Introduction

Xanomeline-trospium, marketed under the brand name Cobenfy, is a novel oral medication for the treatment of schizophrenia in adults that received US Food and Drug Administration (FDA) approval in September 2024. Xanomeline-trospium is the first medication approved to treat schizophrenia that targets cholinergic receptors, breaking from the long-established standard of focusing on dopamine receptors in the treatment of schizophrenia.1 Cobenfy combines xanomeline, a muscarinic M1/M4 agonist, with trospium chloride, a peripherally restricted muscarinic antagonist.2,3 Xanomeline possesses antipsychotic properties without dopamine receptor-blocking activity, but it induces cholinergic adverse events. Trospium mitigates the peripheral cholinergic effects of xanomeline.3

EMERGENT-2 Phase 2 Trial

In the EMERGENT-2 phase 2 trial involving 182 patients experiencing an acute exacerbation of schizophrenia, patients who received a flexible dose of xanomeline-trospium (n = 90) twice daily over 5 weeks demonstrated a significant decrease in Positive and Negative Syndrome Scale (PANSS) total score at week 5, with an average reduction of 17.4 points, compared to a 5.9-point decrease in the placebo group (n = 92).3 Xanomeline-trospium was shown to result in cholinergic and anticholinergic adverse events but did not lead to an increased incidence of extrapyramidal symptoms or weight gain compared to placebo.

EMERGENT-3 Phase 3 Trial

The EMERGENT-3 phase 3 trial was a multicenter, randomized, double-blind, placebo-controlled study conducted between April 1, 2021, and December 7, 2022, across 30 inpatient sites in the United States and Ukraine.4 The trial design mirrored that of the EMERGENT-2 trial, with the primary endpoint being the change in PANSS total score from baseline to week 5. The results of EMERGENT-3, which included 256 participants aged 18 to 65 years with schizophrenia experiencing acute psychosis randomized to receive either twice-daily oral xanomeline-trospium (n = 125) or placebo (n = 131), confirmed the findings of EMERGENT-2. At week 5, xanomeline-trospium significantly reduced PANSS total score compared to placebo, with an average reduction of 20.6 points for the xanomeline-trospium group versus a 12.2-point reduction for the placebo group (least squares mean difference: −8.4; 95% CI: −12.4 to −4.3; P < 0.001; Cohen effect size: 0.60).4

The most common treatment-emergent adverse events (TEAEs) in the xanomeline-trospium group compared to the placebo group were nausea (19.2% vs 1.6%), dyspepsia (16.0% vs 1.6%), vomiting (16.0% vs 0.8%), and constipation (12.8% vs 3.9%). No clinically meaningful changes were observed in extrapyramidal motor symptom scales, weight gain, or insomnia from baseline to week 5.4

Conclusion

The EMERGENT-3 trial findings and consistent results from the EMERGENT-1 and EMERGENT-2 trials support the potential of xanomeline-trospium as a novel class of antipsychotic medications without dopamine receptor-blocking activity. In the EMERGENT-3 trial, adults with schizophrenia experiencing acute psychosis who received xanomeline-trospium showed statistically significant and clinically meaningful improvement in schizophrenia symptoms and generally tolerated the treatment well.4 Xanomeline-trospium could be a promising option for patients unable to tolerate traditional antipsychotic medications targeting dopamine receptors due to side effects such as extrapyramidal symptoms, weight gain, or sedation.

References:

  1. US Food and Drug Administration. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. Accessed October 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia  
  2. Cobenfy. Prescribing information. Accessed October 9, 2024. https://packageinserts.bms.com/pi/pi_cobenfy.pdf  
  3. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726. doi:10.1056/NEJMoa2017015
  4. 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(8):749-756. doi:10.1001/jamapsychiatry.2024.0785