New antipsychotic drug KarXT

doi:10.12092/j.issn.1009-2501.2026.03.015

Abstract

Abstract:

At present, antipsychotic drugs mainly act on dopamine receptors, but the improvement of negative symptoms and cognitive symptoms is limited. There are extrapyramidal adverse reactions, metabolic syndrome, endocrine disorders and other adverse reactions, which some patients can not tolerate. KarXT (trade name Cobenfy), a novel antipsychotic drug approved by the FDA for the treatment of schizophrenia in adults, acts on M1 and M4 muscarinic acetylcholine receptors (mAChR). The results of current clinical trials have shown that KarXT can improve the positive symptoms, negative symptoms and cognitive impairment of schizophrenia, and the adverse reactions are mainly gastrointestinal symptoms. This article reviews the latest literature on the pharmacological mechanism, pharmacokinetics, clinical evaluation, and safety of KarXT.

Key words: antipsychotic agents, clinical trial, drug evaluation, drug-related side effects and adverse reactions, cognitive dysfunction

CLC Number:

R971

Xin LIU, Xiaolin LIU, Yanan ZHOU, Jinguo ZHAI. New antipsychotic drug KarXT[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(3): 428-432.

References 23

1	Komatsu Y, Takehara M, Hart X, et al. Advancements in non-dopaminergic treatments for schizophrenia: a systematic review of pipeline developments[J]. Pharmacopsychiatry, 2024, 57 (5): 221- 231. doi: 10.1055/a-2307-6484
2	Kinon BJ, Leucht S, Tamminga C, et al. Rationale for adjunctive treatment targeting multiple mechanisms in schizophrenia [J]. J Clin Psychiatry, 2024, 85(3): 23nr15240.
3	Paul SM, Yohn SE, Popiolek M, et al. Muscarinic acetylcholine receptor agonists as novel treatments for schizophrenia[J]. Am J Psychiatry, 2022, 179 (9): 611- 627. doi: 10.1176/appi.ajp.21101083
4	Vasiliu O, Budeanu B, Cătănescu MȘ. The new horizon of atipsychotics beyond the classic dopaminergic hypothesis—the case of the xanomeline–trospium combination: a systematic review[J]. Pharmaceuticals, 2024, 17 (5): 610. doi: 10.3390/ph17050610
5	Palma JA. Muscarinic control of cardiovascular function in humans: a review of current clinical evidence[J]. Clin Auton Res, 2024, 34 (1): 31- 44. doi: 10.1007/s10286-024-01016-5
6	Correll CU, Abi-Dargham A, Howes O. Emerging treatments in schizophrenia [J]. J Clin Psychiatry, 2022, 83(1): SU21024IP21021.
7	Xin R, Chen Z, Fu J, et al. Xanomeline protects cortical cells from oxygen-glucose deprivation via inhibiting oxidative stress and apoptosis[J]. Front Physiol, 2020, 11, 656. doi: 10.3389/fphys.2020.00656
8	Paul SM, Yohn SE, Brannan SK, et al. Muscarinic receptor activators as novel treatments for schizophrenia[J]. Biol Psychiatry, 2024, 96 (8): 627- 637. doi: 10.1016/j.biopsych.2024.03.014
9	Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease[J]. Arch Neurol, 1997, 54 (4): 465- 473. doi: 10.1001/archneur.1997.00550160091022
10	Kaul I, Sawchak S, Correll CU, et al. 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[J]. Lancet, 2024, 403 (10422): 160- 170. doi: 10.1016/S0140-6736(23)02190-6
11	Breier A, Brannan SK, Paul SM, et al. Evidence of trospium's ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results[J]. Psychopharmacology (Berl), 2023, 240 (5): 1191- 1198. doi: 10.1007/s00213-023-06362-2
12	Administration USFaD. COBENFY (xanomeline and trospium chloride) capsules, for oral use Initial U. S. Approval: 2024 [EB/OL]. (2024-09) [2024-12-09]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf.
13	Brannan SK, Sawchak S, Miller AC, et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia[J]. N Engl J Med, 2021, 384 (8): 717- 726. doi: 10.1056/NEJMoa2017015
14	Sauder C, Allen LA, Baker E, et al. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study[J]. Transl Psychiatry, 2022, 12 (1): 491. doi: 10.1038/s41398-022-02254-9
15	Weiden PJ, Breier A, Kavanagh S, et al. Antipsychotic efficacy of KarXT (Xanomeline-Trospium): post hoc analysis of positive and negative syndrome scale categorical response rates, time course of response, and symptom domains of response in a phase 2 study [J]. J Clin Psychiatry, 2022, 83(3): 21m14316.
16	Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial[J]. JAMA Psychiatry, 2024, 81 (8): 749- 756. doi: 10.1001/jamapsychiatry.2024.0785
17	Wright AC, McKenna A, Tice JA, et al. A network meta-analysis of KarXT and commonly used pharmacological interventions for schizophrenia[J]. Schizophr Res, 2024, 274, 212- 219. doi: 10.1016/j.schres.2024.09.023
18	Leber A, Ramachandra R, Ceban F, et al. Efficacy, safety, and tolerability of xanomeline for schizophrenia spectrum disorders: a systematic review[J]. Expert Opin Pharmacother, 2024, 25 (4): 467- 476. doi: 10.1080/14656566.2024.2334424
19	Horan WP, Targum SD, Claxton A, et al. Efficacy of KarXT on negative symptoms in acute schizophrenia: a post hoc analysis of pooled data from 3 trials[J]. Schizophr Res, 2024, 274, 57- 65. doi: 10.1016/j.schres.2024.08.001
20	Nathan PJ, Millais SB, Godwood A, et al. A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild‐to‐moderate Alzheimer's disease[J]. Alzheimers Dement (N Y), 2022, 8 (1): e12273. doi: 10.1002/trc2.12273
21	Sparacino G, Verdolini N, Vieta E, et al. Existing and emerging pharmacological approaches to the treatment of mania: a critical overview[J]. Transl Psychiatry, 2022, 12 (1): 169. doi: 10.1038/s41398-022-01928-8
22	Sutera N. Xanomeline-Trospium in schizophrenia: a detailed review and comparison with the Institute for Clinical and Economic Review's analysis[J]. J Manag Care Spec Pharm, 2024, 30 (6): 629- 632.
23	Correll CU, Angelov AS, Miller AC, et al. Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia[J]. Schizophrenia (Heidelb), 2022, 8 (1): 109. doi: 10.1038/s41537-022-00320-1

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