By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved the first-in-class muscarinic agonist and antagonists for the treatment of schizophrenia in adults. This is the first antipsychotic drug approved in decades and is unique in that it targets cholinergic receptors — unlike traditional agents, which target dopamine receptors.1 Xanomeline is a dual selective agonist for the M1 and M4 muscarinic acetylcholine receptors, whereas trospium, a quaternary ammonium molecule (i.e., low brain penetration) antagonizes the peripheral muscarinic receptors, mitigating the peripheral cholinergic adverse effects of xanomeline.2 It will be distributed by Bristol Myers Squibb as Cobenfy.
Indications
Xanomeline and trospium (KarXT) are indicated for the treatment of schizophrenia in adults.2
Dosage
The recommended initial dosage is 50 mg/20 mg orally twice a day for at least two days, then increased to 100 mg/20 mg twice daily for at least five days.2 The dosage may be increased to 125 mg/30 mg twice daily based on response and tolerability. KarXT are available as xanomeline/trospium 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg, respectively.
Potential Advantages
KarXT provide another treatment for schizophrenia with a completely different mechanism of action. Current antipsychotics generally have been antagonists or partial agonists to dopamine receptors. Xanomeline does not have any effect on other receptor targets (e.g., histaminergic, serotonergic).
Potential Disadvantages
The generalizability of KarXT may be limited because of the study population in the pivotal Phase III trials. Study participants were mainly Black or African-American (61% to 75%) males (75%).3,4 The most common adverse reactions (vs. placebo) are nausea (19% vs. 4%, respectively), dyspepsia (18% vs. 5%, respectively), constipation (17% vs. 7%, respectively), vomiting (15% vs. 1%, respectively), and hypertension (11% vs. 2%, respectively). It should not be used in patients with moderate or severe hepatic impairment, urinary retention, or gastric retention.2
Comments
The efficacy of KarXT was evaluated in two identically designed placebo-controlled studies in adult participants with a diagnosis of schizophrenia per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria.(2-4) Participants had a mean age of 44 years and were 75% male. As mentioned, 68% were Black or African-American. The mean total baseline Positive and Negative Syndrome Score (PANSS) total score was 97. They were randomized 1:1 to KarXT (117:119 in study 1 and 114:120 in study 2). The primary endpoint was the change from baseline in the PANSS total score at week 5. The least square mean changes from baseline were -21.2 and -20.6 for KarXT vs. -11.6 and -12.2 for placebo, respectively. With a placebo-subtracted difference of -9.6 (95% confidence interval [CI], -13.9 to -5.2) and -8.4 (95% CI, -12.4 to -4.3), respectively, for the two studies. These were considered as medium effect size (Cohen’s d of 0.6 to 0.75). Improvement was evident starting week 2.4 More than 50% of participants showed at least 30% reduction in PANSS total score compared to less than 30% for placebo. Benefits were observed for PANSS positive subscale score, negative subscale score, and Marder negative factor scores.
Clinical Implications
The estimates of schizophrenia and related psychotic disorders’ prevalence in the United States range between 0.25% and 0.64%.5 Numerous first- and second-generation antipsychotic agents target dopamine receptors (D1, D2, D3, D4, D5), serotonergic receptors (5-HT2A, 5-HT2C, 5-HT7), and M1 receptors (thioridazine, chlorpromazine).6 Xanomeline exclusively targets M1 and M4 receptors. There are no comparative studies with other antipsychotics, and the efficacy was limited to a five-week trial in mainly African-American males. Its role in pharmacotherapy remains to be determined.
A systemic review and comparison of the recommendations of 10 International clinical practice guidelines found that five recommend first- or second-generation antipsychotics for the first episode of schizophrenia, and five preferred second-generations agents.7 Three guidelines did not recommend olanzapine because of its metabolic side effects and weight gain. KarXT is expected to be available in late October at a cost of $1,850 per month.
References
- U.S. Food and Drug Administration. FDA approves drug with new mechanism of action for treatment of schizophrenia. Revised Sept. 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia
- Bristol Myers Squibb. Cobenfy prescribing information. Revised September 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf
- 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. Lancet 2024;403:160-170.
- Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: A randomized clinical trial. JAMA Psychiatry 2024;81:749-756.
- National Institute of Mental Health. Schizophrenia. https://www.nimh.nih.gov/health/statistics/schizophrenia
- American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia. Washington;2021.
- Keating D, McWilliams S, Schneider I, et al. Pharmacological guidelines for schizophrenia: A systematic review and comparison of recommendations for the first episode. BMJ Open 2017;7:e013881.
The U.S. Food and Drug Administration has approved the first-in-class muscarinic agonist and antagonists for the treatment of schizophrenia in adults. This is the first antipsychotic drug approved in decades and is unique in that it targets cholinergic receptors — unlike traditional agents, which target dopamine receptors.
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