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Title of the Reference Article:

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

Article DOI:

https://doi.org/10.1016/S0140-6736(23)02190-6

Citation: 1. Kaul I, Sawchak S, Correll CU, et al. Group 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. 2024;403(10422):160-170.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02190-6/abstract

. Accessed August 22, 2024.

Authors of the Article:

• Inder Kaul, MD
• Sharon Sawchak, RN
• Prof Christoph U Correll, MD
• Rishi Kakar, MD
• Prof Alan Breier, MD
• Haiyuan Zhu, PhD
• Andrew C Miller, PhD
• Steven M Paul, MD
• Stephen K Brannan, MD

Summary:

The article summarizes the results of the EMERGENT-2 trial, which investigated the efficacy and safety of KarXT, a novel treatment for schizophrenia. KarXT combines xanomeline, a muscarinic receptor agonist, with trospium chloride, which is designed to reduce xanomeline-related side effects. Unlike traditional antipsychotics that block D2 dopamine receptors, KarXT targets muscarinic receptors.

Background:

• There is a critical need for new treatments for schizophrenia that operate through different mechanisms than current D2 dopamine receptor blockers. Xanomeline, a muscarinic receptor agonist, combined with trospium chloride (KarXT), aims to reduce the side effects associated with peripheral muscarinic receptor activation.

Methods:

• EMERGENT-2 was a 5-week, phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate KarXT in 252 acutely psychotic schizophrenia patients.
• Participants: Adults aged 18-65 with schizophrenia, recent psychosis exacerbation, and specific severity scores on the PANSS and CGI-S scales.
• Intervention: Participants received either KarXT or placebo. KarXT dosing started at 50mg xanomeline/20 mg trospium, increasing to 100 mg xanomeline/20 mg trospium, with an optional increase to 125 mg xanomeline/30 mg trospium based on tolerability.
• Primary Endpoint: Change in PANSS total score from baseline to week 5

Findings:

• Efficacy: KarXT significantly reduced PANSS scores compared to placebo (-21.2 vs. -11.6, p<0.0001), with a Cohen’s d effect size of 0.61. It also met all secondary efficacy endpoints.
• Safety: Common adverse events for KarXT included constipation, dyspepsia, and nausea. There were no significant differences in extrapyramidal symptoms or akathisia between KarXT and placebo.
• Tolerability: Despite some gastrointestinal side effects, KarXT was generally well tolerated.

· Adverse Events: Common side effects with KarXT included constipation, dyspepsia, nausea, and vomiting, but rates of extrapyramidal symptoms, akathisia, weight gain, and somnolence were similar to placebo.

Interpretation:

• KarXT showed efficacy in reducing both positive and negative symptoms of schizophrenia and was generally well-tolerated, suggesting it could represent a new class of antipsychotic medication that does not rely on D2 dopamine receptor blockade.

Funding:

• The trial was funded by Karuna Therapeutics.

Notes:

• Additional trials (EMERGENT-3, EMERGENT-4, and EMERGENT-5) are ongoing to further assess KarXT’s efficacy and safety.

*AI was utilized for this summary.