Small Molecule · aticaprant
Aticaprant
Oral, potent, centrally-penetrant, selective kappa-opioid receptor (KOR / OPRK1) antagonist developed as adjunctive therapy for major depressive disorder, particularly MDD with anhedonia. Originated at Eli Lilly (LY2456302), licensed to Cerecor (CERC-501), then acquired by Janssen/Johnson & Johnson (JNJ-67953964). The Phase 3 VENTURA program failed for insufficient efficacy and J&J discontinued the MDD program in March 2025.
Also known as: aticaprant, JNJ-67953964, CERC-501, LY2456302, OpraKappa, 1174130-61-0
- Modality
- Small molecule
- Chemical class
- benzamide, pyrrolidine
- Chemistry
- Single enantiomer
- Mechanism
- KOR antagonist
- Highest phase
- Discontinued
- Lead indication
- Major depressive disorder
- Developer
- Johnson & Johnson (JNJ)
- Trials
- 5 tracked · 622 sites
Mechanism of action
Selective antagonist of the kappa-opioid receptor (KOR / OPRK1). Potent KOR binding (Ki ~0.81 nM) with ~30-fold selectivity over mu and delta opioid receptors; blocks KOR/dynorphin signaling implicated in dysphoria, stress and anhedonia, with the therapeutic hypothesis of restoring reward/dopaminergic function in depression.
| Target | Action | Affinity |
|---|---|---|
| KORprimaryOPRK1 | Antagonist | Ki 0.81 nMⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Aticaprant oral tablet 10 mg once daily (Phase 3 dose in MDD with anhedonia); Phase 1/2 explored 4-25 mg | Oral | Once daily | t½ 35 h · Tmax 1.5 h · F 25% |
Development timeline
- missedPhase 3 VENTURA program failed: J&J discontinued aticaprant for MDD on 2025-03-06 for insufficient efficacy; drug remained safe and well tolerated.↗
- metPhase 2a (NCT03559192) positive: adjunctive aticaprant 10 mg reduced MADRS vs placebo at Week 6 (LSMD -2.1; p=0.044, 1-sided); well tolerated.↗
- Phase 3 VENTURA program initiated (VENTURA-1 NCT05455684 first patient).
- Phase 2a adjunctive MDD study (NCT03559192) completed; positive on primary MADRS endpoint vs placebo.↗
Aticaprant for Major depressive disorder
DiscontinuedDiscontinuedMajor depressive disorder indication →
Adjunctive (add-on to SSRI/SNRI) MDD program. Phase 2a (NCT03559192) was positive: aticaprant 10 mg significantly reduced MADRS vs placebo with a favorable safety profile (Schmidt et al., Neuropsychopharmacology 2024). The Phase 3 VENTURA program (efficacy studies VENTURA-1 NCT05455684 and VENTURA-2 NCT05550532, plus long-term safety/extension studies NCT05518149 and NCT06514742) failed to show sufficient efficacy in the target population. On 2025-03-06, Johnson & Johnson announced discontinuation of the aticaprant MDD program; the drug remained safe and well-tolerated with no new safety signals.
Readouts
- 2025-03-06ReportedTopline datamissed
Phase 3 VENTURA program failed: J&J discontinued aticaprant for MDD on 2025-03-06 for insufficient efficacy; drug remained safe and well tolerated. ↗
- 2024-04-22ReportedFull resultsmetNCT03559192
Phase 2a (NCT03559192) positive: adjunctive aticaprant 10 mg reduced MADRS vs placebo at Week 6 (LSMD -2.1; p=0.044, 1-sided); well tolerated. ↗
Clinical trials
NCT06514742Phase 3Discontinuedn=101
Aticaprant 10 mg as Adjunctive Therapy in Adults With MDD With Moderate-to-severe Anhedonia and Long-term Extension Treatment
terminatedprimaryStudy outcome
Terminated early due to insufficient efficacy of the aticaprant Phase 3 program (sponsor decision, March 2025).
NCT05550532Phase 3Completedn=444
VENTURA-2: Aticaprant 10 mg as Adjunctive Therapy in Adults With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy
missedprimaryChange from baseline in MADRS total score vs placebo (adjunctive, MDD with anhedonia)
Part of the Phase 3 VENTURA program that failed to demonstrate sufficient efficacy in the target population; contributed to J&J's March 2025 discontinuation decision.
NCT05518149Phase 3Discontinuedn=871
Open-label, Long-term Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants With MDD
NCT05455684Phase 3Completedn=513
VENTURA-1: Aticaprant 10 mg as Adjunctive Therapy in Adults With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy
missedprimaryChange from baseline in MADRS total score vs placebo (adjunctive, MDD with anhedonia)
Part of the Phase 3 VENTURA program that failed to demonstrate sufficient efficacy in the target population; contributed to J&J's March 2025 discontinuation decision.
NCT03559192Phase 2Completedn=181
A Phase 2a Study Investigating Efficacy, Safety, Tolerability and Pharmacokinetics of JNJ-67953964 (Aticaprant) in Subjects With Major Depressive Disorder
metprimaryChange from baseline in MADRS total score at Week 6 vs placebo (eITT) — LS mean difference -2.1 (effect size 0.23) (0.044 (1-sided))
Adjunctive aticaprant 10 mg significantly reduced depressive symptoms vs placebo at Week 6 on MADRS; met the prespecified primary endpoint. Well tolerated with no significant safety signals.
Identifiers
- ChEMBL CHEMBL1921847
- PubChem CID 44129648
- FDA UNII DE4G8X55F5
Sources
- Aticaprant — Wikipedia
- Aticaprant 10 mg adjunctive in MDD with anhedonia + extension (NCT06514742) — ClinicalTrials.gov
- Efficacy and safety of aticaprant adjunctive to SSRI/SNRI in MDD: a phase 2 randomized, double-blind, placebo-controlled study (Schmidt et al., Neuropsychopharmacology 2024;49(9):1437-1447) — Neuropsychopharmacology (PubMed)
- J&J drops Phase III MDD programme (VENTURA / aticaprant) due to lack of efficacy — Clinical Trials Arena
- LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist (Rorick-Kehn et al., Neuropharmacology 2014;77:131-144) — Neuropharmacology (PubMed)
- Open-label long-term safety/efficacy of aticaprant in MDD (NCT05518149) — ClinicalTrials.gov
- Phase 2a aticaprant (JNJ-67953964) in MDD (NCT03559192) — ClinicalTrials.gov
- VENTURA-1: aticaprant 10 mg adjunctive in MDD with anhedonia (NCT05455684) — ClinicalTrials.gov
- VENTURA-2: aticaprant 10 mg adjunctive in MDD with anhedonia (NCT05550532) — ClinicalTrials.gov