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Ulotaront

Ulotaront
Clinical data
Other namesSEP-363856; SEP363856; SEP-856; SEP856
Identifiers
  • 1-[(7S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]-N-methylmethanamine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC9H13NOS
Molar mass183.27 g·mol−1
3D model (JSmol)
  • CNC[C@H]1C2=C(CCO1)C=CS2
  • InChI=1S/C9H13NOS/c1-10-6-8-9-7(2-4-11-8)3-5-12-9/h3,5,8,10H,2,4,6H2,1H3/t8-/m0/s1
  • Key:ABDDQTDRAHXHOC-QMMMGPOBSA-N

Ulotaront (INNTooltip International Nonproprietary Name;[1] developmental codes SEP-363856, SEP-856) is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis.[2][3] The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals[2] (which was subsequently merged into Sumitomo Pharma[4]) using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube.[5]

Ulotaront is in phase III clinical trial for schizophrenia, phase II/III for generalised anxiety disorder and major depressive disorder and discontinued for narcolepsy and psychotic disorders.[6]

Research has shown that ulotaront results in a greater reduction from baseline in the PANSS total score than placebo.[7] Treatment with ulotaront, as compared with placebo, was also associated with an improvement in sleep quality.[7] Ulotaront was awarded a Breakthrough Therapy designation due to its increased efficacy and greatly reduced side effects compared to current treatments.[8]

Adverse effects

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The adverse effect profile of ulotaront differs from that of other antipsychotics because its mechanism of action does not involve antagonism of dopamine receptors in the brain, which is responsible for the drug-induced movement disorders (like akathisia) that may occur with those agents.[9] Some adverse events reported in preliminary clinical trials are somnolence, agitation, nausea, diarrhea, and dyspepsia.[9]

Pharmacology

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Pharmacodynamics

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The mechanism of action of ulotaront in the treatment of schizophrenia is unclear. However, it is thought to be an agonist at the trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors.[2][10] This mechanism of action is unique among available antipsychotics, which generally antagonize dopamine receptors (especially dopamine D2 receptor).[11][12]

Ulotaront is a full agonist of the human TAAR1 with an EC50Tooltip half-maximal effective concentration of 140 nM and an EmaxTooltip maximal efficacy of 101.3%.[12] It is also a partial agonist of the serotonin 5-HT1A receptor (EC50 = 2,300 nM; Emax = 74.7%) and of the serotonin 5-HT1D receptor (EC50 = 262 nM; Emax = 57.1%).[12] Conversely, its activities at various other targets, such as various other serotonin receptors as well as adrenergic and dopamine receptors, are much less potent.[12]

Pharmacokinetics

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The precise pharmacokinetic profile of ulotaront has not been reported, though the developer has suggested that the pharmacokinetic data supports once daily dosing.[10]

Research

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As of 2018, Sunovion, the maker of another antipsychotic called lurasidone (Latuda), is conducting clinical trials on ulotaront in partnership with the preclinical research company PsychoGenics.[3][13][14] The U.S. Food and Drug Administration has granted ulotaront the breakthrough therapy designation.[10][15] In addition to schizophrenia, ulotaront is also being studied for the treatment of psychosis associated with Parkinson's disease.[15]

The Brief Negative Symptom Scale (BNSS) has been used to assess the effect of Ulotaront on the negative symptoms of schizophrenia.[16]

In July 2023, the pharmaceutical company behind the drug announced that the drug had failed to outperform placebo in the treatment of acutely psychotic patients with schizophrenia, as measured by the PANSS.[17]

See also

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References

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  1. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 34 (3). 2020. Proposed INN: List 124 – COVID-19 (special edition)
  2. ^ a b c "SEP 363856". AdisInsight. Springer Nature Switzerland AG. Retrieved 29 December 2018.
  3. ^ a b Brooks M. "New Psychotropic Drug for Schizophrenia Promising in Early Testing". Medscape. Reuters Health Information. Retrieved 29 December 2018.
  4. ^ "US Sumitomo Pharma Subsidiaries Combine to Form Sumitomo Pharma America". American Pharmaceutical Review. 7 April 2023. Archived from the original on 11 July 2023. Retrieved 10 July 2023.
  5. ^ "Sunovion Presents Data From Marketed and Late-Stage Development Psychiatric Compounds At The American Psychiatric Association (APA) Annual Meeting 2021". www.businesswire.com. 2021-05-03. Retrieved 2021-09-09.
  6. ^ https://adisinsight.springer.com/drugs/800036955
  7. ^ a b Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, Loebel A (April 2020). "A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia". The New England Journal of Medicine. 382 (16): 1497–1506. doi:10.1056/NEJMoa1911772. PMID 32294346.
  8. ^ "Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia". www.businesswire.com. 2019-05-10. Retrieved 2021-09-09.
  9. ^ a b Brooks M. "'Game Changer' for Schizophrenia on the Horizon?". Medscape. WebMD LLC. Retrieved 21 June 2019.
  10. ^ a b c "Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia". Bloomberg.com. Bloomberg L.P. 10 May 2019. Retrieved 21 June 2019.
  11. ^ Koblan K, Hopkins S, Justine K, Hailong C, Goldman R, Loebel A (2019). "O12.5. Efficacy and Safety of Sep-363856, A Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia: A 4-Week, Randomized, Placebo-Controlled Trial". Schizophrenia Bulletin. 45 (Suppl 2): S199. doi:10.1093/schbul/sbz021.269. PMC 6455810.
  12. ^ a b c d Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T, Leahy E, Koblan KS (October 2019). "SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action" (PDF). J Pharmacol Exp Ther. 371 (1): 1–14. doi:10.1124/jpet.119.260281. PMID 31371483.
  13. ^ "Sunovion – Our Therapies". www.sunovion.us. Sumitomo Dainippon Pharma Co., Ltd. Retrieved 29 December 2018.
  14. ^ "About Us". www.psychogenics.com. PsychoGenics. Retrieved 29 December 2018.
  15. ^ a b "Drug Receives FDA's Breakthrough Therapy Designation for Treating Individuals with Schizophrenia". Pharmacy Times. Pharmacy & Healthcare Communications, LLC. Retrieved 21 June 2019.
  16. ^ Tatsumi K, Kirkpatrick B, Strauss GP, Opler M (April 2020). "The brief negative symptom scale in translation: A review of psychometric properties and beyond". European Neuropsychopharmacology. 33: 36–44. doi:10.1016/j.euroneuro.2020.01.018. PMID 32081498. S2CID 211141678.
  17. ^ Ernst D (2023-08-01). "Disappointing Results for Ulotaront in Two Phase 3 Schizophrenia Trials". Medical Professionals Reference. Retrieved 2023-08-11.