Darigabat

Darigabat (developmental code names CVL-865, PF-06372865, PF-6372865) is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders. It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued. It is taken via oral administration.

Darigabat acts as a GABAA receptor positive allosteric modulator  It is specifically a positive allosteric modulator that selectively targets α2, α3, and α5 subunit-containing GABAA receptors, with minimal functional activity at α1 subunit-containing GABAA receptors. A dose of darigabat that achieved more than 80% receptor occupancy showed no somnolence with dose titration, whereas benzodiazepines, which are non-selective GABAA receptor positive allosteric modulators, achieve only 10 to 15% receptor occupancy whilst producing significant or severe somnolence. It is theorized that α1 subunit-containing GABAA receptors preferentially mediate sedation, amnesia, and ataxia, whereas α2 and α3 subunit-containing GABAA receptors mediate anxiolysis. However, this model has also been questioned. α1 subunit-containing GABAA receptors are said to be completely unaffected by darigabat. The elimination half-life of darigabat is 11hours and it is metabolized mainly by CYP3A4.

In clinical trials conducted thus far, side effects of darigabat have included dizziness, fatigue, headache, mild-to-moderate somnolence, bradyphrenia (slowness of thought), modest memory impairment, mild cognitive impairment, balance impairment, and feeling abnormal. It has been described as well-tolerated.

Darigabat was originated by Pfizer and is under development by Cerevel Therapeutics and Pfizer. As of January 2023, it is in phase 2 clinical trials for epilepsy and seizures, phase 1 trials for panic disorder, and preclinical development for anxiety disorders. Development for back pain was discontinued due to lack of effectiveness in a phase 2 trial, while development for generalized anxiety disorder was discontinued due to business reasons as well as lack of effectiveness in a phase 2 trial.