to the global mental health crisis ought to be as diverse as possible. To this end, GABA Therapeutics is pursuing a natural approach based on the brain’s ability to correct imbalances that underlie many CNS disorders.
Neurosteroids – for example allopregnanolone — are a particularly promising type of endogenous signaling molecule. Made in the brain from cholesterol, neurosteroids 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.
Enter GABA Therapeutics’ flagship compound, deuterated etifoxine.
The original, non-deuterated drug (etifoxine: Stresam) was developed by Hoechst to compete with the tranquilizing and sedative benzodiazepines of the 1960s (e.g. Valium and Librium). Unfortunately, it was mischaracterized as a mild benzodiazepine, despite its lack of typical benzodiazepine side effects, like sedation and ataxia. Since then, though one pharmaceutical distributor has continued producing the drug off-patent in relatively limited markets, the drug was never developed in the U.S. or broader European markets.
In the 2000s, French researchers finally found that etifoxine does not interact with the benzodiazepine binding site on the GABAA receptor at all. Sophisticated molecular biology techniques along with single cell electrophysiological experiments demonstrated that the drug was very selective in enhancing GABAA activity through a unique interaction with another binding site on the GABAA receptor.
Further research revealed an even more significant discovery: Through a GABA-independent mechanism, the drug also increases levels of natural neurosteroids which in turn lead to positive allosteric modulation of GABAA receptors. Therefore, the clinically observed effects result from the drug’s direct effect on GABAA channels in combination with an enhancement of GABAergic effects by the neurosteroid allopregnanolone. Scientists quickly took notice of this unique biological action and began to explore etifoxine for other indications where neurosteroids had shown efficacy.
Before too long, etifoxine appeared poised to make a comeback for a broader population.
How does etifoxine work – and is it safe?
In contrast to benzodiazepines, etifoxine appears to produce its anxiolytic effects through a dual mechanism, binding directly to GABAA receptors as well as the mitochondrial translocator protein TSPO, leading to increases in endogenous neurosteroids. GRX-917, GABA Therapeutics’ flagship product, has an identical mechanism of action, biology and pharmacology as etifoxine, but is deuterated (i.e. has specific hydrogen atoms replaced by isotopic deuterium atoms) and thus boasts improved pharmacokinetics.
By increasing action at GABA channels, etifoxine slows excess neuronal excitation, ameliorating anxiety symptoms. Importantly, since over-activation of GABA channels can lead to oversedation and other undesired effects, GRX-917 and etifoxine increase activation only at selected subunits of GABAA channels, boosting GABAergic transmission via preferential positive allosteric modulation (PAM) of β2/3-subunit-containing GABA receptors (at a site distinct from benzodiazepines). By contrast, drugs like alcohol, barbiturates, benzodiazepines and Propofol, also work at GABA, but increase action at GABA channels nonselectively.
Additionally, both GRX-917 and Etifoxine function as powerful stimulators of neurosteroid biosynthesis, prompting the body to increase levels of these natural anxiety fighting compounds. This is accomplished by increasing activity of a protein called TSPO, which is believed to control the flow of cholesterol into a cellular organelle called the mitochondrion, where it is then converted into neurosteroids.
Comparison of the three of the best known TSPO compounds for ability to enhance neurosteroid synthesis activity: etifoxine, XBD173 (aka. Emapunil, AC-5216) and diazepam.
The unique combination of the drug’s selective effects at GABA channels, coupled with the ability to substantially increase the levels of important, natural neurosteroids, give the drug an anxiolytic profile of fast onset without the dangers or typical side-effects of benzodiazepines. Upregulation of neuroactive steroids by etifoxine may also account for its recently discovered neurotrophic, neuroprotective and anti-inflammatory properties. As shown in figure 1, in rats, etifoxine shows almost double the enhancement in neurosteroid synthesis activity at 24-hours post-incubation as compared with its nearest competitor, Emapunil.
In terms of safety, in 2012, the French National Agency for the Safety of Medicines and Health Products released a pharmacovigilance study that found no cases of abuse, misuse, or dependence after analysing over 14 millions prescriptions of etifoxine between 2000 and 2012. Moreover, adverse drug reactions occurred in just 21 per million treatments (0.0021%).
Clinical studies have shown that etifoxine has equivalent speed of onset and efficacy as the world’s top two selling benzodiazepines (Xanax® and Ativan®), but with minimal to no side effects. A comparative trial even found significantly less rebound anxiety upon abrupt cessation of etifoxine compared with Xanax® and Ativan®.
The drug is contraindicated in instances of shock, as well as severely impaired liver and kidney function.
Anxiety disorders are the most common mental illness in the United States, affecting 40 million adults, or 19% of the U.S. population. Yet only 37% of anxiety disorder patients receive effective treatment. This represents one of America’s largest unmet medical needs, primarily due to the limitations of U.S. anxiety medications.
GABA Therapeutics is planning to develop GRX-917 for anxiety in the United States, Europe and several other countries. GRX-917 will initially be developed for treatment of Generalized Anxiety Disorder (GAD) and then expanded into other anxiety indications. in addition, the drug has demonstrated efficacy in numerous animal models for:
- Neuropathic and inflammatory pain
- Multiple sclerosis,
- Alzheimer’s disease
- Traumatic brain injury
- Nerve/spinal cord injury
- Retinal/macular degeneration
In short, the potential of GRX-917 is extensive and extends well beyond anxiety alone. Importantly, GRX-917 is not expected to be a controlled substance, since it does not bind to the benzodiazepine site on the GABAA receptor. Etifoxine is not a controlled substance in France or any other country in which it is sold, and no clinically competitive anti-anxiety drug is on market or in late stage development.
Based on the extensive, 35+ years of clinical experience with etifoxine and its excellent efficacy and safety profile, the development of GRX-917 is considered very low risk. Nevertheless, extensive trials will still be necessary for FDA approval, and GABA Therapeutics is currently in the process of kicking off a comprehensive preclinical and clinical development program including both etifoxine and GRX-917.
In November 2019, GABA Therapeutics announced that it had received approval to conduct a phase I clinical trial of the anxiolytic etifoxine in Melbourne, Australia. The Alfred Ethics Committee approved a phase I, two-stage, double-blind, placebo-controlled single and multiple dose study to evaluate the pharmacokinetics, pharmacodynamics, and safety of oral etifoxine in normal healthy volunteers. Dosing for the study will begin in January 2020 and will be conducted at Nucleus Network in Melbourne, Victoria.
“Providing a safe way to meaningfully alleviate anxiety for the millions of people struggling without alternatives is critical,” said Dr. Ian Massey, founder and CEO of GABA Therapeutics.
“We stand not only to improve peoples’ quality of life, but to help them better engage with all aspects of their healthcare — mental and otherwise.”