Long-Term Safety, Tolerability, and Efficacy of Xanomeline and Trospium Chloride in People with Schizophrenia: Results From the 52-Week, Open-Label EMERGENT-5 Trial

Introduction: The dual M1/M4 preferring muscarinic receptor agonist xanomeline in combination with the peripherally restricted pan muscarinic receptor antagonist trospium chloride is an investigational treatment for schizophrenia and other neuropsychiatric disorders. Unlike most currently available antipsychotics, xanomeline/trospium (formerly known as KarXT) has no direct D2 dopamine receptor antagonism activity. In the three pivotal, 5-week, randomized, double-blind, placebo-controlled EMERGENT trials, xanomeline/trospium improved symptoms and was generally well tolerated in people with schizophrenia experiencing acute psychosis.
Objective: Assess the long-term safety, tolerability, and efficacy of xanomeline/trospium in people with schizophrenia with no prior exposure to xanomeline/trospium.
Methods: EMERGENT-5 (NCT04820309) was a 52-week, open-label trial enrolling participants with schizophrenia, a Positive and Negative Syndrome Scale (PANSS) score ≤80, a Clinical Global Impression-Severity (CGI-S) score ≤4, and no prior xanomeline/trospium exposure. Participants received twice-daily oral dosing at xanomeline 50 mg/trospium chloride 20 mg and titrated to a maximum dose of xanomeline 125 mg/trospium chloride 30 mg. Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to discontinuation. Efficacy outcomes included change from baseline to week 52 in PANSS total, PANSS positive subscale, PANSS negative subscale, and CGI-S scale scores.
Results: 566 participants were included in the safety population for safety analyses and 558 participants were included in the modified intent-to-treat population for efficacy analyses. The trial was recently completed, safety and efficacy analyses are underway, and results will be presented at the meeting.
Conclusions: Xanomeline/trospium is a promising investigational treatment for schizophrenia based on muscarinic receptor agonism.