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Xanomeline/trospium chloride
Medication From Wikipedia, the free encyclopedia
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Xanomeline/trospium chloride, sold under the brand name Cobenfy, is a fixed-dose combination medication used for the treatment of schizophrenia.[1] It contains xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist.[1] Xanomeline is a functionally-preferring muscarinic acetylcholine receptor M4 and M1 receptor agonist.[1] Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.[1]
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.[2][3]
In September 2024, it was approved for medical use in the United States.[2][3] 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.[2][4] The FDA considers it to be a first-in-class medication.[5] 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.[6]
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Medical uses
Xanomeline/trospium chloride is indicated for the treatment of schizophrenia in adults.[1][2]
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.[2]
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.[2][3]
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Mechanism of action
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Preclinical data supports the hypothesis that xanomeline's central mechanism of action is mediated primarily through stimulation of brain muscarinic M4 and M1 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 the cerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality.[8] 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.[9][10]
Trospium chloride is a non-selective muscarinic antagonist, but does not cross the blood–brain barrier. 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.[11]
History
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Xanomeline was first synthesized 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 psychotic symptoms.[12] In a follow-up placebo-controlled study in participants with treatment resistant schizophrenia, similar antipsychotic activity was observed with xanomeline.[13] 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 a 2021 placebo controlled phase II clinical trial, KarXT met the primary endpoint.[14] In March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in a phase III trial, EMERGENT-3, and that it was submitting the drug for approval by the US Food and Drug Administration (FDA).[15] In November 2023, the FDA began its review and set the PDUFA date for September 2024.[16]
The effectiveness of xanomeline/trospium chloride for the treatment of schizophrenia in adults was evaluated in two studies with identical designs.[2] Study 1 (NCT04659161) and study 2 (NCT04738123) 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 the positive 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 Cobenfy to Bristol-Myers Squibb.[2]
The FDA approved xanomeline/trospium chloride based on evidence from two clinical trials of 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]
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Society and culture
Legal status
Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.[2][3][17]
Economics
In 2024, Bristol Myers Squibb purchased Karuna Therapeutics for US$14 billion.[18] Bristol Myers Squibb set the wholesale cost of the combo at $1,850 a month.[18][19]
Research
Long-acting injectable
A long-acting injectable (LAI) formulation of xanomeline/trospium chloride is under development for the treatment of schizophrenia.[20][21] It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI.[20][21] The formulation specifically contains a prodrug of xanomeline and a prodrug of trospium chloride and is expected to have a multi-month duration.[21] As of May 2024, TerXT is in the preclinical stage of development.[20]
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References
External links
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