Trial Data Show Long-Term Safety, Efficacy of Xanomeline/Trospium for Schizophrenia

New data from the 5-week EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials demonstrate that xanomeline and trospium (Cobenfy; Bristol Myers Squibb) improved symptoms of schizophrenia in patients experiencing acute psychosis and was generally well tolerated. The findings were presented at the American Association of Psychiatric Pharmacists 2025 meeting.¹

Cobenfy Clinical Trials

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Xanomeline and trospium was approved by the FDA for the treatment of schizophrenia in adults in September 2024, marking the first approved schizophrenia treatment that targets cholinergic receptors as opposed to dopamine receptors. Its effectiveness was evaluated in 2 studies with identical designs (Study 1 and Study 2), with a primary efficacy measure of change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 5.²

Participants in the trials were 75% male; 67.9% Black or African American and 30.9% White. According to the findings, participants with schizophrenia achieved more improvement in their symptoms after 5 weeks of treatment than patients given placebo.³

Investigators found that the treatment worked similarly in both men and women, and in White and Black patients. However, they noted that the number of participants of other races was limited, so differences in how well Cobenfy worked in other races could not be determined. Additionally, differences in how the treatment worked in adults older than 65 could not be determined because all patients were younger than 65 years of age.³

The most common adverse effects (AEs) were nausea, dyspepsia, constipation, vomiting, high blood pressure, abdominal pain, diarrhea, increased heart rate, dizziness, and gastrointestinal reflux disease.³

The EMERGENT-4 Trial

The EMERGENT-4 trial was a 52-week, open-label extension trial enrolling patients who completed EMERGENT-2 or -3. Participants were given twice-daily oral doses of xanomeline 50 mg/trospium 20 mg, titrated to a maximum dose of 125 mg/30 mg. Efficacy measures included changes in PANSS scores and the proportion of patients with a 30% or greater reduction in PANSS total score, and safety measures included treatment-emergent AEs (TEAEs) and TEAEs leading to discontinuation.¹

The safety and modified intention to treat (mITT) populations included 152 and 111 participants, respectively. Treatment with xanomeline and trospium was generally well tolerated, with 53.3% of patients experiencing 1 or more TEAEs, and 10.5% having a TEAE leading to discontinuation. The most common TEAEs were nausea (9.2%), dyspepsia (8.6%), vomiting (8.6%), weight increase (5.9%), dry mouth (5.3%), and hypertension (5.3%). Xanomeline and trospium was not associated with significant extrapyramidal symptoms, prolactin elevations, or metabolic changes.¹

Additionally, efficacy improvements were seen as early as 2 weeks and continued through week 52. More than 69% of patients who completed the trial achieved a 30% or greater improvement in PANSS total score.¹

Pharmacists’ Role

Psychiatric pharmacists play a crucial role in optimizing medication management for individuals with schizophrenia. Staying abreast of the latest clinical trial data, such as the outcomes demonstrated in the EMERGENT-1, -2, and -3 trials for xanomeline and trospium, is essential for evidence-based practice. This new treatment option, with its unique mechanism of action targeting cholinergic receptors, offers a potential alternative for patients who have not responded adequately to existing antipsychotics or who experience intolerable AEs. Understanding the efficacy data, including the significant improvement in PANSS total score observed within 5 weeks, allows pharmacists to contribute meaningfully to treatment decisions, ensuring patients have access to the most effective and well-tolerated therapies available.

Furthermore, a thorough understanding of the trial data empowers psychiatric pharmacists to provide comprehensive patient education and monitoring. Being knowledgeable about the common adverse effects, such as nausea, dyspepsia, and constipation, allows pharmacists to proactively counsel patients on potential adverse effects and strategies for their management. Moreover, the trial’s findings regarding the safety and tolerability of xanomeline and trospium, including the low rates of extrapyramidal symptoms, prolactin elevations, or metabolic changes, are vital for assessing the overall risk-benefit profile of this medication. By integrating this information into their practice, psychiatric pharmacists can enhance patient adherence, improve treatment outcomes, and ultimately contribute to a higher quality of life for individuals living with schizophrenia.

REFERENCES

1. Kaul I, Claxton A, Sauder C, et al. Long-term safety and efficacy of xanomeline and trospium chloride in schizophrenia: results from the 52-week, open-label EMERGENT-4 trial. Presented at: American Association of Psychiatric Pharmacists. April 28, 2025. Accessed May 2, 2025. https://aapp.org/ed/meeting/2025/poster/620960-long-term-safety-and-efficacy-xanomeline-and-trospium-chloride

2. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. News release. FDA. September 26, 2024. Accessed May 2, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

3. Drug Trials Snapshot: COBENFY. FDA. Updated January 15, 2025. Accessed May 2, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-cobenfy