aticaprant (JNJ-67953964) / J&J - LARVOL DELTA

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=101 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | N=350 ➔ 101

Enrollment change • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Kappa Opioid Receptors Diminish Spontaneous Dopamine Signals in Awake Mice Through Multiple Mechanisms. (PubMed, Neuropharmacology) - "Next, mice were systemically administered the KOR agonist U50,488H in the presence or absence of the KOR antagonist aticaprant...The effects of KOR activation were stronger in males, while effects of KOR antagonism were stronger in females. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DA transporter-mediated uptake, and reducing the frequency of signals."

Journal • Preclinical

Anhedonia: Current and future treatments. (PubMed, PCN Rep) - "Drugs such as vortioxetine, agomelatine, bupropion, ketamine, and brexpiprazole show promising anti-anhedonic effects, while traditional antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and, even more so, selective serotonin reuptake inhibitors (SSRIs), are less effective...Innovative treatments, such as aticaprant and psilocybin, showed promising results...The reviewed evidence underscores the importance of routine assessment of anhedonia and the integration of symptom-specific strategies. Tailoring interventions to address individual patterns of reward disruption may optimize outcomes for patients with anhedonia."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-LT: A Study of Aticaprant in Adult and Elderly Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=840 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2025 ➔ Apr 2025 | Trial primary completion date: Oct 2025 ➔ Apr 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=350 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2026 ➔ May 2025 | Trial primary completion date: Jun 2026 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=444 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Nov 2024 | Trial primary completion date: Jul 2025 ➔ Nov 2024

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-5: A Study of Aticaprant Plus an Antidepressant to Prevent Return of Depression Symptoms in Participants With Major Depressive Disorder Who Experience a Loss of Interest and Pleasure (clinicaltrials.gov) - P3 | N=660 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | Trial completion date: May 2027 ➔ May 2025 | Trial primary completion date: May 2027 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Study to Explore the Efficacy of JNJ-67953964 in the Treatment of Depression (clinicaltrials.gov) - P2 | N=181 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-1: A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=513 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=710 | Recruiting | Sponsor: Janssen Research & Development, LLC | Completed ➔ Recruiting | N=444 ➔ 710 | Trial completion date: Nov 2024 ➔ Jul 2025 | Trial primary completion date: Nov 2024 ➔ Jul 2025

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=444 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed | N=710 ➔ 444

Enrollment change • Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-5: A Study of Aticaprant Plus an Antidepressant to Prevent Return of Depression Symptoms in Participants With Major Depressive Disorder Who Experience a Loss of Interest and Pleasure (clinicaltrials.gov) - P3 | N=660 | Recruiting | Sponsor: Janssen Research & Development, LLC

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Adjunctive Aticaprant and Anhedonia in Major Depressive disorder (ECNP 2024) - "Tolerability and safety were reassuring. These promising Results of the co-administration of aticaprant to an SSRI/SNRI in depressed patients with prominent anhedonia support he further investigation of aticaprant in larger trials."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-1: A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=538 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jan 2025 ➔ Sep 2024

Trial completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Sex differences in the Protein Kinase A signaling of chronic postsurgical pain sensitization is medi (IASP 2024) - "We then pharmacologically or surgically activated or inhibited ARs with 4 experiments: 1) in female mice, we administered testosterone enanthate (TE, 0.45 mg/kg, subcutaneous) or vehicle (sesame oil) for two weeks (n = 5-8); 2) in female mice, we spinally administered TE (10 µg, intrathecal) or vehicle (cremophore: ethanol: saline – 1:1:8) (n = 6-8); 3) in male mice, we administered flutamide (50 mg/kg, subcutaneous) to block AR (n = 6-12); 4) male mice received orchiectomy (surgical removal of testes) or sham surgery (n = 6-8). After each of these interventions, we administered vehicle, PKA inhibitor H89 (10 nmol, i.t.), and/or KOR antagonist LY2456302 (10 µg, i.t.) in a 2×2 design in both male and female mice... We found that pharmacological or surgical interruption of AR prevented the ability of a PKA inhibitor to prevent pain reinstatement in male mice, whereas pharmacological activation of AR recruited the ability of PKA to prevent reinstatement in..."

Immunology • Pain • AR • ER

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=350 | Recruiting | Sponsor: Janssen Research & Development, LLC

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Preclinical and clinical efficacy of kappa opioid receptor antagonists for depression: A systematic review. (PubMed, J Affect Disord) - "Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms."

Journal • Preclinical • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-1: A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=538 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Oct 2024 ➔ Jan 2025

Trial completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=710 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Feb 2025 ➔ Oct 2024

Trial completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=710 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Oct 2024 ➔ Feb 2025

Trial completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Aticaprant, a kappa opioid receptor antagonist, and the recovered 'interest and pleasure' in the concept of major depressive disorder. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Tolerability and safety were reassuring. These promising results of the co-administration of aticaprant to an SSRI/SNRI in depressed patients with prominent anhedonia support he further investigation of aticaprant in larger trials."

Clinical • Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Aticaprant: (a κ-opioid receptor antagonist) for major depressive disorder. (PubMed, Expert Opin Emerg Drugs) - "Early evidence indicates Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study. (PubMed, Neuropsychopharmacology) - "One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials."

Clinical • Journal • P2 data • CNS Disorders • Depression • Dermatology • Infectious Disease • Major Depressive Disorder • Mood Disorders • Pain • Pruritus • Psychiatry

VENTURA-1: A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=538 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Jun 2024 ➔ Sep 2024

Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Microdosing Partial Agonists Inactivates Kappa Opioid Receptors - An Alternative Strategy for Human Trials (ACNP 2023) - "Two pharmacological types of selective KOR antagonists have been described – reversible competitive (e.g. Aticaprant and NMRA-140) and KOR-inactivating antagonists (e.g. norBNI and JDTic); however, which type would be more effective is not yet clear. Low, repeated doses of nalmefene and nalfurafine inactivated KOR by the established JNK mechanism. We show that ROS generation via KOR agonism with nalfurafine was dependent on estrus cycle stage, with high estradiol during proestrus (like the estrogen spike before ovulation in human females) blocking generation of ROS. This presents a unique problem when examining long-lasting inactivation in women."

Addiction (Opioid and Alcohol) • CNS Disorders • Cognitive Disorders • Pain • NR3C1 • PRDX6