Therapeutics

Seltorexant

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Overview

Name: Seltorexant
Synonyms: JNJ-42847922, MIN-202
Chemical Name: [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Janssen

Background

Seltorexant is a selective antagonist of the human orexin-2 receptor. The neuropeptide orexin regulates wakefulness; inhibiting orexin receptor signaling promotes sleep. This drug is in advanced clinical development for treating depression, where it is thought to be effective by improving sleep. It is being tested to treat agitation and aggression in people with AD.

In preclinical work in rats, orally administrated seltorexant rapidly entered the brain, and induced and prolonged sleep. In humans, it increased sleepiness after a single dose, with acceptable pharmacokinetics and safety (Bonaventure et al., 2015). 

This compound was originally discovered at Minerva Neurosciences. That company was developing it in collaboration with Janssen, but their partnership ended in 2020, and now Janssen is solely responsible for its development.

Findings

Since 2009, Janssen has completed more than 20 Phase 1 studies of seltorexant. In people with insomnia, the drug reduced time to fall asleep and increased sleep time (van der Ark et al., 2018; De Boer et al., 2018). In patients with major depression and persistent insomnia, it eased core symptoms of depression, and improved sleep (Brooks et al., 2019; Recourt et al., 2019). In a Phase 2 trial, adding seltorexant improved depression in people who had responded poorly to serotonin reuptake inhibitors. The drug was most effective in people with the worst sleep problems at the start of the study (Savitz et al., 2021). The most common adverse effects were headache, sleepiness, and nausea. Two Phase 3 trials are now testing six weeks of suvorexant added on to antidepressants in people with major depression and insomnia. The studies, in a total of 1,270 patients, will finish in 2023, and the company anticipates FDA submission later that year.

In May 2022, Janssen began a Phase 2 trial of seltorexant in 86 people with probable Alzheimer’s disease and significant agitation or aggression. Patients will take a single 20 mg tablet or matching placebo daily for six weeks, against a primary outcome of the Agitation and Aggression domain scores of the Neuropsychiatric Inventory-Clinician rating. Secondary outcomes are change in Cohen-Mansfield Agitation Inventory, sleep, and plasma drug levels. The study is running at 35 locations in the U.S., with completion anticipated in April 2023.

For details on seltorexant trials, see clinicaltrials.gov.

Last Updated: 17 Jan 2023

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References

Paper Citations

  1. van der Ark PD, Golor G, van Nueten L, Nandy P, de Boer P. Multiple daytime administration of the selective orexin-2 receptor antagonist JNJ-42847922 induces somnolence in healthy subjects without residual central effects. J Psychopharmacol. 2018 Dec;32(12):1330-1340. Epub 2018 Sep 5 PubMed.
  2. De Boer P, Drevets WC, Rofael H, van der Ark P, Kent JM, Kezic I, Parapatics S, Dorffner G, van Gerven J, Beneš H, Keicher C, Jahn H, Seiden DJ, Luthringer R. A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity. J Psychopharmacol. 2018 Jun;32(6):668-677. Epub 2018 May 31 PubMed.
  3. Brooks S, Jacobs GE, de Boer P, Kent JM, Van Nueten L, van Amerongen G, Zuiker R, Kezic I, Luthringer R, van der Ark P, van Gerven JM, Drevets W. The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia. J Psychopharmacol. 2019 Feb;33(2):202-209. Epub 2019 Jan 15 PubMed.
  4. Recourt K, de Boer P, Zuiker R, Luthringer R, Kent J, van der Ark P, Van Hove I, van Gerven J, Jacobs G, van Nueten L, Drevets W. The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder. Transl Psychiatry. 2019 Sep 3;9(1):216. PubMed.
  5. Savitz A, Wajs E, Zhang Y, Xu H, Etropolski M, Thase ME, Drevets WC. Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study. Int J Neuropsychopharmacol. 2021 Dec 8;24(12):965-976. PubMed.
  6. Bonaventure P, Shelton J, Yun S, Nepomuceno D, Sutton S, Aluisio L, Fraser I, Lord B, Shoblock J, Welty N, Chaplan SR, Aguilar Z, Halter R, Ndifor A, Koudriakova T, Rizzolio M, Letavic M, Carruthers NI, Lovenberg T, Dugovic C. Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia. J Pharmacol Exp Ther. 2015 Sep;354(3):471-82. Epub 2015 Jul 15 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Bai P, Liu Y, Xu Y, Striar R, Yuan G, Afshar S, Langan AG, Rattray AK, Wang C. Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging. Bioorg Chem. 2022 Jun;123:105779. Epub 2022 Apr 4 PubMed.
  2. Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J. Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders. Expert Opin Drug Metab Toxicol. 2020 Nov;16(11):1063-1078. Epub 2020 Oct 4 PubMed.
  3. Letavic MA, Bonaventure P, Carruthers NI, Dugovic C, Koudriakova T, Lord B, Lovenberg TW, Ly KS, Mani NS, Nepomuceno D, Pippel DJ, Rizzolio M, Shelton JE, Shah CR, Shireman BT, Young LK, Yun S. Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate. J Med Chem. 2015 Jul 23;58(14):5620-36. Epub 2015 Jul 8 PubMed.
  4. Fagan H, Jones E, Baldwin DS. Orexin Receptor Antagonists in the Treatment of Depression: A Leading Article Summarising Pre-clinical and Clinical Studies. CNS Drugs. 2023 Jan;37(1):1-12. Epub 2022 Nov 27 PubMed.
  5. Wu X, Xue T, Chen Z, Wang Z, Chen G. Orexin Receptor Antagonists and Insomnia. Curr Psychiatry Rep. 2022 Oct;24(10):509-521. Epub 2022 Aug 16 PubMed.