P19: Design of ADEPT-2, a phase 3, parallel group study to evaluate xanomeline and trospium as a treatment for psychosis associated with Alzheimer’s disease dementia

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 M1/M4 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. Xanomeline and trospium 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 xanomeline and trospium 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 xanomeline and trospium or placebo in a double-blinded manner for 12 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 baseline to end of Week 12 in the Neuropsychiatric Inventory-Clinical (NPI-C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from baseline to end of Week 12 in the Cohen- Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of xanomeline and trospium compared with placebo in subjects with ADP. The study started in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.

Conclusions: ADEPT-2 is designed to assess the safety and efficacy of xanomeline and trospium for the treatment of psychosis in patients with AD dementia. If ADEPT-2 is successful, xanomeline and trospium have the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.