Xanomeline/trospium chloride

{{Short description|Medication}} {{Use dmy dates|date=September 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | type = combo | image = Xanomeline and trospium chloride.svg | image_class = skin-invert-image | width = | alt = | caption = Xanomeline (top) and trospium chloride (bottom)

| component1 = Xanomeline | class1 = Muscarinic agonist | component2 = Trospium chloride | class2 = Muscarinic antagonist (peripherally selective)

| tradename = Cobenfy | Drugs.com = {{drugs.com|monograph|xanomeline-tartrate-and-trospium-chloride}} | MedlinePlus = a624070 | DailyMedID = Xanomeline and trospium | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | ATC_prefix = N05 | ATC_suffix = AX50 | ATC_supplemental =

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Cobenfy FDA label">{{cite web | title=Cobenfy- xanomeline and trospium chloride capsule, coated pellets; Cobenfy- xanomeline and trospium chloride kit | website=DailyMed | date=30 September 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f0e73bf-6025-44f6-ab64-0983322de0df | access-date=11 November 2024}}</ref> | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status =

| CAS_number = | CAS_supplemental = | PubChem = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = | UNII = | KEGG = D12968 | ChEBI = | ChEMBL = | synonyms = KarXT }}

'''Xanomeline/trospium chloride''', sold under the brand name '''Cobenfy''', is a fixed-dose combination medication used for the treatment of schizophrenia.<ref name="Cobenfy FDA label" /> It contains xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist.<ref name="Cobenfy FDA label" /> Xanomeline is a functionally-preferring muscarinic acetylcholine receptor M4 and M1 receptor agonist.<ref name="Cobenfy FDA label" /> Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.<ref name="Cobenfy FDA label" />

The most common side effects of xanomeline/trospium chloride include nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness, and gastroesophageal reflux.<ref name="FDA PR 20240926" /><ref name="Cobenfy FDA snapshot" />

In September 2024, it was approved for medical use in the United States.<ref name="FDA PR 20240926">{{cite press release | title=FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia | website=U.S. Food and Drug Administration (FDA) | date=26 September 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | access-date=27 September 2024 | archive-date=27 September 2024 | archive-url=https://web.archive.org/web/20240927004824/https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | url-status=live }} {{PD-notice}}</ref><ref name="Cobenfy FDA snapshot">{{cite web | title=Drug Trials Snapshots: Cobenfy | website=U.S. Food and Drug Administration | date=26 September 2024 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-cobenfy | access-date=24 June 2025}} {{PD-notice}}</ref> It is the first antipsychotic drug approved by the US Food and Drug Administration (FDA) to treat schizophrenia that targets cholinergic receptors as opposed to dopamine receptors, which has long been the standard of care.<ref name="FDA PR 20240926" /><ref>{{cite web |access-date=28 October 2024 |title=Novel Drug Approvals for 2024 |url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 |website=U.S. Food and Drug Administration (FDA) }}</ref> The FDA considers it to be a first-in-class medication.<ref>{{cite report | title=New Drug Therapy Approvals 2024 | website=U.S. Food and Drug Administration (FDA) | date=January 2025 | url=https://www.fda.gov/media/184967/download | format=PDF | access-date=21 January 2025 | archive-url=https://web.archive.org/web/20250121045744/https://www.fda.gov/media/184967/download | archive-date=21 January 2025 | url-status=live }}</ref> Trospium chloride is a peripherally selective non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's mechanism of action in this context is hypothesized to be via modulating certain neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which can provide therapeutic benefits in schizophrenia and related conditions.<ref name="Mirza_2003">{{cite journal | vauthors = Mirza NR, Peters D, Sparks RG | title = Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists | journal = CNS Drug Reviews | volume = 9 | issue = 2 | pages = 159–186 | date = 2003 | pmid = 12847557 | pmc = 6741650 | doi = 10.1111/j.1527-3458.2003.tb00247.x }}</ref>

== Medical uses == Xanomeline/trospium chloride is indicated for the treatment of schizophrenia in adults.<ref name="Cobenfy FDA label" /><ref name="FDA PR 20240926" />

== Adverse effects == The US Food and Drug Administration (FDA) prescribing information for the combination includes warnings that xanomeline/trospium chloride can cause urinary retention, increased heart rate, decreased gastric movement or angioedema (swelling beneath the skin) of the face and lips.<ref name="FDA PR 20240926" />

The most common side effects of xanomeline/trospium chloride include nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness, and gastroesophageal reflux disease.<ref name="FDA PR 20240926" /><ref name="Cobenfy FDA snapshot" />

==Mechanism of action== Preclinical data supports the hypothesis that xanomeline's central mechanism of action is mediated primarily through stimulation of brain muscarinic M4 and M1 receptors.<ref>{{cite journal | vauthors = Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A | title = Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice | journal = Schizophrenia Research | volume = 42 | issue = 3 | pages = 249–259 | date = May 2000 | pmid = 10785583 | doi = 10.1016/s0920-9964(99)00138-3 | s2cid = 54259702 }}</ref> M4 muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinforcement, and reward perception. M1 muscarinic receptors are most highly expressed in the cerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality.<ref>{{cite book | vauthors = Volpicelli LA, Levey AI | title = Acetylcholine in the Cerebral Cortex | chapter = Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus | series = Progress in Brain Research | volume = 145 | pages = 59–66 | date = 2004 | pmid = 14650906 | doi = 10.1016/s0079-6123(03)45003-6 | publisher = Elsevier | isbn = 9780444511256 }}</ref> Unlike direct dopamine D2 and serotonin 5-HT2A blocking antipsychotic medications, M4 and M1 receptor stimulation indirectly rebalances dopaminergic and glutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both psychosis and cognitive symptom domains while M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.<ref>{{cite journal | vauthors = Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA | title = Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice | journal = European Journal of Pharmacology | volume = 603 | issue = 1–3 | pages = 147–149 | date = January 2009 | pmid = 19111716 | doi = 10.1016/j.ejphar.2008.12.020 }}</ref><ref>{{cite journal | vauthors = Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC | title = Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia | journal = The American Journal of Psychiatry | volume = 179 | issue = 9 | pages = 611–627 | date = September 2022 | pmid = 35758639 | doi = 10.1176/appi.ajp.21101083 | s2cid = 250070840 }}</ref>

Trospium chloride is a non-selective muscarinic antagonist, but does not cross the blood–brain barrier.<ref>{{cite journal | vauthors = Chancellor MB, Staskin DR, Kay GG, Sandage BW, Oefelein MG, Tsao JW | title = Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder | journal = Drugs & Aging | volume = 29 | issue = 4 | pages = 259–273 | date = April 2012 | pmid = 22390261 | doi = 10.2165/11597530-000000000-00000 }}</ref> As a result, it is able to counteract the peripheral side effects of xanomeline caused by M4 and M1 receptor activation without affecting the central nervous system.<ref>{{cite journal | vauthors = Kidambi N, Elsayed OH, El-Mallakh RS | title = Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia | journal = Neuropsychiatric Disease and Treatment | volume = 19 | pages = 1145–1151 | date = 2023 | pmid = 37193547 | pmc = 10183173 | doi = 10.2147/NDT.S406371 | quote = Trospium has a highly polarized tertiary amine structure that prevents it from entering into the central nervous system. Coadministration of trospium and xanomeline is believed to block the unwanted peripheral cholinergic side effects of xanomeline. Indeed, the combination appears to be associated with a 50% reduction of cholinergic side effects in healthy volunteers. | doi-access = free }}</ref>

==History== Xanomeline was first synthesized in 1997 in a collaboration between pharmaceutical firms Eli Lilly and Novo Nordisk with the goal of delaying cognitive decline in people with Alzheimer's disease. In a phase II study, significant improvements in cognition were observed in people with Alzheimer's along with surprising improvements in behavioral symptoms such as hallucinations, delusions, suspiciousness and agitation.<ref>{{cite journal | vauthors = Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM | title = Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease | journal = Archives of Neurology | volume = 54 | issue = 4 | pages = 465–473 | date = April 1997 | pmid = 9109749 | doi = 10.1001/archneur.1997.00550160091022 }}</ref> In a follow-up placebo-controlled study in participants with schizophrenia, similar effects on symptoms of psychosis was observed with xanomeline.<ref>{{cite journal | vauthors = Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC | title = Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia | journal = The American Journal of Psychiatry | volume = 165 | issue = 8 | pages = 1033–1039 | date = August 2008 | pmid = 18593778 | doi = 10.1176/appi.ajp.2008.06091591 | s2cid = 24308125 }}</ref> However, cholinergic-mediated side effects prevented advancement of xanomeline into phase III trials.

Xanomeline was licensed to Karuna Therapeutics in 2012 and KarXT was subsequently created as a dual drug formulation by adding trospium. Trospium is a non-brain-penetrant and non-selective muscarinic receptor blocker that may ameliorate the peripheral side effects of xanomeline. In 2019, the EMERGENT-1 placebo controlled phase II clinical trial of KarXT in adults with schizophrenia met the primary endpoint of a change from baseline in the positive and negative syndrome scale (PANSS) total score at week 5 vs. placebo.<ref>{{Cite web |title=Positive Top-line Results for Novel Agent in Acute Psychosis |url=https://www.medscape.com/viewarticle/921496 |access-date=2025-09-22 |website=Medscape |language=en}}</ref> The results from the trial were subsequently published in the New England Journal of Medicine.<ref>{{cite journal | vauthors = Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A | title = Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia | journal = The New England Journal of Medicine | volume = 384 | issue = 8 | pages = 717–726 | date = February 2021 | pmid = 33626254 | pmc = 7610870 | doi = 10.1056/NEJMoa2017015 }}</ref> In August 2022, Karuna Therapeutics announced that KarXT has achieved the primary endpoint in the phase III EMERGENT-2 trial and in March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in the phase III EMERGENT-3, and that it was submitting the drug for approval by the US Food and Drug Administration (FDA).<ref>{{cite press release |url=https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-results-phase-3-0 |title=Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia |date=20 March 2023 |website=Karuna Therapeutics |access-date=25 September 2023 |archive-date=30 July 2023 |archive-url=https://web.archive.org/web/20230730112319/https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-results-phase-3-0 |url-status=live }}</ref> The results from the EMERGENT-2 and EMERGENT-3 clinical trials were published in the LANCET and JAMA-Psychiatry respectively.<ref>{{cite journal | vauthors = Kaul I, Sawchak S, Correll CU, Kakar R, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK | title = Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial | journal = Lancet | volume = 403 | issue = 10422 | pages = 160–170 | date = January 2024 | pmid = 38104575 | doi = 10.1016/S0140-6736(23)02190-6 }}</ref><ref>{{cite journal | vauthors = Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK | title = Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial | journal = JAMA Psychiatry | volume = 81 | issue = 8 | pages = 749–756 | date = August 2024 | pmid = 38691387 | pmc = 11063924 | doi = 10.1001/jamapsychiatry.2024.0785 }}</ref> In September 2023, Karuna announced that it has submitted the new drug application (NDA) for KarXT and in November 2023, the FDA began its review and set the PDUFA date for September 2024.<ref>{{Cite web |date=29 November 2023 |title=FDA kicks off review of Karuna's schizophrenia drug KarXT |url=https://pharmaphorum.com/news/fda-kicks-review-karunas-schizophrenia-drug-karxt |access-date=13 December 2023 |website=pharmaphorum |archive-date=13 December 2023 |archive-url=https://web.archive.org/web/20231213051418/https://pharmaphorum.com/news/fda-kicks-review-karunas-schizophrenia-drug-karxt |url-status=live }}</ref>

The FDA evaluated the effectiveness of xanomeline/trospium chloride for the treatment of schizophrenia in adults based on two studies with identical designs.<ref name="FDA PR 20240926" /> Study 1 (NCT04659161, EMERGENT-2) and study 2 (NCT04738123, EMERGENT-2) were 5-week, randomized, double-blind, placebo-controlled, multi-center studies in adults with a diagnosis of schizophrenia according to DSM-5 criteria.<ref name="Cobenfy FDA label" /><ref name="FDA PR 20240926" /> The primary efficacy measure was the change from baseline in the positive and negative syndrome scale (PANSS) total score at week 5.<ref name="FDA PR 20240926" /> The PANSS is a 30-item scale that measures symptoms of schizophrenia.<ref name="FDA PR 20240926" /> Each item is rated by a clinician on a seven-point scale.<ref name="FDA PR 20240926" /> In both studies, the participants who received xanomeline/trospium chloride experienced a meaningful reduction in symptoms from baseline to week 5 as measured by the PANSS total score compared to the placebo group.<ref name="FDA PR 20240926" /> The FDA granted the approval of xanomeline/tropsium to Bristol-Myers Squibb, which acquired Karuna Therapeutics during the FDA review in March 2024. <ref name="FDA PR 20240926" /> Xanomeline/trospium, also known as KarXT, is marketed under the name Cobenfy.<ref>{{Cite web |title=COBENFY™ (xanomeline and trospium chloride) for Schizophrenia |url=https://www.cobenfy.com/ |access-date=2025-09-22 |website=www.cobenfy.com |language=en}}</ref> Cobenfy is a trademark of Karuna Therapeutics.

The EMERGENT-2 and EMERGENT-3 trials enrolled 470 adults with schizophrenia.<ref name="Cobenfy FDA snapshot" /> The trials were conducted at 39 sites in the United States and Ukraine.<ref name="Cobenfy FDA snapshot" /> There were 425 trial participants from the United States.<ref name="Cobenfy FDA snapshot" /> The efficacy of the combination (which is a measure of how well the drug works) was evaluated in two clinical trials for 470 participants with schizophrenia, and safety was assessed in the two trials in a total of 504 participants with schizophrenia who received at least one dose of xanomeline/trospium chloride.<ref name="Cobenfy FDA snapshot" /> The same trials were used to assess efficacy and safety.<ref name="Cobenfy FDA snapshot" /> The number of participants representing efficacy findings differs from the number of participants representing safety findings due to different pools of study participants analyzed for efficacy and safety.<ref name="Cobenfy FDA snapshot" /> In the trials, participants were randomly assigned to receive xanomeline/trospium chloride or placebo, and neither participants nor care providers knew which treatment was given during the trial.<ref name="Cobenfy FDA snapshot" /> Symptoms of schizophrenia were measured using a clinician-administered measure of schizophrenia symptoms called the Positive and Negative Syndrome Scale (PANSS).<ref name="Cobenfy FDA snapshot" /> The benefit of COBENFY was assessed in both trials by determining the improvement in schizophrenia symptoms (the difference in PANSS scores before and after five weeks of treatment).<ref name="Cobenfy FDA snapshot" />

== Society and culture == === Legal status === Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.<ref name="FDA PR 20240926" /><ref name="Cobenfy FDA snapshot" /><ref>{{cite press release | title=U.S. Food and Drug Administration Approves Bristol Myers Squibb's Cobenfy (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults | publisher=Bristol Myers Squibb | via=Business Wire | date=27 September 2024 | url=https://www.businesswire.com/news/home/20240925382351/en/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibb%E2%80%99s-COBENFY%E2%84%A2-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults | access-date=27 September 2024}}</ref>

=== Economics === In 2024, Bristol Myers Squibb purchased Karuna Therapeutics for {{US$|14 billion}}.<ref name="WaPo">{{cite news | vauthors = Gilbert D |title=FDA approves new type of antipsychotic drug, a potential 'game changer' |url=https://www.washingtonpost.com/business/2024/09/26/fda-antipsychotic-mental-illness-alzheimers/ |access-date=26 September 2024 |newspaper=The Washington Post |date=26 September 2024 |archive-date=26 September 2024 |archive-url=https://web.archive.org/web/20240926232646/https://www.washingtonpost.com/business/2024/09/26/fda-antipsychotic-mental-illness-alzheimers/ |url-status=live }}</ref> Bristol Myers Squibb set the wholesale cost of the combo at $1,850 a month.<ref name="WaPo" /><ref>{{cite news | vauthors = Barry E, Jewett C | title=F.D.A. Approves a New Antipsychotic Drug | website=The New York Times | date=26 September 2024 | url=https://www.nytimes.com/2024/09/26/health/fda-schizophrenia-drug.html | access-date=27 September 2024 | archive-date=26 September 2024 | archive-url=https://web.archive.org/web/20240926230814/https://www.nytimes.com/2024/09/26/health/fda-schizophrenia-drug.html/ | url-status=live }}</ref>

== Research == === Long-acting injectable prodrugs === A long-acting injectable (LAI) formulation of xanomeline/trospium chloride prodrugs is under development for the treatment of schizophrenia.<ref name="AdisInsight-LAI">{{cite web | title=Trospium/xanomeline Prodrug | website=AdisInsight | date=11 July 2024 | url=https://adisinsight.springer.com/drugs/800078447 | access-date=29 October 2024}}</ref><ref name="KuntzClark2024" /> It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI.<ref name="AdisInsight-LAI" /><ref name="KuntzClark2024" /> The prodrugs are slowly metabolized to xanomeline and trospium chloride, and are expected to have a duration of several months.<ref name="KuntzClark2024">{{cite web | vauthors = Kuntz L, Clark S | title=TerXT: Combination of Xanomeline and Trospium Prodrugs for Schizophrenia | website=Psychiatric Times | date=24 May 2024 | url=https://www.psychiatrictimes.com/view/terxt-combination-of-xanomeline-and-trospium-prodrugs-for-schizophrenia | access-date=29 October 2024}}</ref> As of May 2024, TerXT is in the preclinical stage of development.<ref name="AdisInsight-LAI" />

== References == {{reflist}}

== External links == * {{ClinicalTrialsGov|NCT04659161|A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-2)}} * {{ClinicalTrialsGov|NCT04738123|A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)}}

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