Safety and Efficacy of KarXT (Xanomeline–Trospium) in Patients With Schizophrenia: Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial (EMERGENT-2)

Abstract: Background: In the 5-week, randomized, double-blind, placebo-controlled, phase 2 EMERGENT-1 study (NCT03697252), the M1/M4 preferring muscarinic receptor agonist KarXT met primary and secondary efficacy endpoints and was safe and generally well tolerated. Methods: EMERGENT-2 (NCT04659161) is a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Key inclusion criteria included recent worsening of positive symptoms warranting hospitalization, a Positive and Negative Syndrome Scale (PANSS) total score ≥80, and a Clinical Global Impression–Severity (CGI-S) score of ≥4 (moderately ill). Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints were change from baseline to week 5 in PANSS positive score, PANSS negative score, PANSS negative Marder factor score, and CGI-S scores vs placebo. Analyses accounted for multiplicity by using a fixed sequence testing procedure. Results: Approximately 246 patients at 22 US study sites were enrolled. Study data are being analyzed and will be available at the time of the meeting. Baseline demographics, the results from primary and key secondary efficacy outcomes, and the safety and tolerability of KarXT will be presented. Conclusions: KarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to direct dopamine D2 receptor antagonists.Short Description: Results from the EMERGENT-2 trial of KarXT (xanomeline–trospium) will be presented. EMERGENT-2 is a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic inpatients with schizophrenia. Results from primary and key secondary outcomes and the safety and tolerability of KarXT will be presented. KarXT has the potential to be the first in a new class of treatment based on muscarinic receptor agonism for patients with schizophrenia.Name of Sponsoring Organization(s): This research was funded by Karuna Therapeutics.