darigabat (CVL-865) / AbbVie - LARVOL DELTA

An Open-label Extension Trial of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=105 | Terminated | Sponsor: AbbVie | Completed ➔ Terminated; Closed early after CVL-865-SZ-001 (NCT04244175) did not meet its primary objective

Trial termination • CNS Disorders • Epilepsy

Characterisation of GABA2/3 positive allosteric modulators (PAMs) in tests of anxiety and side effect. (Neuroscience 2025) - "For example DGB (0.5-5mg/kg) did not impair attention (% correct: Veh: 92+2%, DGB(5): 90+2%), or reaction time (Veh: 0.70+0.01s, DGB(5): 0.70+0.01s). In sum, the rat CER assay was able to demonstrate an anxiolytic-like profile of the α2/α3- and α3-GABAAR subtype-selective compounds darigabat, TPA023B and SAN711, all of which showed an improved side effect profile relative to the non-selective GABAAR PAM diazepam."

Adverse events • CNS Disorders • Epilepsy • Mood Disorders • Psychiatry

A Study to Evaluate Efficacy, Safety, and Tolerability of Darigabat in Participants With Panic Disorder (clinicaltrials.gov) - P2 | N=80 | Completed | Sponsor: AbbVie | Recruiting ➔ Completed | N=246 ➔ 80

Enrollment change • Trial completion • CNS Disorders • Mood Disorders

An Open-label Extension Trial of CVL-865 As Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=105 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Dec 2024 | Trial primary completion date: Jul 2025 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Nonsedating anxiolytics. (PubMed, Pharmacol Biochem Behav) - "This has rekindled the interest in the GABAA-receptor (GABAAR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam...Advances in molecular biology gave birth to a host of subtype selective GABAAR-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865)...In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABAAR for improved therapeutic gain and reduced side effects."

Journal • Review • Anesthesia • CNS Disorders • Depression • Hepatology • Mood Disorders • Psychiatry

New Insights Into Pharmacology of GABAA Receptor Alpha Subunits-Selective Modulators. (PubMed, Am J Ther) - "Future drug discovery efforts are encouraged to focus on positive allosteric modulators that selectively target the α2, α3 subunits and negative/positive allosteric modulators that target the α5 subunit of the GABAA receptor. The pursuit of ligands possessing only anxiolytic effects or those enhancing cognition continues to be an important focus for future research, with promising advancements depicted in recent studies."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Epilepsy • Insomnia • Mood Disorders • Neuralgia • Pain • Psychiatry • Sleep Disorder

CVL-865-HV-1004: A Trial to Assess the Absorption, Metabolism, Excretion, and Mass Balance of [14C]-Darigabat After a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Completed

Trial completion

A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=154 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Epilepsy

CVL-865-HV-1004: A Trial to Assess the Absorption, Metabolism, Excretion, and Mass Balance of [14C]-Darigabat After a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | Not yet recruiting ➔ Recruiting

Enrollment open

An Open-label Extension Trial of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=105 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy

A Trial to Assess the Absorption, Metabolism, Excretion, and Mass Balance of [14C]-Darigabat After a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Cerevel Therapeutics, LLC

New P1 trial

A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=154 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy

A Study to Evaluate Efficacy, Safety, and Tolerability of Darigabat in Participants With Panic Disorder (clinicaltrials.gov) - P2 | N=246 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Mood Disorders

A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Cerevel Therapeutics, LLC

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

A Study to Evaluate Efficacy, Safety, and Tolerability of Darigabat in Participants With Panic Disorder (clinicaltrials.gov) - P2 | N=228 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Mood Disorders

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development. (PubMed, CNS Drugs) - "The first group consists of positive allosteric modulators of GABA receptors and includes Staccato alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101...These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents..."

Journal • Review • CNS Disorders • Epilepsy • Gene Therapies

Open-label Trial to Evaluate the Effect Carbamazepine on Darigabat Pharmacokinetics in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed

Trial completion

A Study to Evaluate Efficacy, Safety, and Tolerability of Darigabat in Participants With Panic Disorder (clinicaltrials.gov) - P2 | N=228 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Mood Disorders

An Open-label Extension Trial of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=120 | Enrolling by invitation | Sponsor: Cerevel Therapeutics, LLC | Trial completion date: Sep 2024 ➔ Jun 2025 | Trial primary completion date: Aug 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

A Study to Evaluate Efficacy, Safety, and Tolerability of Darigabat in Participants With Panic Disorder (clinicaltrials.gov) - P2 | N=228 | Not yet recruiting | Sponsor: Cerevel Therapeutics, LLC

New P2 trial • CNS Disorders • Mood Disorders

Open-label Trial to Evaluate the Effect Carbamazepine on Darigabat Pharmacokinetics in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2023 ➔ Jun 2023

Enrollment closed • Trial completion date

Open-label Trial to Evaluate the Effect Carbamazepine on Darigabat Pharmacokinetics in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | Not yet recruiting ➔ Recruiting

Enrollment open

A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | Trial completion date: Jul 2023 ➔ Jun 2024 | Trial primary completion date: Jun 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Open-label Trial to Evaluate the Effect Carbamazepine on Darigabat Pharmacokinetics in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Cerevel Therapeutics, LLC

New P1 trial

Phase 1 Trial of Darigabat for the Reduction of Acute Psychological and Physiological Panic and Fear Symptoms Following CO2 Inhalation in Healthy Participants (AAN 2023) - P1 | "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. 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."

Clinical • P1 data • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry