Psych Congress 2025 | San Diego, CA
Xanomeline–trospium (X/T), a dual M1/M4 muscarinic receptor agonist combined with a peripherally restricted muscarinic antagonist, was recently approved for the treatment of schizophrenia in adults. Earlier clinical studies established its efficacy when administered twice daily on an empty stomach; however, food intake has been shown to reduce trospium bioavailability, potentially influencing tolerability. The current phase 4 open-label study (NCT06572449) evaluated whether gradual titration and an acclimation period could permit dosing with food without compromising safety or effectiveness.
Study Design
This inpatient, multicenter, two-cohort, two-period trial enrolled adults aged 18–65 years with a DSM-5 diagnosis of schizophrenia, and stable symptoms as assessed by a Positive and Negative Syndrome Scale (PANSS) total score ≤80, and Clinical Global Impression–Severity (CGI-S) score ≤4. All participants went through a washout from current antipsychotics before starting X/T.
During Period 1 (weeks 1–4), participants received twice-daily X/T on an empty stomach, beginning with 50 mg/20 mg for 1 week and titrating to 100 mg/20 mg. Cohort 1 escalated further to 125 mg/30 mg as tolerated, while Cohort 2 remained on 100 mg/20 mg. In Period 2 (weeks 5–8), participants continued on their stable dose but took each dose within 30 minutes of a meal or snack. Safety was assessed in all treated participants; efficacy analyses included those who completed the Day 56 efficacy assessment. Pharmacokinetic samples were collected on Days 22 (fasted) and 43 (fed).
The pooled safety population included 173 participants (mean age 44.6 years; 73% male; 74% Black or African American). Mean baseline PANSS and CGI-S scores were 64.1 and 3.2, respectively.
Key Findings
Overall, 64.2% of participants experienced ≥1 treatment-emergent adverse event (TEAE) during Period 1 (fasted) compared with 39.0% during Period 2 (with food). No serious adverse events occurred. Six TEAEs led to discontinuation (three per period), four of which were deemed treatment related. The incidence of both procholinergic and anticholinergic TEAEs decreased during period two when X/T was dosed with a meal or snack.
The most frequent TEAEs in Period 1 were nausea (22.5%), dyspepsia (15.6%), headache (15.0%), constipation (12.7%), vomiting (11.6%), and gastroesophageal reflux (8.7%). In Period 2, only vomiting (7.8%), nausea (5.8%), and dyspepsia (5.2%) occurred in ≥5% of participants. All events were mild or moderate in intensity.
Mean PANSS total scores improved from baseline by −2.7 points at the end of Period 1 and −4.8 points at the end of Period 2, with similar outcomes across dose groups. CGI-S scores decreased modestly from baseline during Period 1 (−0.2) and remained stable thereafter (−0.3 at Day 56). These findings indicate that symptom stability was maintained throughout both fasting and fed dosing periods.
Pharmacokinetic analyses showed that, when X/T was taken with food, trospium dose-normalized area under the curve (AUC) and maximum concentration (Cmax) decreased by 34.5% and 43.4%, respectively, less than the 70%–90% reductions previously observed under high-fat meal conditions. Xanomeline exposure was not meaningfully altered. Importantly, the smaller reduction in trospium exposure occurred alongside lower rates of gastrointestinal events and no loss of clinical benefit.
Clinical Implications
After a 4-week acclimation period under fasting conditions, switching to administration with food did not increase adverse events or diminish efficacy. The smaller-than-expected decrease in trospium exposure suggests that dosing flexibility may be feasible in routine practice, though food intake was not standardized. These findings provide additional reassurance regarding the safety and pharmacologic stability of X/T during continued treatment in adults with schizophrenia. Further, efficacy scores decreased gradually from baseline in this study of stable patients with schizophrenia and was maintained after the 4-week period of acclimation.
