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].
| 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].
| 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:
Cortical dysregulation: 5-HT2A receptor dysfunction contributes to aberrant sensory processing and distorted perception
Glutamatergic interaction: 5-HT2A signaling modulates glutamatergic activity through mGlu2/3 receptor cross-talk
Dopamine modulation: 5-HT2A antagonism indirectly reduces dopaminergic hyperactivity in mesolimbic pathways
Sleep-wake cycle: 5-HT2A activation is involved in wakefulness and attention, disrupted in ADMolecular Mechanism
Mermaid diagram (expand to render)
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
All three substudies are analyzed independently of each other, allowing for seamless enrollment and efficient development.
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
Selective 5-HT2A targeting: Minimizes off-target effects
Inverse agonist activity: Addresses constitutive receptor activity
AD-specific formulation: Tailored for AD patient population
No dopamine blockade: Avoids extrapyramidal symptoms
Once-daily dosing: Simplified administrationClinical 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
Unknown, ClinicalTrials.gov - NCT06159673 (n.d.)
[Unknown, Alzheimer's disease psychosis: prevalence and management. CNS Drugs. 2023 (2023)](https://pubmed.ncbi.nlm.nih.gov/36734987/)
[Unknown, 5-HT2A receptor function in psychosis. J Neurosci. 2024 (2024)](https://pubmed.ncbi.nlm.nih.gov/37289012/)
Unknown, ACADIA Pharmaceuticals Pipeline Presentation (n.d.)
[Unknown, Master protocol designs in Alzheimer's disease clinical trials. Alzheimers Dement. 2024 (2024)](https://pubmed.ncbi.nlm.nih.gov/38154256/)