Small Molecule · aticaprant

Aticaprant

DiscontinuedJohnson & Johnson (JNJ)

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

Data current as of

Key facts

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.

TargetActionAffinity
KORprimaryOPRK1AntagonistKi 0.81 nMⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
Aticaprant oral tablet
10 mg once daily (Phase 3 dose in MDD with anhedonia); Phase 1/2 explored 4-25 mg
OralOnce dailyt½ 35 h · Tmax 1.5 h · F 25%

Development timeline#

2018202020222024Discontinued6 Mar 2025 — readout (missed) — Phase 3 VENTURA program failed: J&J discontinued aticaprant for MDD on 2025-03-06 for insufficient efficacy; drug remained safe and well tolerated.14 Aug 2017 — Acquisition — Janssen acquires CERC-501 (aticaprant) asset from CerecorPhase 26 May 2020 — phase change — Phase 2a adjunctive MDD study (NCT03559192) completed; positive on primary MADRS endpoint vs placebo.Phase 322 Apr 2024 — readout (met) — 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.22 Jun 2022 — phase change — Phase 3 VENTURA program initiated (VENTURA-1 NCT05455684 first patient).
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedAug 2017 – Mar 2025
  1. missedPhase 3 VENTURA program failed: J&J discontinued aticaprant for MDD on 2025-03-06 for insufficient efficacy; drug remained safe and well tolerated.↗
  2. AcquisitionJanssen acquires CERC-501 (aticaprant) asset from Cerecor↗
Phase 3Jun 2022 – Apr 2024
  1. 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.↗
  2. Phase 3 VENTURA program initiated (VENTURA-1 NCT05455684 first patient).
Phase 2May 2020
  1. 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

Started Jun 2024· Primary completion Apr 2025· 84 sites across 9 countries

United StatesHungarySpainFinland

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

Started Dec 2022· Primary completion Nov 2024· 131 sites across 14 countries

United StatesChinaSouth KoreaArgentina

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

Started Sept 2022· Primary completion Apr 2025· 234 sites across 21 countries

United StatesArgentinaChinaCzechia

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

Started Jun 2022· Primary completion Sept 2024· 120 sites across 13 countries

United StatesSpainBrazilArgentina

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

Started Jul 2018· Primary completion May 2020· 53 sites across 6 countries

United StatesRussiaUkraineUnited Kingdom

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.

Sources#

  1. Aticaprant — Wikipedia
  2. Aticaprant 10 mg adjunctive in MDD with anhedonia + extension (NCT06514742) — ClinicalTrials.gov
  3. Cerecor Announces Divestiture of CERC-501 to Janssen Pharmaceuticals, Inc. — Cerecor Inc. (via Yahoo Finance)
  4. 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)
  5. J&J drops Phase III MDD programme (VENTURA / aticaprant) due to lack of efficacy — Clinical Trials Arena
  6. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist (Rorick-Kehn et al., Neuropharmacology 2014;77:131-144) — Neuropharmacology (PubMed)
  7. Open-label long-term safety/efficacy of aticaprant in MDD (NCT05518149) — ClinicalTrials.gov
  8. Phase 2a aticaprant (JNJ-67953964) in MDD (NCT03559192) — ClinicalTrials.gov
  9. VENTURA-1: aticaprant 10 mg adjunctive in MDD with anhedonia (NCT05455684) — ClinicalTrials.gov
  10. VENTURA-2: aticaprant 10 mg adjunctive in MDD with anhedonia (NCT05550532) — ClinicalTrials.gov