Deuterated Etifoxine (GRX-917): A possible alternative to current frontline anxiety medications with a potentially improved safety profile

With this series of weekly blog posts, I will highlight our clinical-stage compounds and why we are so excited about their potential in mental health indications.

Anxiety disorders collectively are the most common mental health conditions in the United States, affecting 40 million adults—or 19% of the U.S. population.?Yet less than half of people who need care receive it. This represents one of America’s largest unmet medical needs.

Background on atai

Our company, atai Life Sciences (Nasdaq: ATAI), is a clinical-stage biopharmaceutical company aiming to accelerate the development of new medicines across its companies to achieve clinically meaningful and sustained behavioral change in mental health patients. ?

We have a pipeline of 5 clinical-stage drug development programs, several of which are envisioned to be paired with a proprietary, internally-developed digital therapeutics platform. Of these 5 clinical drug candidates, 3 are psychedelic and 2 are non-psychedelic in nature. In addition, we use AI-based computational and medicinal chemistry approaches as part of our drug discovery efforts to generate the next generation of psychedelic and related molecules. We also have a 22.4% stake in COMPASS Pathways (separately listed on Nasdaq; CMPS).

History of GRX-917

Neurosteroids – a class of endogenous molecules that includes allopregnanolone — are a promising target for pharmacotherapy.

Made in the mitochondria from cholesterol, neurosteroids are essential for normal brain biochemistry. They are thought to induce potent anxiolytic, antidepressant, anticonvulsant, and analgesic effects through positive allosteric modulation of GABA-A receptors, the main inhibitory neurotransmitter system in the brain.

This is the mechanism that deuterated etifoxine targets.

By way of background, etifoxine (Stresam?) was developed by Hoechst to compete with benzodiazepines in the 1960s (e.g. Valium? (diazepam) and Librium? (chlordiazepoxide)). The compound was brought to market in France in 1979 and continues to be sold in numerous markets, thought it was never developed for the U.S.

Multiple studies have shown etifoxine to work as rapidly as benzodiazepines such as lorazepam and clonazepam but with fewer side effects.

While initially (mis)characterized as a milder benzodiazepine-like drug, in the 2000s, French researchers determined that while etifoxine is a low potency agonist at the GABA-A receptor, it does not interact with the benzodiazepine binding site on the GABA-A receptor.

Further research revealed an even more significant discovery: the drug increases the production of natural neurosteroids through its potent agonist activity at the mitochondrial translocator protein (TSPO). This, in turn, leads to positive allosteric modulation of the GABA-A receptor system via the neurosteroid intermediary.??

In 2012, decades after etifoxine hit the market, the French National Agency for the Safety of Medicines and Health Products?released a pharmacovigilance study?that found only sporadic case of abuse, misuse, or dependence after analyzing over 14 million prescriptions of etifoxine between 2000 and 2012.

GRX-917 – one of atai’s flagship compounds — is a deuterated version of etifoxine, meaning specific hydrogen atoms have been replaced by isotopic deuterium (“heavy hydrogen”) atoms. In general, deuteration increases the metabolic stability of molecules, but has limited impact on their pharmacology. Indeed, GRX-917 has been shown to have the same neurosteroidogenic mechanism-of-action as etifoxine in both in vitro and in vivo preclinical models, though with improved pharmacokinetics in animals.

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.

Current status & next steps

In June 2021, we initiated a Phase 1 single and multiple ascending dose trial of GRX-917. The Phase 1 trial was a randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of single and multiple-ascending doses of GRX-917 up to 500mg in single doses and 300mg given every twelve hours for seven days, respectively.

In January 2023, we announced positive results from the study. We found it to be well-tolerated and confirmed an improved pharmacokinetic profile, including longer half-life and increased bioavailability compared to etifoxine. Quantitative electroencephalography (qEEG) data also showed dose-dependent increases in frontal beta power, providing evidence of target engagement. In contrast to current first-line anxiety disorder treatments such as benzodiazepines, sedation was found to be comparable to placebo.

The compelling Phase 1 results supported an acceleration our clinical development plan to proceed directly into a Phase 2 study in patients with an anxiety disorder.

Deuterated etifoxine represents a potential opportunity to give millions of people in the United State a safer, effective alternative to currently available frontline medications.

With additional research and patient education, we hope to not only give a new tool to people living with anxiety, but also encourage others to seek the care they need.

Learn more about our programs here.

References

1. Anxiety and Depression Association of America (2021)
2. Vicente et al, “Etifoxine is non-inferior than clonazepam for reduction of anxiety symptoms in the treatment of anxiety disorders: a randomized, double-blind, non-inferiority trial”, Psychopharmacology, July 2020
3. Nguyen et al., “Efficacy of etifoxine compared to lorazepam monotherapy” (2006)
4. Liere et al, “Differential effects of the 18-kDa translocation protein (TSPO) ligand etifoxine on steroidogenesis in rat brain, plasma, and steroidogenic glands: Pharmacodynamic studies,” Psychoneuroendocrinology, 2017
5. Cottin et al., “Safety profile of etifoxine: A French pharmacovigilance survey” (2016)
6. GABA Therapeutics generated data