Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease

Abstract Background Psychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off‐label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M 1 /M 4 preferring muscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. KarXT is an investigational treatment that combines xanomeline with trospium, an FDA‐approved non‐specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood‐brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain. Methods ADEPT‐2 trial is a phase 3, randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the safety and efficacy of KarXT for the treatment of ADP. Subjects aged 55‐90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either KarXT or placebo in a double‐blinded manner for 14 weeks and subjects who complete the study will be eligible to participate in a one‐year, open‐label safety extension study. Results The primary efficacy endpoint of the study is change from Randomization to End of Treatment in the Neuropsychiatric Inventory‐Clinical (NPI‐C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from Randomization to End of Treatment in the Cohen‐Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of KarXT compared with placebo in subjects with ADP. The study is planned to start in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia. Conclusion ADEPT‐2 is designed to assess the safety and efficacy of KarXT for the treatment of psychosis in patients with AD dementia. If ADEPT‐2 is successful, KarXT has the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.