ACP-204 for Alzheimer's Disease Psychosis (NCT06159673)

Overview

ACP-204 is a novel selective serotonin 5-HT2A receptor antagonist/inverse agonist being developed by ACADIA Pharmaceuticals Inc. for the treatment of psychosis associated with Alzheimer's disease (AD). This represents a significant advancement in addressing a critically underserved patient population — individuals with AD who experience hallucinations and delusions[@clinicaltrialsgov].

Alzheimer's disease psychosis (ADP) affects approximately 25-50% of patients with Alzheimer's disease, manifesting as visual or auditory hallucinations, delusions, and other psychotic symptoms. Currently, there are no FDA-approved treatments specifically for ADP, making this a significant unmet medical need[@alzheimers2023].

Trial Information

| Attribute | Details |
|-----------|---------|
| NCT Number | NCT06159673 |
| Sponsor | ACADIA Pharmaceuticals Inc. |
| Drug | ACP-204 |
| Phase | Phase 2/3 (Master Protocol) |
| Indication | Alzheimer's Disease Psychosis |
| Status | Recruiting |
| Start Date | November 14, 2023 |
| Primary Completion | January 2028 (estimated) |
| Estimated Completion | February 2028 |
| Total Participants | 1,074 (estimated) |
| Study Design | Master protocol with 3 independent substudies |

Mechanism of Action

5-HT2A Receptor Antagonism

Overview

ACP-204 is a novel selective serotonin 5-HT2A receptor antagonist/inverse agonist being developed by ACADIA Pharmaceuticals Inc. for the treatment of psychosis associated with Alzheimer's disease (AD). This represents a significant advancement in addressing a critically underserved patient population — individuals with AD who experience hallucinations and delusions[@clinicaltrialsgov].

Alzheimer's disease psychosis (ADP) affects approximately 25-50% of patients with Alzheimer's disease, manifesting as visual or auditory hallucinations, delusions, and other psychotic symptoms. Currently, there are no FDA-approved treatments specifically for ADP, making this a significant unmet medical need[@alzheimers2023].

Trial Information

| Attribute | Details |
|-----------|---------|
| NCT Number | NCT06159673 |
| Sponsor | ACADIA Pharmaceuticals Inc. |
| Drug | ACP-204 |
| Phase | Phase 2/3 (Master Protocol) |
| Indication | Alzheimer's Disease Psychosis |
| Status | Recruiting |
| Start Date | November 14, 2023 |
| Primary Completion | January 2028 (estimated) |
| Estimated Completion | February 2028 |
| Total Participants | 1,074 (estimated) |
| Study Design | Master protocol with 3 independent substudies |

Mechanism of Action

5-HT2A Receptor Antagonism

ACP-204 is described as a potent and selective antagonist/inverse agonist of the 5-hydroxytryptamine (serotonin) receptor subtype 2A (5-HT2A). The 5-HT2A receptor is a G-protein coupled receptor (GPCR) densely expressed in cortical layer 1, pyramidal neurons of the prefrontal cortex, and key regions involved in sensory processing and perception[@hta2024].

Why 5-HT2A in Alzheimer's Disease Psychosis?

The 5-HT2A receptor plays a critical role in the pathophysiology of psychosis:

Molecular Mechanism

Comparison with Other 5-HT2A Agents

| Drug | Company | Indication | Status |
|------|---------|------------|--------|
| ACP-204 | ACADIA | AD Psychosis | Phase 2/3 recruiting |
| Pimavanserin | ACADIA | Parkinson's Disease Psychosis | FDA Approved |
| Risperidone | Various | Off-label AD psychosis | Generic |
| Quetiapine | AstraZeneca | Off-label AD psychosis | Generic |

Pimavanserin (Nuplazid®), also developed by ACADIA, is FDA-approved for Parkinson's disease psychosis. ACP-204 represents an advancement with improved selectivity and AD-specific formulation.

Trial Design

Master Protocol Structure

This is a master protocol containing three independent, seamlessly enrolling, double-blind, placebo-controlled studies:

Substudy 1 (Phase 2)

• Purpose: Evaluate efficacy and dose-response
• Arms: ACP-204 30 mg vs. ACP-204 60 mg vs. Placebo
• Design: Dose-finding to identify optimal dose for Phase 3

Substudy 2A (Phase 3)

• Purpose: Confirmatory efficacy study
• Arms: ACP-204 (dose from Part 1) vs. Placebo

Substudy 2B (Phase 3)

• Purpose: Confirmatory efficacy study
• Arms: ACP-204 (dose from Part 1) vs. Placebo

Key Study Parameters

| Parameter | Details |
|-----------|---------|
| Randomization | 1:1:1 (in Phase 2) |
| Treatment Duration | 6 weeks (double-blind) |
| Masking | Quadruple (participant, care provider, investigator, outcomes assessor) |
| Allocation | Randomized, parallel-group |
| Primary Endpoint | Change from baseline in SAPS-H+D at Week 6 |

Efficacy Endpoints

Primary Endpoint

• Scale for the Assessment of Positive Symptoms - Hallucinations and Delusions (SAPS-H+D) total score change from baseline at Week 6
• The SAPS-H+D combines two subscales:
• SAPS-H: 7-item hallucinations domain
• SAPS-D: 13-item delusions domain

Secondary Endpoints

• Clinical Global Impression-Improvement in ADP context (CGI-I-ADP) score at Week 6
• Safety and tolerability assessments
• Pharmacokinetic evaluations

Patient Population

Inclusion Criteria

• Age 55-95 years
• Possible or probable AD (2011 NIA-AA criteria)
• Meets IPA criteria for psychosis in major or mild neurocognitive disorder
• Evidence of amyloid plaque deposition (blood-based biomarker or PET/CSF)
• MMSE score 6-24
• Psychotic symptoms for at least 2 months
• Has a designated study partner/caregiver
• Stable on cholinesterase inhibitor or memantine if applicable

Exclusion Criteria

• Psychotic symptoms primarily due to delirium, substance abuse, or other psychiatric conditions
• History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm
• Atrial fibrillation
• Symptomatic orthostatic hypotension
• Treatment with anti-tau therapy or donanemab within 2 months

Safety Considerations

5-HT2A Antagonist Safety Profile

Based on the mechanism, expected adverse effects may include:

• Gastrointestinal: Nausea, diarrhea
• CNS: Headache, dizziness, somnolence
• Cardiovascular: Orthostatic hypotension (addressed in exclusion criteria)

Advantages of ACP-204

Clinical Development Context

Unmet Need in AD Psychosis

Alzheimer's disease psychosis represents a significant challenge:

• Prevalence: 25-50% of AD patients develop psychosis
• Impact: Associated with faster cognitive decline, earlier nursing home placement
• Mortality: Increased mortality risk
• Caregiver burden: Severe emotional and practical burden
• No approved treatments: No FDA-approved therapy specifically for ADP

Current Off-Label Options

| Treatment | Limitations |
|-----------|-------------|
| Risperidone | Extrapyramidal symptoms, stroke risk |
| Quetiapine | Sedation, metabolic effects |
| Aripiprazole | Limited efficacy data in ADP |
| Pimavanserin | Approved only for PDP, not ADP |

Cross-Links to NeuroWiki

• [Alzheimer's Disease Psychosis](/diseases/alzheimer-disease-psychosis) — Target indication
• [5-HT2A Receptor Pathway](/proteins/ht2a-receptor) — Drug target
• [Serotonin Signaling in Neurodegeneration](/mechanisms/serotonin-signaling) — Mechanism context
• [Psychosis in Neurodegenerative Diseases](/diseases/psychosis-neurodegenerative) — Disease context
• [ACADIA Pharmaceuticals](/companies/acadia-pharmaceuticals) — Sponsor
• [Pimavanserin](/clinical-trials/pimavanserin-parkinsons-psychosis) — Related compound

Sites and Recruitment

The trial is recruiting at numerous sites globally, including:

• [United States**: Arizona, California, Florida, Texas, Pennsylvania, and others](/genes/ar)
• Brazil: Multiple sites in Brasília, Curitiba, Porto Alegre, Rio de Janeiro, São Paulo
• [Bulgaria**: Sofia, Plovdiv, Pleven, Kardzhali](/genes/ar)
• Chile: Santiago, Antofagasta
• Czech Republic: Prague, Brno
• [France**: Paris, Lyon, Dijon, Toulouse](/genes/ran)
• Italy: Rome, Milan, Brescia
• Mexico: Mexico City, Monterrey
• Serbia: Belgrade, Kragujevac, Niš
• South Korea: Seoul, Incheon
• Spain: Seville, Zamora
• Taiwan: Taipei, Kaohsiung, Tainan

Industry Context

ACADIA Pharmaceuticals

ACADIA is a leader in neuropsychiatric drug development:

• Pimavanserin (Nuplazid): FDA-approved for Parkinson's disease psychosis
• Trofinetide (Daybue): FDA-approved for Rett syndrome
• Pipeline focus: CNS disorders with high unmet need

Market Opportunity

• AD psychosis affects ~1.5-3 million patients in the US
• Estimated annual market: $5+ billion
• First-mover advantage for FDA-approved ADP treatment

External Links

• [ClinicalTrials.gov - NCT06159673](https://clinicaltrials.gov/show/NCT06159673)
• [ACADIA Pharmaceuticals](https://acadia.com/)
• [SAPS-H+D Scale Validation](https://pubmed.ncbi.nlm.nih.gov/2565678/)

References