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Cerevel Therapeutics Announces Phase 1 Results for darigabat, a Novel α2/3/5-subtype GABAA Positive Allosteric Modulator in Development to Treat Epilepsy
darigabat is the first in a new class of treatments for epilepsy;
Data presented at 2019 Annual Meeting of American Epilepsy Society
BOSTON – December 8, 2019 – Cerevel Therapeutics, a company dedicated to unraveling the mysteries of the brain to treat neuroscience diseases, announced today results of a Phase 1 dose-escalation clinical trial1 evaluating the safety, tolerability and pharmacokinetics of multiple repeated doses of darigabat (formerly PF-06372865) in healthy volunteers. darigabat is an investigational therapy in development for the treatment of epilepsy. In this trial, darigabat was observed to be rapidly absorbed and well tolerated in healthy volunteers. The data are being presented today during a poster presentation session at the American Epilepsy Society (AES) 2019 Meeting in Baltimore.
“We are encouraged by these Phase 1 trial results, which provide evidence that darigabat is well tolerated at and beyond the target therapeutic doses being studied. Additionally, it provides further evidence that darigabat has a differentiated safety profile from benzodiazepines, a class of medicines used for the acute treatment of some forms of epilepsy but whose use is limited due to side effects, addiction liabilities and loss of efficacy with chronic use,” said Raymond Sanchez, M.D., chief medical officer of Cerevel Therapeutics. “These new dose-ranging data support the continued development of darigabat as a new treatment option to help improve the lives of people with epilepsy with the potential for efficacy with fewer side effects as well as the potential for chronic use. We look forward to advancing the clinical development program of darigabat as we proceed to a Phase 2 trial in patients with drug-resistant focal onset seizures.”
The randomized, double-blind, placebo-controlled Phase 1 trial enrolled 18 healthy volunteers and assessed the pharmacokinetics, safety and tolerability of multiple doses of darigabat given orally twice daily over 21 days at doses higher than previously evaluated. The trial included two cohorts, both titrated in the first seven days, with darigabat or placebo, followed by a maintained dosage for the remaining 14 days. Cohort 1 received a maximum of 25 mg twice-daily doses of the treatment, while Cohort 2 received a maximum of 42.5 mg twice-daily doses. At select timepoints on days 1 and 21, serial pharmacokinetic samples were collected. Safety evaluations included adverse event monitoring, clinical laboratory testing, vital signs, electrocardiograms and physical examinations.
- All adverse events were mild. Dizziness was the most frequent event, reported by one trial participant taking placebo, two subjects titrated to 25 mg BID darigabat and three subjects titrated to 42.5 mg BID darigabat. No serious adverse events were reported.
- Trial participants did not experience somnolence (drowsiness) with increasing doses of darigabat, including at the highest dose evaluated (42.5 mg twice daily for 14 days).
- No trial participants experienced withdrawal symptoms when darigabat was discontinued, despite treatment with doses achieving an estimated 80% GABAA receptor occupancy based on prior PET receptor occupancy trial characterization. This is in contrast to benzodiazepines, which cause adverse effects such as somnolence with low levels of GABAA receptor occupancy.
darigabat is a novel α2/3/5-subtype selective GABAA receptor positive allosteric modulator. It has been structurally differentiated from classical benzodiazepines to minimize activity at α1-containing receptors which is believed to help mitigate many of the adverse events associated with this class of medicines.
Approximately 65 million people worldwide suffer from epilepsy, according to the Epilepsy Foundation, and it affects people of all ages. Epilepsy is a spectrum condition with a wide range of seizure types and control that varies from person-to-person. It is estimated that approximately 30% of people with epilepsy fail to achieve seizure control despite the use of two or more antiepileptic drugs (whether in monotherapy or in combination). These patients continue to experience uncontrolled breakthrough episodes that negatively impact quality of life, increase the risk of sudden unexplained death and place a substantial burden on patients and caregivers. As such, antiepileptic therapies that employ new mechanisms are desperately needed.
About Cerevel Therapeutics
Cerevel Therapeutics is dedicated to unraveling the mysteries of the brain to treat neuroscience diseases. The company seeks to unlock the science surrounding new treatment opportunities through understanding the neurocircuitry of neuroscience diseases and associated symptoms. Cerevel Therapeutics has a diversified pipeline comprising five clinical-stage investigational therapies and several preclinical compounds with the potential to treat a range of neuroscience diseases, including Parkinson’s, epilepsy, schizophrenia and substance use disorders. Headquartered in Boston, 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 cerevelstg.wpengine.com
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1The study was conducted by Pfizer Inc. prior to Cerevel Therapeutics’ formation.