Ulotaront

{{Short description|Investigational antipsychotic}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | IUPAC_name = 1-[(7''S'')-5,7-dihydro-4''H''-thieno[2,3-c]pyran-7-yl]-''N''-methylmethanamine | image = SEP-363856.svg | image_class = skin-invert-image | width = 150

| C=9 | H=13 | N=1 | O=1 | S=1 | SMILES = CNC[C@H]1C2=C(CCO1)C=CS2 | StdInChI_Ref = | StdInChI = 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 | StdInChIKey_Ref = | StdInChIKey = ABDDQTDRAHXHOC-QMMMGPOBSA-N }}

'''Ulotaront''' ({{Abbrlink|INN|International Nonproprietary Name}};<ref name="WHO-INN2020">{{cite journal | title = International Nonproprietary Names for Pharmaceutical Substances (INN) | journal = WHO Drug Information | volume = 34 | issue = 3 | date = 2020 | quote = Proposed INN: List 124 – COVID-19 (special edition) | url = https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl124.pdf?sfvrsn=6437f035_10&download=true }}</ref> 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.<ref name="AdisInsight">{{cite web | title = SEP 363856 | work = AdisInsight | url = https://adisinsight.springer.com/drugs/800036955 | publisher = Springer Nature Switzerland AG | access-date = 29 December 2018 }}</ref><ref name="Medscape 18">{{cite web | vauthors = Brooks M | title = New Psychotropic Drug for Schizophrenia Promising in Early Testing | url = https://www.medscape.com/viewarticle/906892?src=wnl_edit_tpal&uac=194606CT&impID=1846550&faf=1 | website = Medscape | publisher = Reuters Health Information | access-date = 29 December 2018 | archive-date = 21 June 2019 | archive-url = https://web.archive.org/web/20190621232748/https://www.medscape.com/viewarticle/906892?src=wnl_edit_tpal&uac=194606CT&impID=1846550&faf=1 | url-status = dead }}</ref> The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals<ref name="AdisInsight" /> (which was subsequently merged into Sumitomo Pharma<ref>{{cite journal | title = US Sumitomo Pharma Subsidiaries Combine to Form Sumitomo Pharma America | journal = American Pharmaceutical Review | date = 7 April 2023 | url = https://www.americanpharmaceuticalreview.com/1315-News/595974-US-Sumitomo-Pharma-Subsidiaries-Combine-to-Form-Sumitomo-Pharma-America | access-date = 10 July 2023 | archive-date = 11 July 2023 | archive-url = https://web.archive.org/web/20230711134301/https://www.americanpharmaceuticalreview.com/1315-News/595974-US-Sumitomo-Pharma-Subsidiaries-Combine-to-Form-Sumitomo-Pharma-America/ | url-status = dead }}</ref>) using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube.<ref>{{Cite web | title = Sunovion Presents Data From Marketed and Late-Stage Development Psychiatric Compounds At The American Psychiatric Association (APA) Annual Meeting 2021 | date = 2021-05-03 | url = https://www.businesswire.com/news/home/20210503005385/en/Sunovion-Presents-Data-From-Marketed-and-Late-Stage-Development-Psychiatric-Compounds-At-The-American-Psychiatric-Association-APA-Annual-Meeting-2021 | access-date = 2021-09-09 | website = www.businesswire.com | language = en }}</ref>

Ulotaront is in phase III clinical trial for schizophrenia, phase II/III for generalized anxiety disorder and major depressive disorder, and discontinued for narcolepsy and psychotic disorders.<ref>{{cite web | title = Ulotaront - Otsuka Pharmaceutical/Sumitomo Pharma - AdisInsight | url = https://adisinsight.springer.com/drugs/800036955 }}</ref>

Research has shown that ulotaront results in a greater reduction from baseline in the PANSS total score than placebo.<ref name="Koblan_2020">{{cite journal | vauthors = Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, Loebel A | title = A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia | journal = The New England Journal of Medicine | volume = 382 | issue = 16 | pages = 1497–1506 | date = April 2020 | pmid = 32294346 | doi = 10.1056/NEJMoa1911772 | doi-access = free }}</ref> Treatment with ulotaront, as compared with placebo, was also associated with an improvement in sleep quality.<ref name="Koblan_2020" /> Ulotaront was awarded a Breakthrough Therapy designation due to its increased efficacy and greatly reduced side effects compared to current treatments.<ref>{{Cite web | title = Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia | date = 2019-05-10 | url = https://www.businesswire.com/news/home/20190510005212/en/Sunovion-and-PsychoGenics-Announce-that-SEP-363856-Has-Received-FDA-Breakthrough-Therapy-Designation-for-the-Treatment-of-People-with-Schizophrenia | access-date = 2021-09-09 | website = www.businesswire.com | language = en }}</ref>

==Adverse effects== Some adverse events reported in preliminary clinical trials are somnolence, agitation, nausea, diarrhea, and dyspepsia.<ref name="Medscape Game Changer" /> 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.<ref name="Medscape Game Changer">{{cite web | vauthors = Brooks M | title = 'Game Changer' for Schizophrenia on the Horizon? | url = https://www.medscape.com/viewarticle/913348 | website = Medscape | publisher = WebMD LLC | access-date = 21 June 2019 }}</ref>

==Pharmacology==

===Pharmacodynamics=== 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.<ref name="AdisInsight" /><ref name="Bloomberg" /> This mechanism of action is unique among available antipsychotics, which generally antagonize dopamine receptors (especially dopamine D2 receptor).<ref name="Koblan et al 2019">{{cite journal | vauthors = Koblan K, Hopkins S, Justine K, Hailong C, Goldman R, Loebel A | title = 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 | journal = Schizophrenia Bulletin | volume = 45 | issue = Suppl 2 | pages = S199 | year = 2019 | pmc = 6455810 | doi = 10.1093/schbul/sbz021.269 | doi-access = free }}</ref><ref name="Dedic_2019" />

Ulotaront is a full agonist of the human TAAR1 with an {{Abbrlink|EC50|half-maximal effective concentration}} of 140{{nbsp}}nM and an {{Abbrlink|Emax|maximal efficacy}} of 101.3%.<ref name="Dedic_2019">{{cite journal | vauthors = Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T, Leahy E, Koblan KS | title = SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 371 | issue = 1 | pages = 1–14 | date = October 2019 | pmid = 31371483 | doi = 10.1124/jpet.119.260281 | url = https://www.psychogenics.com/wp-content/uploads/2019/07/SEP-363856-A-NOVEL-PSYCHOTROPIC-AGENT-WITH-A-UNIQUE-NON-D2-RECEPTOR-MECHANISM-OF-ACTION-JULY-2019.pdf }}</ref> It is also a partial agonist of the serotonin 5-HT1A receptor ({{Abbr|EC50|half-maximal effective concentration}} = 2,300{{nbsp}}nM; {{Abbr|Emax|maximal efficacy}} = 74.7%) and of the serotonin 5-HT1D receptor ({{Abbr|EC50|half-maximal effective concentration}} = 262{{nbsp}}nM; {{Abbr|Emax|maximal efficacy}} = 57.1%).<ref name="Dedic_2019" /> Conversely, its activities at various other targets, such as various other serotonin receptors as well as adrenergic and dopamine receptors, are much less potent.<ref name="Dedic_2019" />

TAAR1 agonism is known to reduce the firing rate of dopaminergic neurons. The inhibitory effects of TAAR1 agonists on dopaminergic neurotransmission are most pronounced in hyperdopaminergic states.<ref>{{cite journal | vauthors = Achtyes ED, Hopkins SC, Dedic N, Dworak H, Zeni C, Koblan K | title = Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 273 | issue = 7 | pages = 1543–1556 | date = October 2023 | pmid = 37165101 | pmc = 10465394 | doi = 10.1007/s00406-023-01580-3 }}</ref>

Ulotaront decreases basal locomotor activity in rodents and this effect was absent in TAAR1 knockout mice.<ref name="Kuvarzin_2023" /> It prevented the hyperlocomotion induced by the NMDA receptor antagonist phencyclidine (PCP).<ref name="Kuvarzin_2023">{{cite journal | vauthors = Kuvarzin SR, Sukhanov I, Onokhin K, Zakharov K, Gainetdinov RR | title = Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders | journal = Biomedicines | volume = 11 | issue = 7 | pages = 1977 | date = July 2023 | pmid = 37509616 | pmc = 10377193 | doi = 10.3390/biomedicines11071977 | doi-access = free }}</ref><ref name="Begni_2021">{{cite journal | vauthors = Begni V, Sanson A, Luoni A, Sensini F, Grayson B, Munni S, Neill JC, Riva MA | title = Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856 | journal = International Journal of Molecular Sciences | volume = 22 | issue = 8 | pages = 4119 | date = April 2021 | pmid = 33923479 | pmc = 8073823 | doi = 10.3390/ijms22084119 | doi-access = free }}</ref><ref name="Dedic_2019" /> Conversely, ulotaront did not affect dextroamphetamine-induced hyperlocomotion.<ref name="Kuvarzin_2023" /><ref name="Begni_2021" /> Similarly, it did not reverse apomorphine-induced climbing behavior.<ref name="Kuvarzin_2023" />

===Pharmacokinetics=== The precise pharmacokinetic profile of ulotaront has not been reported, though the developer has suggested that the pharmacokinetic data supports once daily dosing.<ref name="Bloomberg" />

==Research== 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.<ref name="Medscape 18"/><ref name="Sunovion Drugs">{{cite web | title = Sunovion – Our Therapies | url = http://www.sunovion.us/our-therapies/ | website = www.sunovion.us | publisher = Sumitomo Dainippon Pharma Co., Ltd. | access-date = 29 December 2018 }}</ref><ref name="PsychoGenics">{{cite web | title = About Us | url = http://www.psychogenics.com/index.html | website = www.psychogenics.com | publisher = PsychoGenics | access-date = 29 December 2018 }}</ref> The US Food and Drug Administration (FDA) has granted ulotaront the breakthrough therapy designation.<ref name="Bloomberg">{{cite news | title = Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia | date = 10 May 2019 | url = https://www.bloomberg.com/press-releases/2019-05-10/sunovion-and-psychogenics-announce-that-sep-363856-has-received-fda-breakthrough-therapy-designation-for-the-treatment-of-people | newspaper = Bloomberg.com | publisher = Bloomberg L.P. | access-date = 21 June 2019 }}</ref><ref name="Pharm Times Breakthrough Status">{{cite web | title = Drug Receives FDA's Breakthrough Therapy Designation for Treating Individuals with Schizophrenia | url = https://www.pharmacytimes.com/resource-centers/mental-health/drug-receives-fdas-breakthrough-therapy-designation-for-treating-individuals-with-schizophrenia | website = Pharmacy Times | publisher = Pharmacy & Healthcare Communications, LLC | access-date = 21 June 2019 | archive-date = 21 June 2019 | archive-url = https://web.archive.org/web/20190621230141/https://www.pharmacytimes.com/resource-centers/mental-health/drug-receives-fdas-breakthrough-therapy-designation-for-treating-individuals-with-schizophrenia | url-status = dead }}</ref> In addition to schizophrenia, ulotaront is also being studied for the treatment of psychosis associated with Parkinson's disease.<ref name="Pharm Times Breakthrough Status" />

The ''Brief Negative Symptom Scale'' (BNSS) has been used to assess the effect of Ulotaront on the negative symptoms of schizophrenia.<ref>{{cite journal | vauthors = Tatsumi K, Kirkpatrick B, Strauss GP, Opler M | title = The brief negative symptom scale in translation: A review of psychometric properties and beyond | journal = European Neuropsychopharmacology | volume = 33 | pages = 36–44 | date = April 2020 | pmid = 32081498 | doi = 10.1016/j.euroneuro.2020.01.018 | s2cid = 211141678 }}</ref>

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.<ref>{{Cite web | vauthors = Ernst D | title = Disappointing Results for Ulotaront in Two Phase 3 Schizophrenia Trials | date = 2023-08-01 | url = https://www.empr.com/home/news/drugs-in-the-pipeline/disappointing-results-for-ulotaront-in-two-phase-3-schizophrenia-trials/ | access-date = 2023-08-11 | website = Medical Professionals Reference | language = en-US }}</ref>

== References == {{Reflist}}

Category:5-HT1A agonists Category:5-HT1D agonists Category:Secondary amines Category:Antipsychotics Category:Experimental drugs developed for schizophrenia Category:TAAR1 agonists Category:Thiophenes