Long-Term Efficacy and Safety of Xanomeline and Trospium in Schizophrenia: EMERGENT-5 Trial Findings

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CONFERENCE REPORTER

A 52-week, open-label phase 3 trial (EMERGENT-5) has confirmed the long-term efficacy, safety, and tolerability of xanomeline and trospium in adults with schizophrenia. The results, derived from a large, multicenter outpatient study, show that the treatment leads to sustained symptom improvement while maintaining a favorable safety profile with minimal adverse effects. The new information was presented via poster session at the 30th Annual Nevada Psychiatric Association National Psychopharmacology Update.

Sustained Symptom Improvement Over 52 Weeks

The EMERGENT-5 trial followed 277 participants, all of whom had stable schizophrenia symptoms with no prior exposure to xanomeline and trospium. The study found significant and durable improvements in key clinical measures, including the Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression–Severity scale, and PANSS subscale scores. By week 52, 30% of participants achieved at least a 30% reduction in PANSS total scores, supporting xanomeline and trospium’s effectiveness in managing schizophrenia symptoms.

A Novel Mechanism of Action

Xanomeline functions as an M1/M4-preferring muscarinic receptor agonist, while trospium chloride reduces peripheral side effects. This offers a new approach for treating schizophrenia, reducing the risk of common adverse effects associated with conventional treatments.

Favorable Safety and Tolerability Profile

Long-term treatment with xanomeline and trospium was generally well tolerated. The most common treatment-emergent adverse events were mild to moderate gastrointestinal issues, including nausea (21.4%), vomiting (17.8%), and constipation (16.8%). Serious adverse events were rare, with only 1.6% of participants experiencing severe events. The treatment was not associated with significant weight gain or metabolic disturbances, with participants experiencing an average weight reduction of 2.2 kg over 52 weeks. Additionally, there were no significant changes in prolactin levels or movement-related adverse effects, such as tardive dyskinesia.

Study Design and Participant Demographics

The study enrolled a diverse population, with 66.3% male and 33.7% female participants. Racial and ethnic diversity was also represented, with 68.7% identifying as Black or African American, 29% as White, and 21% as Hispanic or Latino. All participants initiated treatment with a twice-daily regimen, titrating from 50 mg xanomeline and 20 mg trospium chloride to a maximum dose of 125 mg xanomeline and30 mg trospium chloride over the course of the trial.

Future Implications for Schizophrenia Treatment

With the US Food and Drug Administration approval of xanomeline and trospium for schizophrenia, the EMERGENT-5 trial provides long-term data supporting its efficacy and safety. The findings reinforce the treatment’s potential as an alternative to conventional antipsychotics.

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Reference

1. Kaul I, Claxton A, Sauder C, et al. Long-term safety, tolerability, and efficacy of xanomeline and trospium chloride in people with schizophrenia: results from the 52-week, open-label EMERGENT-5 trial. Presented at: Nevada Psychiatric Association 30th Annual Psychopharmacology Update; February 13, 2025.