KarXT (Xanomeline and Trospium) for the Treatment of Agitation in Schizophrenia: PANSS–EC Results from Three Randomized, Double-Blind, Placebo-Controlled Trials

Acute agitation is common in people with schizophrenia, and the Positive and Negative Syndrome Scale – Excited Component (PANSS–EC composed of excitement, tension, hostility, uncooperativeness, and poor impulse control items) has been used to assess the efficacy of agitation treatments. KarXT combines the dual M1/M4 preferring muscarinic receptor agonist xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride.
Three 5-week, randomized, double-blind, placebo-controlled studies EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT-04738123) met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 versus placebo, improved other key efficacy measures and was generally safe and well-tolerated. Post hoc analysis of the change from baseline of PANSS–EC score was conducted using methods similar to that for the primary endpoint.
PANSS–EC scores were significantly reduced with KarXT as compared with placebo at Week 5 across all three EMERGENT studies. In EMERGENT-1, KarXT (n=90) was statistically significantly superior (p=0.0002) to placebo (n=92) in decrease (improvement) of PANSS–EC score at Week 5. In EMERGENT-2, KarXT (n=126) was statistically significantly superior (p=0.0026) to placebo (n=126) at Week 5. In EMERGENT-3, KarXT (n=125) was statistically significantly superior (p < 0.0001) to placebo (n=131) at Week 5.
KarXT has potential to be the first in a new class of treatments for people with schizophrenia based on muscarinic receptor agonism. Post hoc analyses showed improvement in agitation as measured by the PANSS–EC.