Phase 1 Trial of Darigabat for the Reduction of Acute Psychological and Physiological Panic and Fear Symptoms Following CO2 Inhalation in Healthy Participants (S8.005)

Objective:

To evaluate the panicolytic effect of 2 dose strengths of darigabat in reducing panic and fear symptoms following carbon dioxide (CO₂) inhalation by healthy participants.

Background:

Panic disorder is associated with subjective and physiological symptoms which no single drug class adequately addresses. Darigabat, in development for neurological and psychiatric disorders, was designed to have nonsedative panicolytic potential by selectively enhancing the effect of GABA at α2/3/5, while sparing activity at α1 GABA_A receptor subtypes.

Design/Methods:

This phase 1 randomized, double-blind, crossover, placebo- and active-controlled trial (NCT04592536) enrolled adults sensitive to anxiogenic effects of 35% CO₂ double-breath inhalation. Participants were randomized to receive placebo and either 1 of 3 active treatments in 3 separate cohorts for 8 days: darigabat 7.5 or 25 mg twice daily (BID) or alprazolam 1 mg BID. Target darigabat doses were achieved following a 4-day titration. After each crossover period, CO₂ challenge was performed 3 hours post-dose. Panic and fear symptoms were measured before and immediately after CO₂ inhalation using the Panic Symptom List-IV total score (PSL-IV; primary endpoint) and fear visual analog scale (VAS Fear; secondary endpoint). Each participant's placebo treatment served as their own control.

Results:

Fifty-six participants were randomized. On Day 8, darigabat 7.5-mg and 25-mg BID groups demonstrated a 3.9-point (nominal P=0.036) and 4.5-point (nominal P=0.008) improvement on the PSL-IV versus placebo, respectively. Darigabat groups demonstrated a 12.8-point (nominal P=0.026) and 7.8-point (nominal P=0.282) improvement on the VAS Fear versus placebo, respectively. The positive control (alprazolam 1 mg BID) exhibited panicolytic effect compared with placebo, in line with expectations. Darigabat was generally well tolerated, with no serious adverse events and no discontinuations in darigabat cohorts.

Conclusions:

The panicolytic potential of darigabat was validated, warranting further evaluation in patients with panic disorder. Disclosure: Dr. Gurrell has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Gurrell has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Cerevel Therapeutics. Dr. Gurrell has stock in Pfizer Ltd. Ms. Chang has received personal compensation for serving as an employee of Cerevel. Ms. Chang has stock in Cerevel Therapeutics. Dr. Dandurand has received personal compensation for serving as an employee of Cerevel. Dr. Dandurand has received personal compensation for serving as an employee of Otsuka. Dr. Dandurand has stock in Cerevel Therapeutics. An immediate family member of Dr. Dandurand has stock in Velocit . An immediate family member of Dr. Dandurand has stock in Cerebus. Dr. Duvvuri has received personal compensation for serving as an employee of Cerevel. Dr. Duvvuri has stock in Cerevel Therapeutics. Dr. Duvvuri has stock in Pfizer. Amy Guigliano has nothing to disclose. Dr. Pastino has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Pastino has received personal compensation for serving as an employee of PRA Health Sciences. Dr. Pham has nothing to disclose. Dr. Versavel has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Versavel has received stock or an ownership interest from Cerevel Therapeutics. Dr. Jacobs has nothing to disclose. Mr. Pour has nothing to disclose. Dr. Zuiker has nothing to disclose. Dr. Sanchez has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Sanchez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Coleman Research. Dr. Sanchez has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Cerevel Therapeutics. Dr. Sanchez has received stock or an ownership interest from Cerevel Therapeutics. Dr. Sanchez has received personal compensation in the range of $500-$4,999 for serving as a Consultant with GLG. Dr. Renger has received personal compensation for serving as an employee of Cerevel Therapeutics.