Long-Term Safety and Efficacy of KarXT (Xanomeline and Trospium Chloride) in Schizophrenia: Results from the 52-Week, Open-Label EMERGENT-4 Trial

KarXT, an investigational treatment for schizophrenia, combines the M1/M4 preferring muscarinic receptor agonist xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride. In the 5-week EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials, KarXT improved symptoms and was generally well tolerated in people with schizophrenia experiencing acute psychosis.
EMERGENT-4 (NCT04659174) was a 52-week, open-label extension trial enrolling participants who completed the EMERGENT-2 (NCT04659161) or EMERGENT-3 (NCT04738123) trials. Participants received twice-daily oral doses of KarXT, xanomeline 50 mg/trospium 20 mg, titrated to a maximum dose of 125 mg/30 mg. Safety measures included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Efficacy measures included changes in PANSS scores and the proportion of participants with ≥30% reduction in PANSS total score. Safety analyses included participants receiving ≥1 KarXT dose. Efficacy analyses included participants receiving ≥1 dose of KarXT with ≥1 postbaseline PANSS assessment.
The safety and mITT populations included 152 and 111 participants, respectively. KarXT was generally well tolerated; 53.3% had ≥1 TEAE, and 10.5% had a TEAE leading to discontinuation. The most common TEAEs were nausea (9.2%), dyspepsia (8.6%), vomiting (8.6%), weight increase (5.9%), dry mouth (5.3%), and hypertension (5.3%). KarXT was not associated with significant extrapyramidal symptoms, prolactin elevations, or metabolic changes. Efficacy improvements were seen as early as 2 weeks and continued through week 52, with >69% of completers achieving ≥30% improvement in PANSS total score.
KarXT was generally well tolerated and associated with continued symptom improvement over 52 weeks, supporting its potential as a novel treatment option for schizophrenia.