Background

ACP-204 acts as an inverse agonist at the 5-HT2A serotonin receptor. It is currently being developed for the treatment of Alzheimer’s disease psychosis. Acadia’s previous 5-HT2A inverse agonist Nuplazid is approved for Parkinson’s disease psychosis. In 2022, the FDA declined to approve Nuplazid for Alzheimer’s disease, citing a lack of evidence for its effectiveness.

According to the company website, ACP2-4 is a next-generation 5-HT2A blocker designed to mitigate Nuplazid’s shortcomings. These include the heart rhythm disturbance of QT prolongation, which can be lethal, as well as dosing limitations and delayed onset of action.

Findings

No Phase 1 trials are registered. In investor presentations, Acadia claims that in Phase 1, ACP-204 caused no QT wave prolongation, was able to be dosed to twice the levels of Nuplazid, and reached steady-state pharmacokinetics in half the time (slides 18/19 JPM24.pdf).

In November 2023, the company began a Phase 2/3 program. The initial Phase 2 study evaluates the efficacy and dose response of six weeks of 30 or 60 mg ACP-204, or placebo, in approximately 1,074 participants with Alzheimer’s disease and psychosis. The primary endpoint is change in the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions subscales (SAPS-H+D) at week six; clinician-rated improvement in symptoms serves as a secondary endpoint. Based on the results, two Phase 3 studies will each enroll 378 patients with Alzheimer’s disease and psychosis, for six weeks of treatment at one or both doses, against the same endpoints. Patients who complete the study will have the option of enrolling in a long-term open-label extension. The trial will enroll worldwide, and finish in February 2028.

For details on these trials, see clinicaltrials.gov.