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.
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.
| 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 |
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.
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 AD
flowchart TD
A["ACP-204"] --> B["5-HT2A Receptor Inverse Agonist"]
B --> C["Blocks Constitutive Activity"]
B --> D["Antagonizes Serotonin Binding"]
C --> E["Reduces Basal Receptor Signaling"]
D --> F["Prevents Agonist-Induced Signaling"]
E --> G["Normalized Cortical Activity"]
F --> G
G --> H["Reduced Psychotic Symptoms"]
G --> I["Improved Reality Testing"]
H --> J["Reduction in Hallucinations"]
H --> K["Reduction in Delusions"]
| 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.
This is a master protocol containing three independent, seamlessly enrolling, double-blind, placebo-controlled studies:
- 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
- Purpose: Confirmatory efficacy study
- Arms: ACP-204 (dose from Part 1) vs. Placebo
- 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.
| 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 |
- 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
- Clinical Global Impression-Improvement in ADP context (CGI-I-ADP) score at Week 6
- Safety and tolerability assessments
- Pharmacokinetic evaluations
- 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
- 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
Based on the mechanism, expected adverse effects may include:
- Gastrointestinal: Nausea, diarrhea
- CNS: Headache, dizziness, somnolence
- Cardiovascular: Orthostatic hypotension (addressed in exclusion criteria)
- 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 administration
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
| Treatment |
Limitations |
| Risperidone |
Extrapyramidal symptoms, stroke risk |
| Quetiapine |
Sedation, metabolic effects |
| Aripiprazole |
Limited efficacy data in ADP |
| Pimavanserin |
Approved only for PDP, not ADP |
¶ Sites and Recruitment
The trial is recruiting at numerous sites globally, including:
- United States**: Arizona, California, Florida, Texas, Pennsylvania, and others
- Brazil: Multiple sites in Brasília, Curitiba, Porto Alegre, Rio de Janeiro, São Paulo
- Bulgaria**: Sofia, Plovdiv, Pleven, Kardzhali
- Chile: Santiago, Antofagasta
- Czech Republic: Prague, Brno
- France**: Paris, Lyon, Dijon, Toulouse
- Italy: Rome, Milan, Brescia
- Mexico: Mexico City, Monterrey
- Serbia: Belgrade, Kragujevac, Niš
- South Korea: Seoul, Incheon
- Spain: Seville, Zamora
- Taiwan: Taipei, Kaohsiung, Tainan
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
- AD psychosis affects ~1.5-3 million patients in the US
- Estimated annual market: $5+ billion
- First-mover advantage for FDA-approved ADP treatment