atai Life Sciences N.V. and its subsidiary GABA Therapeutics, announced final positive results from a Phase 1 clinical trial of GRX-917 that were previously announced as preliminary results during atai's R&D day. The randomized, double-blind, placebo-controlled trial was designed to evaluate the safety, tolerability, and pharmacokinetic profile of single and multiple ascending doses of orally administered GRX-917. Overall, compared to placebo, GRX-917 was well-tolerated and neither dose-related nor dose-limiting adverse events were observed.

There were no serious adverse events reported nor discontinuations due to drug administration. Furthermore, in contrast to current first-line anxiety disorder treatments such as benzodiazepines, sedation was found to be comparable to placebo. Dose-dependent increases in qEEG beta power, a biomarker for GABA receptor activation, was demonstrated in subjects who received GRX-917 but not with those who received a placebo, providing evidence of target engagement consistent with GRX-917's putative mechanism of action.

GRX-917 is a deuterated version of etifoxine, which is an anxiolytic approved in France, with rapid onset and efficacy comparable to leading benzodiazepines like alprazolam and lorazepam that are currently considered the standard of care but is non-addictive with minimal side effects. Etifoxine is thought to achieve its anxiolytic activity by increasing endogenous production of brain neurosteroids like allopregnanolone. Dysregulation of neurosteroidogenesis has been implicated in a broad range of neuropsychiatric diseases including generalized anxiety disorder (GAD), anxious depression, social anxiety disorder (SAD), panic disorder, and postpartum depression.

In the single-ascending dose (SAD) portion of the trial, adverse events were observed in 53% (17/32) of GRX-917 treated subjects, comparable to 50% (5/10) observed in placebo-treated subjects. Adverse events related to GRX-917 specifically occurred in 25% (8/32) of subjects and were all mild in severity. In the multiple-ascending dose (MAD) portion of the trial, adverse events were observed in 60.5% (26/43) of GRX-917 treated subjects, also comparable to 60% (9/15) observed in placebo-treated subjects.

Adverse events related to GRX-917 specifically occurred in 32.6% (14/43) of subjects and were all mild in severity. The results of these two trial phases indicate that there were no dose-limiting adverse events in trial subjects at higher dosages and no benzodiazepine-like side effects, including sedation were observed. Dose- and exposure-dependent increases in beta power were observed by quantitative electroencephalogram (qEEG) in healthy volunteers receiving single doses of GRX-917 but not in those who received a placebo.

These results show that GRX-917 has measurable effects on the central nervous system and provide evidence of GABA receptor target engagement and mechanism of action.