Phase 3 ADAGIO Trials to Evaluate Schizophrenia Medication Cobenfy for Alzheimer Disease Agitation

Two ongoing phase 3 trials, ADAGIO-1 (NCT07011732) and ADAGIO-2 (NCT07011745), are evaluating the efficacy and safety of xanomeline–trospium (X/T; Cobenfy; BMS) for agitation associated with Alzheimer disease (AD), a neuropsychiatric complication affecting approximately half of patients. Presented as a poster at the 2026 AD/PD International Conference in Copenhagen, the trials reflect growing interest in muscarinic receptor modulation as a therapeutic strategy for behavioral symptoms of dementia.¹

ADAGIO Trials: Design and Clinical End Points

Despite the high prevalence and clinical burden of agitation in AD, treatment options remain limited, with only 1 FDA-approved therapy currently available. ADAGIO-1 and ADAGIO-2 are identical, randomized, double-blind, placebo-controlled phase 3 studies enrolling approximately 704 total participants aged 55 to 90 years with biomarker-confirmed AD and clinically significant agitation.¹

Eligible participants must demonstrate persistent agitation for at least 2 weeks prior to screening, defined using established clinical tools including the Neuropsychiatric Inventory (NPI/NPI-NH), Clinical Global Impressions–Severity (CGI-S), and Cohen-Mansfield Agitation Inventory–International Psychogeriatric Association (CMAI-IPA) criteria. The studies are led by several investigators, including Rosalinda Sepulveda, MD, PhD, Medical Director of Clinical Development at Neumora.

Both studies are designed with a 14-week treatment duration, with the primary endpoint defined as change from baseline in CMAI-IPA total score. Key secondary outcomes include changes in CGI-S scores, alongside additional safety and efficacy assessments.¹ Recruitment is ongoing, and results from these trials are expected to provide pivotal evidence regarding the role of muscarinic receptor agonism in managing agitation in AD.

Mechanistic Rationale for Muscarinic Modulation

X/T combines xanomeline, an M1/M4-preferring muscarinic receptor agonist, with trospium chloride, a peripherally restricted muscarinic antagonist designed to mitigate peripheral cholinergic adverse effects.1

This mechanism represents a departure from dopamine receptor blockade, which underlies many currently used therapies. Muscarinic receptor activation is thought to influence both cholinergic and dopaminergic signaling, pathways implicated in agitation and other behavioral and psychological symptoms of dementia (BPSD).²

Prior clinical data provide a rationale for this approach. X/T has already demonstrated antipsychotic efficacy in schizophrenia, including statistically significant reductions in Positive and Negative Syndrome Scale (PANSS) scores in the phase 3 EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) trials.² These findings supported its FDA approval for schizophrenia in 2024.³

Additionally, post hoc analyses of the EMERGENT program suggested improvements in agitation among patients with schizophrenia, further supporting investigation in neurodegenerative populations.¹

Looking Ahead

With enrollment ongoing, ADAGIO-1 and ADAGIO-2 are poised to provide critical phase 3 data on the efficacy and safety of X/T in AD-related agitation. If successful, these trials could expand the clinical utility of Cobenfy beyond schizophrenia and into neurodegenerative disease, addressing a major unmet need in dementia care.

REFERENCES
1. Ramsay I, Marcus R, Shao Y, Grossberg G, Schieber F, Sepulveda R. Two parallel phase 3 trials to evaluate X/T for the treatment of agitation associated with Alzheimer’s disease (ADAGIO-1/ADAGIO-2). Presented at: 2026 AD/PD Conference; March 17-21; Copenhagen, Denmark. ABSTRACT 533
2. Golden JC, Murphy KS, Tampi RR. From schizophrenia to dementia: Is Cobenfy a potential treatment for behavioral and psychological symptoms of dementia? J Int Med Res. 2026;54(1):03000605261417092
3. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. News release. FDA. September 26, 2024. Accessed March 17, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia