Categorial Response Rates, Time Course of Response, and Symptom Domains of Response With KarXT (Xanomeline-Trospium) in the Phase 3 EMERGENT-2 Study

This work was sponsored by Karuna Therapeutics. KarXT combines xanomeline, a dual M1/M4 muscarinic receptor agonist, with trospium chloride, a peripherally restricted muscarinic receptor antagonist. It aims to maintain xanomeline's CNS benefits while reducing peripheral side effects. In EMERGENT-2, a 5-week phase 3 trial, KarXT met the primary endpoint, improved secondary outcomes, and was well tolerated in schizophrenia with acute psychosis. We conducted post hoc analyses to assess PANSS categorical response rates and response across PANSS Marder 5-factor symptom domains in EMERGENT-2. Analyses were conducted in the modified intent-to-treat (mITT) population evaluating response rates at weeks 2 to 5 based on PANSS total score reductions of ≥20%, ≥30%, ≥40%, and ≥50%. NNT values were calculated for each threshold at week 5. PANSS Marder 5-factor analysis was used to evaluate symptom domain response. The mITT population included 236 people (KarXT, n=117; placebo, n=119). PANSS response rates at week 5 with KarXT ranged from 53.8% for the ≥20% threshold to 17.1% for the ≥50% threshold. NNTs values ranged from 6-17. Significant improvements with KarXT were observed starting at different time points for each threshold. PANSS Marder 5-factor subscale scores also demonstrated significant reductions with KarXT compared to placebo at week 5. In the EMERGENT-2 trial, KarXT exhibited higher response rates in clinically meaningful PANSS total score improvement thresholds and demonstrated improvements across all 5 Marder factor subscale domains. These results support the efficacy of KarXT and its potential as a novel treatment option for schizophrenia, based on muscarinic receptor agonism as an alternative to direct dopamine D2 receptor antagonists.