CEREVEL THERAPEUTICS HOLDINGS, INC. In healthy volunteers, both the 7.5 mg and 25 mg twice-daily doses of darigabat demonstrated a clinically meaningful and statistically significant improvement in the Panic Symptoms List score after eight days of dosing compared with placebo
Darigabat was generally well-tolerated; resulted in no serious adverse events and no treatment-related discontinuations in the trial
Cerevel intends to advance development of darigabat in anxiety-related disorders
Conference call and webcast scheduled for today at
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
“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,” said chief medical officer of Cerevel,
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 GABAA receptor PAM being developed as a potential treatment for anxiety and epilepsy. By selectively targeting the alpha 2, 3 and 5 subunits of the GABAA 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 GABAA 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
Results Summary
The chart below summarizes the observed placebo-adjusted anxiolytic effect on the primary and secondary endpoints. On both endpoints, a reduction in the score indicates anxiolytic effect.
| Day 8 (vs. pbo) | Darigabat 7.5 mg BID (N=18) | Darigabat 25 mg BID (N=18) | Alprazolam 1mg BID (N=18) |
| ∆ in PSL-IV total score | -3.9 pts (p=0.036) | -4.5 pts (p=0.008) | -1.6 pts (p=0.286) |
| ∆ in Fear VAS score | -12.8 pts (p=0.026) | -7.8 pts (p=0.282) | -0.9 pts (p=0.876) |
The data presentation can be found on the
Darigabat is also being studied as a potential treatment for epilepsy, for which non-selective GABAA 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.
About the Phase 1 Healthy Volunteer Clinical Trial in Acute Anxiety
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.
About Anxiety
Anxiety disorders are the most common form of mental illness in
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This press release contains forward-looking statements that are based on management’s beliefs and assumptions and on information currently available to management. In some cases, you can identify forward-looking statements by the following words: “may,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “anticipate,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “ongoing” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. These statements involve risks, uncertainties and other factors that may cause actual results, levels of activity, performance, or achievements to be materially different from the information expressed or implied by these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained in this press release, we caution you that these statements are based on a combination of facts and factors currently known by us and our projections of the future, about which we cannot be certain. Forward-looking statements in this press release include, but are not limited to, statements about the potential attributes and benefits of our product candidates, including the ability of darigabat to achieve anxiolytic activity while minimizing side effects, to be a daily maintenance treatment and to transform the treatment paradigm in anxiety; the format and timing of our product development activities and clinical trials, including the timing of the Phase 2 proof-of-concept trial of darigabat in focal epilepsy and advancing development of darigabat in anxiety-related disorders; the ability to compete with other companies currently marketing or engaged in the development of treatments for relevant indications; the size and growth potential of the markets for product candidates and ability to serve those markets; and the rate and degree of market acceptance of product candidates, if approved. We cannot assure you that the forward-looking statements in this press release will prove to be accurate. Furthermore, if the forward-looking statements prove to be inaccurate, the inaccuracy may be material. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties, including, among others: clinical trial results may not be favorable; uncertainties inherent in the product development process (including with respect to the timing of results and whether such results will be predictive of future results); the impact of COVID-19 on the timing, progress and results of ongoing or planned clinical trials; other impacts of COVID-19, including operational disruptions or delays or to our ability to raise additional capital; whether and when, if at all, our product candidates will receive approval from the FDA or other regulatory authorities, and for which, if any, indications; competition from other biotechnology companies; uncertainties regarding intellectual property protection; and other risks identified in our
Media Contact:
anna.robinson@cerevel.com
Investor Contact:
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References:
1. Terlizzi EP, Villarroel MA. Symptoms of generalized anxiety disorder among adults:
2. Santomauro DF, Herrera AMM, Shadid J, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic.
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