Safety and tolerability of KarXT (xanomeline–trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia

Abstract

AbstractKarXT combines xanomeline, an M1/M4 preferring muscarinic agonist with no direct D2 receptor antagonism, with the peripherally restricted anticholinergic trospium. In EMERGENT-1 (NCT03697252), a 5-week, randomized, double-blind, placebo-controlled, phase 2 study in inpatients with schizophrenia, KarXT met the primary efficacy endpoint, numerous secondary endpoints, and was generally well tolerated. Here, we conducted additional post hoc analyses of safety and tolerability data of KarXT from EMERGENT-1 with a particular focus on adverse events (AEs) that may be associated with muscarinic receptor agonism (nausea or vomiting) or antagonism (dry mouth or constipation). A total of 179 patients received at least one dose of either KarXT (n = 89) or placebo (n = 90) and were included in the analyses. KarXT was associated with a low overall AE burden. The majority of procholinergic and anticholinergic AEs with KarXT were mild, occurred in the first 1−2 weeks of treatment, and were transient with a median duration ranging from 1 day for vomiting to 13 days for dry mouth. No patients in either treatment group discontinued the study due to any procholinergic or anticholinergic AEs. Incidence of somnolence/sedation AEs with KarXT were low and similar to those in the placebo group. KarXT was associated with no significant or clinically relevant changes in body weight, metabolic parameters, or vital signs. KarXT was generally well tolerated with an AE profile consistent with the activity of xanomeline–trospium at muscarinic receptors.