15. DESIGN OF THE PHASE 2/3, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDIES INVESTIGATING THE EFFICACY AND SAFETY OF ACP-204, A NOVEL 5-HT2A INVERSE AGONIST, IN ALZHEIMER’S DISEASE PSYCHOSIS

Introduction

Approximately 30% of patients with Alzheimer’s disease experience hallucinations and/or delusions related to Alzheimer’s disease psychosis (ADP). Patients are often managed with off-label antipsychotics, which are associated with considerable safety concerns. ACP-204 is a 5-HT2A selective inverse agonist and antagonist (and, less so, 5-HT2C). It was developed with an improved pharmacological profile compared with first-in-class pimavanserin. Here we describe the study design for 3 independent phase 2 and 3 studies of ACP-204.

Methods

The master protocol ACP-204-006 (NCT06159673) includes 3 similar, independent, operationally seamless, double-blind, placebo-controlled, multicenter studies investigating the efficacy and safety of ACP-204 in ADP. Eligibility criteria include individuals 55-95 years of age with Alzheimer’s disease and psychosis. Part 1 (phase 2) will evaluate efficacy and dose response of ACP-204 60 mg and 30 mg vs placebo in participants with ADP. Part 2A and Part 2B (phase 3) will either confirm both doses, or pursue only a single dose from Part 1. Participants in each of the 3 independent studies will be randomized 1:1:1 to receive ACP-204 60 mg, 30 mg, or 0 mg (placebo) for 6 weeks in a double-blind treatment period. Part 1 will enroll ∼318 total participants (∼106 per arm), and Parts 2A and 2B separately will each enroll ∼378 total participants (∼126 per arm), providing ≥80% (Part 1) or ≥85% (Part 2A and 2B) power to detect a significant effect of ACP-204 over placebo at alpha level 0.05 using a two-sided test. Participants who complete Part 1, 2A, or 2B may be eligible to roll over into the long-term open-label extension (OLE) study, ACP-204-008 (NCT06194799). Each of the 3 studies will include a ≤42-day screening period, 6-week double-blind treatment period, 30-day safety follow-up period for participants not rolling over into OLE, and a mortality follow-up for participants with early study termination (Figure 1). The primary, secondary, and select other endpoints are shown in Figure 1.

Results

This ongoing study has an estimated completion date of February 2028.

Conclusions

ACP-204-006 will be the first clinical study to evaluate the efficacy and safety of ACP-204 in patients with ADP, a population with considerable unmet needs.