Safety and efficacy of KarXT (Xanomeline Trospium) in Schizophrenia in the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial

Abstract Introduction KarXT combines the M 1 /M 4 preferring muscarinic receptor agonist xanomeline and peripherally restricted anticholinergic trospium. In phase 2 EMERGENT-1 study, met primary endpoint of a significant reduction in Positive Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, was generally well tolerated. Methods EMERGENT-2 3, randomized, double-blind, placebo-controlled, 5-week trial acutely psychotic patients with schizophrenia inpatient setting. Eligible were randomized 1:1 to or matched placebo. Dosing (mg xanomeline/mg trospium) started at 50 mg/20 mg BID increased maximum 125 mg/30 BID. The change from baseline PANSS score. Key endpoints included positive subscale, negative Marder factor scores compared Efficacy analyses performed using modified intent-to-treat population (patients ≥1 dose study medication, assessment, postbaseline assessment). All receiving drug safety analyses. Results 252 US enrolled. demonstrated statistically clinically meaningful 9.6-point (effect size=0.61) placebo (p<0.0001); improvement starting (first rating) continued end. also endpoints. 2.9-point subscale (p<0.0001), 1.8-point (p=0.0055), 2.2-point (p=0.0022). Overall discontinuation rates similar (25%) (21%). overall treatment-emergent adverse events (TEAEs) rate for 75% 58%, respectively. Discontinuation related TEAEs between (7%) (6%). Rates serious (2%, each group); no determined be related. most common (≥5%) all mild moderate severity constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, diarrhea. not associated sedation/somnolence, weight gain, extrapyramidal symptoms. Conclusions has potential first new class treatments promising alternative postsynaptic dopamine D antagonists. Funding Karuna Therapeutics, Inc.