CVL-865 · program

Darigabat (CVL-865) for Epilepsy

DiscontinuedDiscontinuedAbbVie Inc. (ABBV)

Lead indication for darigabat (CVL-865): adjunctive therapy in adults with drug-resistant (treatment-resistant) focal onset seizures. The pivotal Phase 2 REALIZE trial (NCT04244175, CVL-865-SZ-001) COMPLETED but FAILED its primary endpoint — darigabat (7.5 mg and 25 mg BID) did not separate from placebo on the Response Ratio (RRatio): placebo -24.06, 7.5 mg -22.45 (p=0.823), 25 mg -25.90 (p=0.986). The open-label extension (NCT04686786) was subsequently TERMINATED, with the registry stating it was 'Closed early after CVL-865-SZ-001 (NCT04244175) did not meet its primary objective.' The focal-epilepsy program is therefore discontinued. (Darigabat continues in a separate panic-disorder program, not covered by this record.)

Data current as of

Development timeline

DiscontinuedMay 2024 – Dec 2024
  1. terminatedOpen-label extension (NCT04686786) terminated early after REALIZE missed its primary objective
  2. missedREALIZE Phase 2 in drug-resistant focal onset seizures FAILED — darigabat did not separate from placebo on the primary Response Ratio (p=0.823 at 7.5 mg BID; p=0.986 at 25 mg BID)
Phase 2Jan 2020
  1. Pivotal Phase 2 REALIZE trial (NCT04244175, CVL-865-SZ-001) in adults with drug-resistant focal onset seizures started (adjunctive, randomized, double-blind, placebo-controlled).

Readouts

  • 2024-12-05ReportedRegistry resultsterminatedNCT04686786

    Open-label extension (NCT04686786) terminated early after REALIZE missed its primary objective

  • 2024-05-21ReportedFull resultsmissedNCT04244175

    REALIZE Phase 2 in drug-resistant focal onset seizures FAILED — darigabat did not separate from placebo on the primary Response Ratio (p=0.823 at 7.5 mg BID; p=0.986 at 25 mg BID)

Clinical trials in Epilepsy

NCT04686786CVL-865-SZ-002Phase 2Discontinuedn=105

An Open-label Extension Trial of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures

Started Dec 2020· Primary completion Dec 2024· 📍 56 sites across 7 countries (United States, Australia, Spain, Poland)

terminatedotherOpen-label extension status

Open-label long-term safety extension terminated early. Registry why-stopped reason: 'Closed early after CVL-865-SZ-001 (NCT04244175) did not meet its primary objective.'

NCT04244175CVL-865-SZ-001Phase 2Completedn=154

A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Trial of CVL-865 as Adjunctive Therapy in Adults With Drug-Resistant Focal Onset Seizures (REALIZE Trial)

Started Jan 2020· Primary completion May 2024· 📍 76 sites across 7 countries (United States, Poland, Spain, Australia)

missedprimaryResponse Ratio (RRatio) in focal onset seizure frequency, Maintenance Phase vs Baseline: CVL-865 7.5 mg BID vs placebo — RRatio -22.45 (SD 26.393) for CVL-865 7.5 mg BID vs -24.06 (SD 33.441) for placebo (0.823)

Darigabat 7.5 mg BID did not separate from placebo on the primary Response Ratio endpoint (p=0.823); seizure reduction numerically similar to placebo.

missedprimaryResponse Ratio (RRatio) in focal onset seizure frequency, Maintenance Phase vs Baseline: CVL-865 25 mg BID vs placebo — RRatio -25.90 (SD 33.428) for CVL-865 25 mg BID vs -24.06 (SD 33.441) for placebo (0.986)

Darigabat 25 mg BID did not separate from placebo on the primary Response Ratio endpoint (p=0.986). The trial failed its primary objective at both doses.

missedsecondary50% responder rate (proportion with >=50% reduction in Maintenance Phase focal seizure frequency vs Baseline) — Placebo 30.0%, CVL-865 7.5 mg BID 34.8%, CVL-865 25 mg BID 38.3%

50% responder rates were numerically higher with active treatment but not meaningfully separated from placebo; consistent with a negative primary endpoint.

Formulations

FormulationRouteRegimenPharmacokinetics
Darigabat oral tablet
Immediate-release tablet; dosed BID with titration (e.g., 2.5 mg BID up to 7.5 mg or 25 mg BID target) in the Phase 2 focal-onset seizure trial
OralTwice dailyt½ 11 h · Tmax 1.5 h

Mechanism of action (compound-wide)

Subtype-selective GABA-A receptor positive allosteric modulator at the benzodiazepine site. Functionally selective: strong positive allosteric modulation (~90-140%) of alpha2/alpha3/alpha5-containing GABA-A receptors with negligible functional efficacy (<=~20%) at alpha1-containing receptors, despite high binding affinity at alpha1. Designed to retain anti-seizure/anxiolytic GABAergic efficacy while reducing alpha1-mediated sedation.

TargetActionAffinity
GABA-A receptor alpha-2primaryGABRA2PAMKi 2.9 nMⓘ
GABA-A receptor alpha-1GABRA1PAMKi 0.18 nMⓘ
GABA-A receptor alpha-3GABRA3PAMKi 1.1 nMⓘ
GABA-A receptor alpha-5GABRA5PAMKi 18 nMⓘ

← Full CVL-865 compound page (identity, identifiers, all indications)

Sources

  1. A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures — ClinicalTrials.gov
  2. Darigabat (PF-06372865) GABA-A subtype Ki binding values (alpha1 0.18 nM, alpha2 2.9 nM, alpha3 1.1 nM, alpha5 18 nM); PAM at benzodiazepine site — TargetMol
  3. Open-label extension of CVL-865 in focal onset seizures (NCT04686786) — terminated after REALIZE failure — ClinicalTrials.gov