Abstract Details

Title Phase 1 Trial of Darigabat for the Reduction of Acute Psychological and Physiological Panic and Fear Symptoms Following CO2 Inhalation in Healthy Participants

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S8 - Behavioral and Cognitive Neurology (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

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.

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.

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.

Authors/Disclosures
Ann Dandurand (Cerevel) PRESENTER	No disclosure on file
Rachel Gurrell, PhD (Cerevel Therapeutics)	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.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Gina Pastino, PhD (Cerevel Therapeutics)	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.
	No disclosure on file
Stacey Versavel, PhD (Cerevel Therapeutics)	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.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file