Cerevel Therapeutics Announces Positive Topline Results for Darigabat in Phase 1 Clinical Trial in Acute Anxiety

Cerevel Therapeutics recently announced positive results from its Phase 1 healthy volunteer clinical trial to evaluate darigabat, a novel alpha-2/3/5 selective GABA_A receptor positive allosteric modulator (PAM), in acute anxiety. Both the 7.5 mg twice-daily and the 25 mg twice-daily doses of darigabat demonstrated clinically meaningful and statistically significant anxiolytic activity compared with placebo in this proof-of-principle trial. The positive control alprazolam 1 mg twice-daily exhibited placebo-adjusted anxiolytic activity in line with expectations for this trial design.

After eight days of treatment, the darigabat 7.5 mg and 25 mg twice-daily doses demonstrated a 3.9 point (p=0.036) and 4.5 point (p=0.008) placebo-adjusted improvement, respectively, on the primary endpoint of the Panic Symptoms List (PSL-IV) total score. The alprazolam 1 mg twice-daily dose demonstrated a 1.6 point (p=0.286) placebo-adjusted improvement on the PSL-IV total score. These positive results were further supported by the secondary endpoint, change in the Fear Visual Analog Scale (VAS Fear score), which demonstrated a 12.8 point (p=0.026), 7.8 point (p=0.282), and 0.9 point (p=0.876) placebo-adjusted improvement for the darigabat 7.5 mg, 25 mg, and alprazolam 1 mg twice-daily doses, respectively.

“More than 370 million people worldwide suffer from some form of anxiety and there has been a lack of innovation in this field for more than a decade,” said John Krystal, MD, Chair of the Psychiatry Department at Yale University Medical School. “Cerevel’s trial leveraged a well-established translational model of anxiety. With its differentiated alpha-2/3/5 selective mechanism, darigabat could usher in a new generation of anxiolytics that alleviate symptoms while minimizing side effects.”

“The results of this state-of-the-art and well-executed trial demonstrated proof-of-principle for darigabat as a highly-targeted subtype-selective molecule with potential to transform the treatment paradigm in anxiety,” added Chief Medical Officer of Cerevel, Raymond Sanchez, MD. “While non-selective GABA_A PAMs are widely prescribed across numerous indications, their known tolerability challenges limit them to acute, episodic use, leaving patients seeking better treatment options. Today’s results support proceeding with additional trials in anxiety-related disorders with a goal for darigabat to be a daily maintenance treatment for people suffering from inadequately managed anxiety.”

Darigabat was generally well-tolerated in this trial, with no serious adverse events and no treatment-related discontinuations in the darigabat cohorts. Ninety-seven percent of adverse events (AEs) reported in the two darigabat treatment cohorts were considered mild. The remainder were considered moderate and there were no severe AEs in the darigabat treatment arms. The most common AEs included bradyphrenia, dizziness, somnolence, fatigue, and disturbance in attention, and the AEs observed were consistent with previous trials of darigabat in healthy volunteers.

Darigabat is an alpha-2/3/5 selective GABA_A receptor PAM being developed as a potential treatment for anxiety and epilepsy. By selectively targeting the alpha 2, 3 and 5 subunits of the GABA_A receptor and sparing the alpha 1 subunit, darigabat may have the potential to achieve anxiolytic activity while minimizing the debilitating side effects that limit the use of currently approved benzodiazepines, which are non-selective GABA_A receptor PAMs. These side effects include sedation, cognitive impairment, efficacy tolerance, and abuse potential.

“Cerevel’s differentiated approach to neuroscience – which is grounded in a deep understanding of the brain’s neurocircuitry, targeted receptor subtype selectivity and receptor pharmacology – has once again yielded an important result for the advancement of the understanding and treatment of neuroscience diseases,” said Tony Coles, MD, Chairperson and Chief Executive Officer of Cerevel. “The success of this clinical trial highlights the importance of our innovative, deliberate and thoughtful approach to discovery and clinical development, trial design and execution in achieving results.”

The data presentation can be found on the Cerevel Therapeutics website here. Additional data from the trial will be presented at future scientific conferences.

Darigabat is also being studied as a potential treatment for epilepsy, for which non-selective GABA_A receptor PAMs are used acutely as anticonvulsants. Cerevel is currently conducting REALIZE, a Phase 2 proof-of-concept trial of darigabat in focal epilepsy, which is expected to read out in the second half of 2022. Additionally, Cerevel is conducting an open label extension trial of darigabat in focal epilepsy.

The Phase 1 proof-of-principle trial was a three-cohort, randomized, double-blind, placebo- and active-controlled, crossover trial in healthy volunteers. The primary objective of the trial was to evaluate the anxiolytic effects of multiple doses of darigabat using an experimental medicine model of carbon-dioxide (CO₂) inhalation that is associated with symptoms of anxiety/panic in healthy volunteers. This model is known to be sensitive to the effects of drugs approved for the treatment of anxiety, including benzodiazepines and selective serotonin reuptake inhibitors (SSRIs).

This trial was designed with a maximum duration of approximately thirteen weeks and consisted of a screening/baseline period, a treatment period and a follow-up period. During the screening/baseline period, subjects were exposed to the CO₂ challenge, and only subjects who were sensitive to the anxiogenic effects of 35% CO₂ double-breath inhalation at screening were eligible for randomization during the treatment period. Each treatment period consisted of eight days of dosing followed by the CO₂ challenge performed after dosing on Day 8. Adverse events were reported via participant queries approximately four times daily. The trial was conducted as a two-period, two-sequence crossover design comparing multiple doses of high-dose darigabat (25 mg BID), low-dose darigabat (7.5 mg BID), and alprazolam (1 mg BID) against placebo. Three cohorts of 18 subjects, for a total of 54 subjects, completed the trial. The primary endpoint of the trial was the change in the Panic Symptoms List (PSL-IV) total score, which includes 13 symptoms scored across a range of 0 (absent) to 4 (very intense) and is commonly used to assess panic/anxiety.

Anxiety disorders are the most common form of mental illness in the US, affecting over 45 million adults or approximately 15% of the US population. Globally, more than 370 million people are impacted by an anxiety disorder of some kind. The most common types of anxiety disorders include obsessive-compulsive, post-traumatic stress, social anxiety, panic and generalized anxiety. The social impact of anxiety disorders includes increased risk of suicide, reduced achievement in work and school, increased risk of absenteeism, co-morbid depression, potential for substance abuse and higher healthcare costs.

Cerevel Therapeutics is dedicated to unraveling the mysteries of the brain to treat neuroscience diseases. The company is tackling diseases with a targeted approach to neuroscience that combines expertise in neurocircuitry with a focus on receptor selectivity. Cerevel Therapeutics has a diversified pipeline comprising six clinical-stage investigational therapies and several pre-clinical compounds with the potential to treat a range of neuroscience diseases, including Parkinson’s, epilepsy, schizophrenia, and dementia-related apathy. Headquartered in Cambridge, MA, Cerevel Therapeutics is advancing its current research and development programs while exploring new modalities through internal research efforts, external collaborations, or potential acquisitions. For more information, visit www.cerevel.com.