Xanomeline/trospium chloride

Xanomeline/trospium chloride
Combination of
XanomelineMuscarinic agonist
Trospium chlorideMuscarinic antagonist (peripherally selective)
Clinical data
Trade namesCobenfy
Other namesKarXT
AHFS/Drugs.comCobenfy
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
KEGG

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 M4 and M1 receptor agonist.[1] Trospium chloride is a 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 disease.[2]

In September 2024, it was approved for medical use in the United States.[1][2] 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][3]

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]

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.[4] 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.[5] 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.[6][7]

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.[8]

History

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.[9] In a follow-up placebo-controlled study in participants with treatment resistant schizophrenia, similar antipsychotic activity was observed with xanomeline.[10] 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.[11] 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).[12] In November 2023, the FDA began its review and set the PDUFA date for September 2024.[13]

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]

Society and culture

Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.[1][2][14]

Economics

In 2024, Bristol Myers Squibb purchased Karuna Therapeutics for US$14 billion.[15] Bristol Myers Squibb set the wholesale cost of the combo at $1,850 a month.[15][16]

Research

Long-acting injectable

A long-acting injectable (LAI) formulation of xanomeline/trospium chloride is under development for the treatment of schizophrenia.[17][18] It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI.[17][18] The formulation specifically contains a prodrug of xanomeline and a prodrug of trospium chloride and is expected to have a multi-month duration.[18] As of May 2024, TerXT is in the preclinical stage of development.[17]

References

  1. ^ a b c d e f g h i "Cobenfy- xanomeline and trospium chloride capsule, coated pellets; Cobenfy- xanomeline and trospium chloride kit". DailyMed. 30 September 2024. Retrieved 11 November 2024.
  2. ^ a b c d e f g h i j k l m "FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia". U.S. Food and Drug Administration (FDA) (Press release). 26 September 2024. Archived from the original on 27 September 2024. Retrieved 27 September 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). Retrieved 28 October 2024.
  4. ^ Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, et al. (May 2000). "Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice". Schizophrenia Research. 42 (3): 249–259. doi:10.1016/s0920-9964(99)00138-3. PMID 10785583. S2CID 54259702.
  5. ^ Volpicelli LA, Levey AI (2004). "Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus". Acetylcholine in the Cerebral Cortex. Progress in Brain Research. Vol. 145. Elsevier. pp. 59–66. doi:10.1016/s0079-6123(03)45003-6. ISBN 9780444511256. PMID 14650906.
  6. ^ Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). "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". European Journal of Pharmacology. 603 (1–3): 147–149. doi:10.1016/j.ejphar.2008.12.020. PMID 19111716.
  7. ^ Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". The American Journal of Psychiatry. 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. PMID 35758639. S2CID 250070840.
  8. ^ Kidambi N, Elsayed OH, El-Mallakh RS (2023). "Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia". Neuropsychiatric Disease and Treatment. 19: 1145–1151. doi:10.2147/NDT.S406371. PMC 10183173. PMID 37193547. 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.
  9. ^ Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. (April 1997). "Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease". Archives of Neurology. 54 (4): 465–473. doi:10.1001/archneur.1997.00550160091022. PMID 9109749.
  10. ^ Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, et al. (August 2008). "Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia". The American Journal of Psychiatry. 165 (8): 1033–1039. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778. S2CID 24308125.
  11. ^ Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A (February 2021). "Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia". The New England Journal of Medicine. 384 (8): 717–726. doi:10.1056/NEJMoa2017015. PMC 7610870. PMID 33626254.
  12. ^ "Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia". Karuna Therapeutics (Press release). 20 March 2023. Archived from the original on 30 July 2023. Retrieved 25 September 2023.
  13. ^ "FDA kicks off review of Karuna's schizophrenia drug KarXT". pharmaphorum. 29 November 2023. Archived from the original on 13 December 2023. Retrieved 13 December 2023.
  14. ^ "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" (Press release). Bristol Myers Squibb. 27 September 2024. Retrieved 27 September 2024 – via Business Wire.
  15. ^ a b Gilbert D (26 September 2024). "FDA approves new type of antipsychotic drug, a potential 'game changer'". The Washington Post. Archived from the original on 26 September 2024. Retrieved 26 September 2024.
  16. ^ Barry E, Jewett C (26 September 2024). "F.D.A. Approves a New Antipsychotic Drug". The New York Times. Archived from the original on 26 September 2024. Retrieved 27 September 2024.
  17. ^ a b c "Trospium/xanomeline Prodrug". AdisInsight. 11 July 2024. Retrieved 29 October 2024.
  18. ^ a b c Kuntz L, Clark S (24 May 2024). "TerXT: Combination of Xanomeline and Trospium Prodrugs for Schizophrenia". Psychiatric Times. Retrieved 29 October 2024.
  • Clinical trial number NCT04659161 for "A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-2)" at ClinicalTrials.gov
  • Clinical trial number NCT04738123 for "A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)" at ClinicalTrials.gov