OCCURRENCE OF URINARY RETENTION-RELATED ADVERSE EVENTS WITH XANOMELINE AND TROSPIUM CHLORIDE: RESULTS FROM THE 52-WEEK, OPEN-LABEL EMERGENT-5 TRIAL

Introduction

Xanomeline and trospium chloride (KarXT), the first non-dopaminergic therapy for schizophrenia approved in the United States, combines the dual M1/M4-preferring muscarinic receptor agonist xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. The efficacy and safety of KarXT was shown in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials and the 52-week, open-label EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309) trials. Consistent with guidance on the use of trospium (approved alone for overactive bladder), KarXT is contraindicated in individuals with urinary retention. This report reviews the occurrence of urinary retention-related adverse events (AEs) with KarXT in a long-term trial in adults with schizophrenia (EMERGENT-5).

Methods

EMERGENT-5 enrolled adults aged 18-65 years with schizophrenia, no prior KarXT exposure, and stable symptoms appropriate for outpatient care. Eligible participants had received oral antipsychotic therapy within 30 days of screening and discontinued these medications prior to baseline visits. KarXT treatment started at 50 mg/20 mg (xanomeline/trospium) twice daily (BID) and increased to a maximum of 125 mg/30 mg BID based on tolerability. Analyses were conducted in the overall safety population, defined as all participants who received ≥1 dose of KarXT; post hoc analysis examined subgroups based on sex and age ( < 55 vs ≥55 years).

Results

The safety population (N=566) included 375 males and 191 females, with 369 participants < 55 years of age and 197 participants ≥55 years of age. A total of 16 (2.8%) and 14 (2.5%) participants experienced ≥1 treatment-emergent AE (TEAE) or treatment-related AE (TRAE) of urinary retention, respectively, and 18 (3.2%) and 3 (0.5%) experienced a urinary tract infection (UTI) TEAE or TRAE, respectively. Males and females reported similar incidences of urinary retention TEAEs (2.9% vs 2.6%) and TRAEs (2.4% vs 2.6%). However, in participants aged ≥55 years, both urinary retention TEAEs (4.6%) and TRAEs (3.6%) were more frequent compared with those < 55 years (1.9% and 1.9%, respectively). UTI TEAEs were more common in females than males (5.8% vs 1.9%), whereas the incidences of UTI TRAEs were similar for both groups (0.5% vs 0.5%). UTI TEAEs (3.3% vs 3.0%) and TRAEs (0.3% vs 1.0%) were also similar in both the older and younger age groups. Most urinary retention (14/16) and UTI (17/18) TEAEs were mild or moderate in intensity, with median durations of 30 and 15 days, respectively.

Conclusions

Incidences of urinary retention and UTI TEAEs/TRAEs with KarXT were low and generally mild or moderate in intensity in the 52-week EMERGENT-5 trial of adults with schizophrenia. Although subgroup analyses showed slightly greater incidences of urinary retention TEAEs in participants aged ≥55 versus < 55 years and of UTI TEAEs in females versus males, incidences of these expected TEAEs remained low regardless of age and gender.