 | |
| Combination of | |
|---|---|
| Xanomeline | Muscarinic agonist |
| Trospium chloride | Muscarinic antagonist (peripherally selective) |
| Clinical data | |
| Trade names | Cobenfy |
| Other names | KarXT |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a624070 |
| License data | |
| Routes of administration | By mouth |
| ATC code |
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| Legal status | |
| Legal status | |
| Identifiers | |
| KEGG | |
Xanomeline/trospium chloride, sold under the brand nameCobenfy, is afixed-dose combination medication used for the treatment ofschizophrenia.[1] It containsxanomeline, amuscarinic agonist, andtrospium chloride, amuscarinic antagonist.[1] Xanomeline is a functionally-preferringmuscarinic acetylcholine receptor M4 andM1 receptor agonist.[1] Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.[1]
The most common side effects of xanomeline/trospium chloride includenausea,indigestion,constipation,vomiting,hypertension,abdominal pain,diarrhea,tachycardia (increased heartbeat),dizziness, andgastroesophageal reflux.[2][3]
In September 2024, it was approved for medical use in the United States.[2][3] It is the firstantipsychotic drug approved by the USFood and Drug Administration (FDA) to treat schizophrenia that targetscholinergic receptors as opposed todopamine receptors, which has long been the standard of care.[2][4] The FDA considers it to be afirst-in-class medication.[5]Trospium chloride is aperipherally selectivenon-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline'smechanism of action in this context is hypothesized to be via modulating certainneurotransmitter circuits, includingacetylcholine,dopamine, andglutamate, which can provide therapeutic benefits in schizophrenia and related conditions.[6]
Xanomeline/trospium chloride isindicated for the treatment of schizophrenia in adults.[1][2]
The USFood 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.[2]
The most common side effects of xanomeline/trospium chloride includenausea,indigestion,constipation,vomiting,hypertension,abdominal pain,diarrhea,tachycardia (increased heartbeat),dizziness, andgastroesophageal reflux disease.[2][3]
Preclinical data supports the hypothesis that xanomeline's central mechanism of action is mediated primarily through stimulation of brainmuscarinic M4 andM1 receptors.[7] 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 thecerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality.[8] Unlike directdopamine D2 andserotonin5-HT2A blocking antipsychotic medications, M4 and M1 receptor stimulation indirectly rebalancesdopaminergic andglutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such asschizophrenia andAlzheimer's disease. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate bothpsychosis and cognitive symptom domains while M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.[9][10]
Trospium chloride is anon-selectivemuscarinic antagonist, but does not cross theblood–brain barrier.[11] As a result, it is able to counteract theperipheral side effects ofxanomeline caused by M4 and M1 receptor activation without affecting thecentral nervous system.[12]
Xanomeline was first synthesized in a collaboration between pharmaceutical firmsEli Lilly andNovo 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.[13] In a follow-up placebo-controlled study in participants with schizophrenia, similar effects on symptoms of psychosis was observed with xanomeline.[14] 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 thepositive and negative syndrome scale (PANSS) total score at week 5 vs. placebo.[15] The results from the trial were subsequently published in the New England Journal of Medicine.[16] 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 USFood and Drug Administration (FDA).[17] The results from the EMERGENT-2 and EMERGENT-3 clinical trials were published in the LANCET and JAMA-Psychiatry respectively.[18][19] 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 thePDUFA date for September 2024.[20]
The FDA evaluated the effectiveness of xanomeline/trospium chloride for the treatment of schizophrenia in adults based on two studies with identical designs.[2] 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.[1][2] The primary efficacy measure was the change from baseline in thepositive and negative syndrome scale (PANSS) total score at week 5.[2] The PANSS is a 30-item scale that measures symptoms of schizophrenia.[2] Each item is rated by a clinician on a seven-point scale.[2] 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.[2] The FDA granted the approval of xanomeline/tropsium toBristol-Myers Squibb, which acquired Karuna Therapeutics during the FDA review in March 2024.[2] Xanomeline/trospium, also known as KarXT, is marketed under the name Cobenfy.[21] Cobenfy is a trademark of Karuna Therapeutics.
The EMERGENT-2 and EMERGENT-3 trials enrolled 470 adults with schizophrenia.[3] The trials were conducted at 39 sites in the United States and Ukraine.[3] There were 425 trial participants from the United States.[3] 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.[3] The same trials were used to assess efficacy and safety.[3] 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.[3] 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.[3] Symptoms of schizophrenia were measured using a clinician-administered measure of schizophrenia symptoms called the Positive and Negative Syndrome Scale (PANSS).[3] 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).[3]
Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.[2][3][22]
In 2024,Bristol Myers Squibb purchased Karuna Therapeutics forUS$14 billion.[23] Bristol Myers Squibb set the wholesale cost of the combo at $1,850 a month.[23][24]
Along-acting injectable (LAI)formulation of xanomeline/trospium chloride is under development for the treatment ofschizophrenia.[25][26] It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI.[25][26] The formulation specifically contains aprodrug of xanomeline and a prodrug of trospium chloride and is expected to have a multi-monthduration.[26] As of May 2024, TerXT is in thepreclinical stage of development.[25]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.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.
