Xanomeline-Trospium Improves PANSS Scores for Patients With Schizophrenia

Xanomeline-trospium was found to significantly improve symptom severity of patients with schizophrenia, according to results from a phase 3 clinical trial presented at Psych Congress 2022 held from September 17 to 20, 2022.

This first-in-class therapy combines xanomeline, a dual M₁/M₄ muscarinic receptor agonist, with trospium, a restricted muscarinic receptor antagonist. The EMERGENT-2 study (ClinicalTrials.gov Identifier: NCT04659161) is a phase 3, randomized, double-blind, placebo-controlled, 5-week trial studying the efficacy of xanomeline-trospium in patients with schizophrenia. Patients (N=252) with schizophrenia experiencing symptoms of psychosis were randomly assigned 1:1 to receive either xanomeline-trospium 50 mg/20 mg twice daily, titrating to a maximum of 125 mg/30 mg, or placebo (n=126). The primary endpoint was change in Positive and Negative Syndrome Scale (PANSS) score from baseline, and key secondary endpoints included change from baseline to week 5 in PANSS positive score, PANSS negative score, PANSS negative Marder factor score, and Clinical Global Impression-Severity (CGI-S) scores.

The investigational and control cohorts were primarily men (75.4% vs 75.4%, respectively) and Black (77.0% vs 73.0%, respectively). At baseline, participants were a mean age of 45.6 and 46.2 years with PANSS total scores of 98.3 and 97.9, respectively.

At week 5, a clinically meaningful reduction in PANSS total score was observed among participants who received xanomeline-trospium compared with placebo (mean difference [MD], -21.2 vs -11.6 points; P <.0001). A significant group difference in PANSS total scores were observed as early as week 2 of treatment.

Participants who were xanomeline-trospium also experienced a 2.9-point greater reduction in PANSS positive subscale score (-6.8 vs -3.9, respectively; P <.0001), 1.8-point greater reduction in PANSS negative subscale score (-3.4 vs -1.6, respectively; P =.0055), and 2.2-point greater reduction in PANSS negative Marder factor subscale score (-4.2 vs -3.0, respectively; P =.0022) compared with participants who received placebo.

Treatment-emergent adverse events (TEAEs) occurred among 75% of xanomeline-trospium recipients and 58% of placebo recipients; discontinuation due to TEAEs occurred among 7% and 6% of recipients, respectively. The most frequently-reported TEAEs included constipation, dyspepsia, nausea, vomiting, headache, increased blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea. Xanomeline-trospium was not associated with common problematic side effects seen in other therapies for patients with schizophrenia (somnolence, weight gain, extrapyramidal symptoms).

The major limitation of this study was a short treatment duration. Additional trials are needed to address the long-term treatment outcomes.

Study authors concluded, “[Xanomeline-trospium] has the potential to be the first in a new class of treatments for patients with schizophrenia.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.