seltorexant (MIN-202) / Minerva Neurosciences, J&J, Royalty - LARVOL DELTA

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Nov 2027 ➔ May 2027

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

Efficacy and safety profiles of FDA-approved dual orexin receptor antagonists in depression: A systematic review of pre-clinical and clinical studies. (PubMed, J Psychiatr Res) - "DORAs show potential in improving sleep parameters in individuals with MDD. While their effects on depressive symptoms in this review are modest, further research is needed to assess long-term efficacy, safety, and their impact on depressive symptoms, as well as to explore potential combination therapies."

FDA event • Journal • Preclinical • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Effect of dual orexin receptor antagonists on sleep: A systematic review and meta analysis (ECNP 2025) - "The DORAs included were suvorexant, lemborexant, daridorexant, seltorexant, filorexant and vornorexant. Most DORAs were found to be of robust efficacy, irrespective of diagnosis, although further research is required for most diagnoses. Most DORAs seem to cause notably more somnolence than placebo, which is of great clinical importance."

Retrospective data • Review • Alzheimer's Disease • Bipolar Disorder • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Movement Disorders • Psychiatry • Restless Legs Syndrome • Sleep Disorder

Developments in adjunctive treatment: Seltorexant versus quetiapine in managing major depressive disorder with insomnia symptoms (ECNP 2025) - P3 | "This presentation will focus on the results from a Phase 3, 26-week, international, double-blind, active-controlled study (NCT04513912) of adjunctive seltorexant 20 mg with quetiapine-extended release (XR) as a comparator in MDD with insomnia symptoms in a subgroup of participants (18-74 years) from the European Union and United Kingdom. Y. Flossbach is a full-time employee of Actelion Pharmaceuticals Ltd., a Johnson & Johnson company, and holds stock in Johnson & Johnson"

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

Seltorexant: a safe and well-tolerated adjunctive treatment for adolescent major depressive disorder with comparable pharmacokinetics to adults (ECNP 2025) - "Most patients were taking fluoxetine (56.7%) or escitalopram (36.7%) at baseline. Based on adequate PK characterization with fewer than planned participants, and absence of new safety findings at the interim analysis, agreement was reached with European Health Authorities to terminate the study early. The safety and PK results from the current study support continued development of seltorexant in the paediatric population."

Clinical • PK/PD data • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder • Suicidal Ideation

Hypocretin: a promising target for the regulation of homeostasis. (PubMed, Front Neurosci) - "Dual hypocretin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for insomnia. Selective HCRT-2R agonists-including TAK-861 and ALKS-2680-are in clinical trials for NT1 and show encouraging results. Additionally, HCRT-2R antagonists like seltorexant are being explored for major depressive disorder. This review will highlight the anatomical distribution, receptor mechanisms, and physiological functions of the hypocretin system. It will also focus to discuss its role in narcolepsy, metabolic regulation, and mood disorders, while addressing key challenges and open questions that must be resolved to fully harness hypocretin's therapeutic potential."

Journal • Review • Cataplexy • CNS Disorders • Depression • Excessive Daytime Sleepiness • Insomnia • Major Depressive Disorder • Mood Disorders • Narcolepsy • Psychiatry • Sleep Disorder • LEP

Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial. (PubMed, JAMA Psychiatry) - P2 | "Seltorexant was generally well tolerated. ClinicalTrials.gov Identifier: NCT03375203."

Clinical • Journal • CNS Disorders • Insomnia • Psychiatry • Sleep Disorder

Sleep Deprivation Engages the Orexin/Hypocretin System to Regulate Food Reward Seeking. (PubMed, Int J Neuropsychopharmacol) - "These results highlight Ox2R signaling in counteracting the acute SD effects on food reward seeking in females."

Journal • Sleep Disorder • FOS

A new direction for adjunctive therapy of difficult-to-treat depression: examining the role of orexin receptor antagonists. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Although it is likely that the currently approved Dual Orexin Receptor Antagonists (DORAs)-suvorexant, lemborexant and daridorexant-are safe and useful options for concomitant therapy of insomnia in antidepressant-treated patients, these medications have not been approved for this indication. By contrast, the investigational ORA seltorexant, which is a selective Orexin 2 receptor antagonist, has shown significant antidepressant effects in Phase 2 and Phase 3 trials. Although at least one more unequivocally positive pivotal study will be needed to garner FDA approval for clinical use in the United States, this drug shows promise as a novel and well-tolerated option for patients with difficult to treat depressive episodes."

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

Comparative efficacy and safety of different pharmacological interventions for the treatment of depression associated with insomnia in the elderly population: a systematic review and network meta-analysis. (PubMed, Psychogeriatrics) - "All types of intervention were effective in decreased Insomnia Severity Index (ISI) and depression score, and sertraline had the highest probability of being the most effective intervention in decreasing the ISI (standard mean difference (SMD) = -2.17, 95% confidence interval (95% CI): -2.60, -1.75), Hamilton Depression Scale (HAM-D: SMD = -3.10, 95% CI: -3.60, -2.61) in elderly patients with depression and insomnia...In terms of the number of patients reporting escitalopram and zuranolone, zolpidem, seltorexant and eszopiclone had higher risks of serious adverse events than placebo or other treatments...Escitalopram, zuranolone, and seltorexant did not show overall material benefits in reducing ISI. These results should serve evidence-based clinical practice."

Journal • Retrospective data • Review • CNS Disorders • Depression • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder

Activation of orexin receptor 2 plays anxiolytic effect in male mice. (PubMed, Brain Res) - "In this study, by using behavioral test, stereotaxic surgery and microinjection, virus-mediated knockdown of OX2R and pharmacological method, we found that: (1) Intraperitoneal injection of OX2R antagonist Seltorexant induced increased baseline anxiety-like behaviors in male mice...(3) Intraperitoneal injection of YNT-185 alleviated morphine withdrawal-induced anxiety-like behaviors in male mice. (4) Microinjection of YNT-185 into the VTA played anxiolytic effect in male mice. (5) Virus-mediated OX2R knockdown in the VTA induced anxiety-like behaviors in male mice."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Seltorexant for major depressive disorder. (PubMed, Expert Opin Emerg Drugs) - "Early clinical evidence suggests that seltorexant is effective in treating MDD, both in individuals diagnosed with insomnia and those not, although greater antidepressant effects are observed in individuals with severe sleep disturbance. Results from large phase III clinical trials are needed to confirm efficacy and safety."

Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • Sleep Disorder

Treatment effect and safety of seltorexant as monotherapy for patients with major depressive disorder: a randomized, placebo-controlled clinical trial. (PubMed, Mol Psychiatry) - P1 | "These biomarker data suggest mechanistic hypotheses that may account for the apparent curvilinear dose-response relationship of seltorexant. Trial Registration: ClinicalTrials.gov, NCT03374475."

Clinical • Journal • Monotherapy • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Efficacy of orexin antagonists for the management of major depressive disorder: A systematic review of randomized clinical trials. (PubMed, J Affect Disord) - "However, filorexant did not exhibit a significant difference in MADRS total scores compared to placebo. Taken together, the potential of orexin receptor antagonists, particularly seltorexant, as a novel avenue for managing depressive symptoms in MDD. Further research is warranted to better understand their role in depression treatment and safety profile."

Clinical • Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Phase 3 study of adjunctive seltorexant treatment in adults with major depressive disorder with insomnia symptoms (ECNP 2024) - P3 | "Seltorexant demonstrated statistically significant and clinically meaningful antidepressant effects, beyond improvement of insomnia symptoms, in the global efficacy analysis set of participants with MDD with IS experiencing an inadequate response to SSRI/SNRI. These Results were consistent in the EU efficacy analysis set. The safety and tolerability profile of seltorexant was similar to that of placebo."

Clinical • P3 data • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jun 2027 ➔ Nov 2027

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

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC

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

Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov. (PubMed, Transl Psychiatry) - "The top four most studied drugs, ketamine, sertraline, duloxetine, and fluoxetine, were consistent in both groups, but ClinicalTrials.gov had more trials for each drug compared to the non-ClinicalTrials.gov group. Additionally, 26 investigational antidepressive agents targeting 16 different drug targets were identified, with buprenorphine (opioid agonist), saredutant (NK2 antagonist), and seltorexant (OX2 antagonist) being the most frequently studied. This analysis addresses 40 approved drugs for depression treatment including new drug classes like GABA modulators and NMDA antagonists that are offering new prospects for treating MDD, including drug-resistant depression and postpartum depression subtypes."

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

A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adolescents With Major Depressive Disorder Who Have an Inadequate Response to Selective Serotonin Reuptake Inhibitor (SSRI) and Psychotherapy (clinicaltrials.gov) - P1 | N=31 | Terminated | Sponsor: Janssen Research & Development, LLC | Trial completion date: Mar 2025 ➔ Apr 2024 | Active, not recruiting ➔ Terminated; Following discussion on pediatric strategy with HAs, it was determined that we have sufficient data to inform next steps for the seltorexant pediatric program.

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

A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adult and Elderly Participants With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant and Long-term Safety Extension Treatment With Seltorexant (clinicaltrials.gov) - P3 | N=588 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

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

Seltorexant, Adjunctive to Antidepressants, in Adults with MDD with Insomnia Symptoms: Results of a Double-Blind, Randomized, Placebo-Controlled Study (ASCP 2024) - P3 | "Seltorexant showed statistically significant and clinically meaningful antidepressant effects, beyond improvement of insomnia symptoms, in patients with MDD with IS who had experienced inadequate response to SSRI/SNRI. Seltorexant demonstrated a safety profile similar to placebo. Learning Objectives 1."

Clinical • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Adjunctive Treatment with Seltorexant Improved Patient-Reported Depressive Symptoms, Insomnia Symptoms, and Overall Health in MDD with Insomnia (ASCP 2024) - P3 | "From the patient’s perspective, adjunctive treatment with seltorexant improved depressive symptoms, insomnia symptoms, and HRQoL, compared to placebo, in adults with MDDIS and an inadequate response to SSRI/SNRI. Learning Objectives 1. Describe secondary and exploratory endpoints of a phase 3 study investigating the efficacy and safety of seltorexant, adjunctive to background SSRI/SNRI antidepressant, in patients with major depressive disorder with insomnia symptoms."

Clinical • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adolescents With Major Depressive Disorder Who Have an Inadequate Response to Selective Serotonin Reuptake Inhibitor (SSRI) and Psychotherapy (clinicaltrials.gov) - P1 | N=31 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | N=52 ➔ 31 | Trial primary completion date: Feb 2025 ➔ Apr 2024

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

Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis. (PubMed, Noro Psikiyatr Ars) - "Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed."

Journal • Retrospective data • Review • CNS Disorders • Depression • Insomnia • Mental Retardation • Mood Disorders • Psychiatry • Sleep Disorder

A Study of Seltorexant in Participants With Probable Alzheimer's Disease (clinicaltrials.gov) - P2 | N=70 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Dementia