Background: There are no approved treatments for Alzheimer’s disease psychosis (ADP). Xanomeline, a brain- penetrant M1/M4 preferring muscarinic receptor agonist, showed antipsychotic efficacy in placebo-controlled trials in subjects with AD [Bodick NC et al. 1997; DOI: 10.1001/archneur.1997.00550160091022]. Despite promising efficacy, further development of xanomeline was limited by cholinergic adverse events. The investigational antipsychotic xanomeline and trospium combines xanomeline with trospium, an FDA-approved muscarinic receptor antagonist that does not measurably cross the blood-brain barrier. Trospium acts to mitigate the peripheral procholinergic side effects of xanomeline, providing a strategy for using xanomeline to stimulate brain muscarinic receptors with a decreased side effect burden. Unlike available antipsychotics, xanomeline and trospium have no direct dopamine D2-blocking activity, and as such, its safety and tolerability profile is different.

Methods: The phase 3 ADEPT-1 trial is a double-blind, flexible-dose, placebo-controlled randomized withdrawal study to evaluate the safety and efficacy of xanomeline and trospium in decreasing the risk of relapse in subjects with ADP. Subjects aged 55-90 years with moderate to severe psychosis associated with mild to severe AD (Mini- Mental State Exam score range 8-22) will be enrolled into the study. Subjects will receive single-blind xanomeline and trospium for 12 weeks. Each subject will be flexibly titrated to the maximum dose of xanomeline and trospium 200 mg xanomeline/20 mg trospium/day. At the end of the single-blind treatment, eligible responders will be randomized to either continue xanomeline and trospium or be switched to matched placebo for a 26-week double- blind treatment period. A responder is defined as a subject with a ≥40% decrease (improvement) on the Neuropsychiatric Inventory- Clinician: Hallucinations + Delusions (NPI-C: H+D) score compared with baseline (day 1) and a Clinician Global Impression–Change (CGI-C) score of 1 or 2 (very much improved or improved).

Results: The primary endpoint of the study, time from randomization to relapse during the double-blind, randomized withdrawal treatment, will be evaluated by survival analysis using Kaplan-Meier Methods. The study started in August 2022 and will randomize approximately 200 subjects.

Conclusions: The trial design of the ADEPT-1 study is an efficient way to assess the potential for xanomeline and trospium to provide clinically meaningful benefit in preventing the return of ADP in patients who have responded to xanomeline and trospium.

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.

Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.