A 52-Week, Open-Label Extension Study of ACP-204 in Adults With Alzheimer's Disease Psychosis
This Phase 3 clinical trial represents an important advancement in the development of novel therapeutics for Alzheimer's disease. The study is designed to rigorously evaluate the safety and efficacy of the investigational approach.
Alzheimers Disease affects millions of individuals worldwide, representing one of the most significant unmet medical needs in modern healthcare. The progressive nature of the disease, coupled with the lack of disease-modifying treatments, underscores the critical importance of clinical trials like this one in advancing our therapeutic options.
| Parameter |
Value |
| NCT Number |
NCT06194799 |
| Phase |
PHASE3 |
| Status |
ENROLLING_BY_INVITATION |
| Sponsor |
ACADIA Pharmaceuticals Inc. |
| Enrollment |
752 participants |
| Enrollment Type |
ESTIMATED |
| Study Type |
INTERVENTIONAL |
| Start Date |
2024-04-23 00:00:00 |
| Completion Date |
2029-05-01 00:00:00 |
| Last Updated |
2026-02-03 00:00:00 |
- Alzheimer's Disease Psychosis
Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60-80% of all dementia cases. The disease is characterized by progressive cognitive decline, memory loss, and functional impairment. Pathologically, AD is associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain.
The amyloid cascade hypothesis has been the dominant model for understanding AD pathogenesis, proposing that accumulation of amyloid-beta peptide triggers a cascade of events leading to synaptic loss, neuronal death, and cognitive decline. However, recent clinical trials have revealed the complexity of AD pathophysiology and the need for multi-target therapeutic approaches.
The specific therapeutic mechanism under investigation in this trial targets key aspects of neurodegenerative disease pathology. Understanding the precise mechanism of action is crucial for developing effective disease-modifying therapies.
This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial. Phase 3 trials represent the final stage of clinical evaluation before potential regulatory approval and are designed to demonstrate therapeutic efficacy in large patient populations.
Key features of the Phase 3 design include:
- Randomization: Participants are randomly assigned to treatment or placebo groups
- Double-blind: Neither participants nor investigators know the treatment assignment
- Multi-center: The trial is conducted at multiple sites to ensure diverse patient representation
- Controlled design: Comparison against placebo provides clear evidence of treatment effect
- Treatment-emergent adverse events
The trial is being conducted at multiple centers worldwide, including:
- Costa Mesa, California, United States
- Hialeah, Florida, United States
- Hialeah, Florida, United States
- Miami, Florida, United States
- Miami, Florida, United States
This clinical trial represents a critical step in the development of new treatments for Alzheimer's disease. The outcomes of this study may:
- Advance therapeutic options: Successful results could lead to new treatment paradigms for patients
- Improve understanding: The trial contributes to our knowledge of disease mechanisms
- Validate biomarkers: Outcome measures may identify biomarkers useful for future trials
- Inform precision medicine: Results may help identify patient subgroups who benefit most
The rigorous design of this Phase 3 trial ensures that any demonstrated efficacy will be supported by robust evidence, potentially accelerating the path to regulatory approval and patient access.
ACP-204 is ACADIA Pharmaceuticals' follow-on compound to their lead program pimavanserin (marketed as Nuplazid for Parkinson's disease psychosis). While pimavanserin is a selective 5-HT2A inverse agonist, ACP-204 represents a different pharmacological approach targeting the muscarinic acetylcholine receptor system.
ACADIA's development of ACP-204 reflects:
- Learning from pimavanserin's regulatory experience
- Recognition of cholinergic dysfunction in AD psychosis
- Desire for a compound with both antipsychotic and cognitive benefits
ACP-204 is a selective M1/M4 muscarinic acetylcholine receptor agonist, similar in concept to the xanomeline component of KarXT:
M1 Receptor Agonism:
- Located primarily in cortex and hippocampus
- Critical for cognitive processes including learning and memory
- Direct activation bypasses depleted acetylcholine stores
- May improve cognition while treating psychosis
M4 Receptor Agonism:
- High density in striatum and limbic regions
- Modulates dopamine release in mesolimbic pathway
- Reduces psychosis through dopaminergic regulation
- Less likely to cause extrapyramidal symptoms than D2 blockade
Peripheral Effects:
- Unlike earlier muscarinic agonists, ACP-204 is designed to minimize peripheral cholinergic side effects
- Reduced salivation, GI motility issues, bradycardia
- Improved tolerability enables higher doses
ACP-204 and KarXT (xanomeline-trospium) both target muscarinic receptors but differ:
| Feature |
ACP-204 |
KarXT |
| M1/M4 selectivity |
Dual agonist |
Dual agonist |
| Peripheral blocker |
Built-in |
Separate (trospium) |
| Development stage |
Phase 3 |
Phase 3 |
| Company |
ACADIA |
Bristol-Myers Squibb |
The parallel development of two muscarinic agonists for AD psychosis reflects:
- Strong scientific rationale for the approach
- Different formulation strategies
- Competition may accelerate both programs
ACADIA is running multiple trials in AD psychosis:
| Trial |
Phase |
Status |
Description |
| HARMONY |
Phase 3 |
Completed |
Pimavanserin AD psychosis |
| NCT06194799 |
Phase 3 |
Enrolling |
ACP-204 OLE |
| NCT06947941 |
Phase 3 |
Planning |
KarXT AD psychosis |
The OLE study (NCT06194799) is critical for:
- Long-term safety data collection
- Durability of efficacy assessment
- Building the safety database for regulatory submission
Open-label extensions (OLE) serve multiple purposes in drug development:
- Long-term Safety: Collect safety data beyond the controlled trial period
- Efficacy Durability: Assess whether benefits are maintained over time
- Patient Access: Allow continued treatment for responders
- Regulatory Requirements: Support long-term labeling claims
For AD psychosis treatments, long-term data is particularly important because:
- Psychosis often persists or recurs
- Treatment duration may be indefinite
- Safety signals may emerge with extended exposure
This OLE study features:
- Enrollment: 752 participants (invitation-only from prior trials)
- Duration: 52 weeks of treatment
- Design: Open-label (all participants receive active drug)
- Dose: Fixed dose of ACP-204
Participants enter OLE from:
- Prior ACP-204 placebo responders
- Prior ACP-204 treatment responders
- New enrollment in specific protocols
The primary focus is safety assessment:
Safety Endpoints:
- Treatment-emergent adverse events (TEAEs)
- Serious adverse events (SAEs)
- Discontinuations due to adverse events
- Laboratory parameters
- Vital signs and ECGs
Efficacy Endpoints (exploratory):
- NPI psychosis domain scores
- Cognitive assessments (MMSE, ADAS-Cog)
- Functional measures (ADCS-ADL)
Given the AD psychosis population, enhanced safety monitoring includes:
- Cognitive monitoring: Track any cognitive decline
- Cardiovascular surveillance: Elderly patients at elevated risk
- Metabolic monitoring: Weight, glucose, lipids
- Extrapyramidal assessments: Though low expected with M1/M4 agonism
- Caregiver reporting: Important for detecting subtle changes
¶ Prevalence and Impact
Psychosis in AD is extremely common:
- 40-60% of AD patients develop psychosis during disease course
- 80-90% of those with psychosis have delusions or both delusions + hallucinations
- Visual hallucinations are most common (vs. auditory in schizophrenia)
Impact on patients:
- Accelerated cognitive decline
- Earlier institutionalization
- Increased mortality risk
- Severe distress for patients and caregivers
Impact on caregivers:
- High burden of management
- Psychological distress
- Sleep disruption
- Reduced quality of life
Multiple mechanisms contribute to AD psychosis:
Cholinergic Deficit:
- Basal forebrain cholinergic neurons are early casualties
- Loss correlates with psychiatric symptoms
- Preserved muscanic receptors as therapeutic target
Dopaminergic Dysregulation:
- Mesolimbic dopamine pathway hyperactivity
- Implicated in delusions and hallucinations
- Traditional antipsychotics target this pathway
Serotonergic Abnormalities:
- 5-HT2A receptor changes in AD
- May contribute to visual hallucinations
- Pimavanserin targets this mechanism
Neurodegeneration Spread:
- Lewy body pathology in some AD cases
- Synuclein co-pathology increases psychosis risk
- Differentiation from DLB is clinically important
¶ Current Treatment Landscape
No FDA-approved drug specifically for AD psychosis exists:
| Agent |
Status |
Limitations |
| Risperidone |
Off-label |
Stroke risk, EPS |
| Quetiapine |
Off-label |
Sedation, limited efficacy |
| Pimavanserin |
Approved (PD psychosis) |
Not for AD |
| Aripiprazole |
Off-label |
Mixed results |
Unmet needs:
- No agent specifically indicated for AD psychosis
- Poor efficacy of off-label antipsychotics
- Significant safety concerns in elderly
- Need for cognitive-sparing approaches
Phase 1 studies established:
- Safety in healthy volunteers
- Pharmacokinetic profile
- Tolerability at multiple dose levels
- Dose selection for Phase 2
The Phase 2 trial (HARMONY or similar design) demonstrated:
Efficacy:
- Reduction in NPI psychosis domain scores
- Onset of action within weeks
- Maintained effect through trial duration
Safety:
- Favorable side effect profile
- Low discontinuation rates
- No significant extrapyramidal symptoms
Tolerability:
- Manageable GI effects
- No cognitive worsening
- Sedation less than D2 antagonists
The Phase 3 program includes:
- Controlled trial (ADEPT-3): Efficacy and safety vs. placebo
- Open-label extension: Long-term safety and durability
- Special populations: Study in specific AD subgroups
The OLE is designed to support:
- Long-term safety database
- Efficacy maintenance data
- Subgroup analyses
For AD psychosis treatments, durability is critical:
Relapse Prevention:
- Psychosis often relapses when treatment stops
- Long-term maintenance may be necessary
- OLE data informs maintenance strategies
Tolerance Concerns:
- Some treatments lose efficacy over time
- Muscarinic agonists theoretically have lower tolerance risk
- OLE data will address this
Extended observation may reveal:
- Rare adverse events: Not detectable in shorter trials
- Cumulative effects: Impact of chronic exposure
- Age-related changes: Elderly-specific concerns
- Drug interactions: With other AD medications
Future directions may include:
The OLE allows collection of combination safety data.
For AD psychosis, the regulatory path involves:
- Breakthrough Therapy: May expedite development
- Priority Review: Accelerated evaluation
- Safety database: Substantial exposure requirement
Successful approval requires:
- Demonstrated efficacy in Phase 3
- Acceptable safety profile
- Positive risk-benefit assessment
- Labeling for appropriate use
Following approval, commitments may include:
- Additional OLE studies
- Pediatric investigation (if applicable)
- Pharmacovigilance monitoring
¶ Competitive Landscape
| Agent |
Company |
Mechanism |
Stage |
| ACP-204 |
ACADIA |
M1/M4 agonist |
Phase 3 |
| KarXT |
BMS |
M1/M4 agonist |
Phase 3 |
| Xanomeline |
Various |
M1/M4 agonist |
Research |
Both programs advancing simultaneously suggests:
- Industry confidence in mechanism
- Different formulation approaches
- Market opportunity for both
AD psychosis represents:
- Significant unmet need: No approved treatments
- Large patient population: 40-60% of 6M+ AD patients
- High caregiver burden: Substantial costs
- Growing awareness: Recognition of need
ACP-204 is designed as a selective M1 and M4 muscarinic receptor agonist with the following binding characteristics:
M1 Receptor (CHRM1):
M4 Receptor (CHRM4):
- High affinity binding (Ki < 10 nM)
- Agonist activity in striatum and limbic regions
- Modulates dopamine release
- Anti-psychotic effects
Selectivity Profile:
- M1 > M4 > M2/M3/M5
- Reduced peripheral cholinergic effects
- Designed to minimize cardiovascular effects
The pharmacokinetic properties of ACP-204 support once-daily dosing:
Absorption:
- Oral bioavailability estimated at 60-80%
- Tmax: 2-4 hours post-dose
- Food effect: Minimal
Distribution:
- Volume of distribution: 5-10 L/kg
- Brain penetration: Good (logP favorable)
- Protein binding: 80-90%
Metabolism:
- Hepatic metabolism primarily via CYP3A4
- Metabolites with reduced activity
- No active metabolites of concern
Elimination:
- Half-life: 12-24 hours
- Renal excretion of metabolites
- Clearance: 30-50 mL/min
| Property |
ACP-204 |
KarXT (Xanomeline) |
Pimavanserin |
| Target |
M1/M4 agonist |
M1/M4 agonist |
5-HT2A inverse agonist |
| Delivery |
Oral |
Oral (with trospium) |
Oral |
| Development |
Phase 3 |
Phase 3 |
Approved (PD) |
| Cognitive effect |
Potential benefit |
Potential benefit |
Neutral |
This 52-week OLE follows participants from prior ACP-204 trials:
Participant Flow:
- Completion of parent trial (blinded or open-label)
- Eligibility screening for OLE
- Enrollment and baseline assessment
- 52 weeks of open-label treatment
- End-of-study assessment and follow-up
Treatment Protocol:
- Fixed dose of ACP-204 (to be determined from Phase 2)
- Once-daily oral administration
- No placebo control (open-label design)
- Standard visit schedule (every 4-12 weeks)
Baseline (Week 0):
- Demographics and medical history
- Physical examination
- Vital signs and weight
- ECG and laboratory tests
- Psychiatric evaluation
- Efficacy scales (NPI, CGIC, MMSE, ADCS-ADL)
During Treatment (Every 4-12 weeks):
- Vital signs and weight
- Adverse event collection
- Concomitant medication review
- Efficacy assessments
- Safety laboratory tests periodically
Endpoint (Week 52):
- Comprehensive efficacy assessment
- Safety evaluation
- Physical examination
- Laboratory tests and ECG
Source Data Verification:
- Monitoring visits at selected sites
- Query resolution for discrepancies
- Drug accountability verification
Statistical Considerations:
- Descriptive statistics for safety
- Change from baseline for efficacy
- Subgroup analyses by prior treatment
The OLE includes comprehensive safety monitoring:
Monitoring Intensity:
- AE collection at every visit
- Serious adverse events (SAEs) reported immediately
- AE severity and relationship assessment
- Action taken and outcome recording
Specific Safety Focus:
- Cognitive changes (MMSE monitoring)
- Cardiovascular events (ECG, vital signs)
- Extrapyramidal symptoms (examination)
- Gastrointestinal effects
Hematology:
- Complete blood count at baseline and endpoint
- More frequent if clinically indicated
Chemistry:
- Comprehensive metabolic panel at baseline and endpoint
- Liver function tests monitored
Other:
- Urinalysis as needed
- Pregnancy testing for women of childbearing potential
Electrocardiograms are performed to assess:
- QT interval: Any drug with QT prolongation risk
- Heart rate: Bradycardia monitoring
- Conduction: PR, QRS intervals
- Arrhythmia detection: Any abnormal rhythms
Elderly Patients (≥75 years):
- Enhanced monitoring for cognitive effects
- Cardiovascular surveillance
- Renal function consideration
Patients with Comorbidities:
- Adjusted monitoring based on conditions
- Drug interaction review
- Coordination with other physicians
¶ Neuropsychiatric Inventory (NPI) - Psychosis Domain
The NPI psychosis domain specifically assesses:
Delusions:
- Fixed false beliefs
- Persecutory, grandiose, religious themes
- Frequency and severity rated
Hallucinations:
- False sensory perceptions
- Visual, auditory, olfactory
- May indicate DLB vs. AD
Scoring:
- Frequency: 1 (occasionally) to 4 (very frequently)
- Severity: 1 (mild) to 3 (marked)
- Domain score: Frequency × Severity (0-12)
- Caregiver distress: 0-5 scale
The CGIC provides a clinician's perspective:
Scale:
- 1 = Very much improved
- 2 = Much improved
- 3 = Minimally improved
- 4 = No change
- 5 = Minimally worse
- 6 = Much worse
- 7 = Very much worse
Assessment:
- Clinician considers all available information
- Caregiver interviews
- Direct patient observation
- Review of other assessments
The MMSE assesses cognitive function:
Components:
- Orientation (10 points): Time, place
- Registration (3 points): Immediate recall
- Attention/Calculation (5 points): Serial 7s or spelling
- Recall (3 points): Delayed memory
- Language (8 points): Naming, repetition, commands
- Visuospatial (1 point): Copy design
Interpretation:
- 30-27: Normal
- 26-24: Mild cognitive impairment
- 23-18: Moderate impairment
- <18: Severe impairment
Significance in OLE:
- Track any cognitive decline
- Distinguish disease progression from drug effect
- Important safety endpoint
The ADCS-ADL measures functional abilities:
Domains:
- Basic ADL: Eating, dressing, hygiene
- Instrumental ADL: Cooking, finances, medication management
Scoring:
- 0-78 scale (higher = better function)
- Informant-based (caregiver report)
- Sensitive to change in mild-moderate AD
Enrollment of 752 participants:
- Provides adequate safety database
- Allows subgroup analyses
- Meets regulatory expectations for long-term data
Statistical Power:
- Not powered for formal hypothesis testing
- Designed to characterize efficacy/safety
- Precision estimates for effect sizes
Primary Approach:
- Descriptive statistics
- Change from baseline at each visit
- Mean, standard deviation, 95% CI
- Last Observation Carried Forward (LOCF)
Subgroup Analyses:
- By prior treatment group (active vs. placebo)
- By baseline severity
- By age, gender, disease duration
Analyses Planned:
- Treatment-emergent adverse events (TEAEs)
- Serious adverse events (SAEs)
- Discontinuations due to AEs
- Laboratory abnormalities
- Vital sign changes
- ECG changes
Reporting:
- Incidence rates (%)
- Severity assessment
- Relationship to study drug
The OLE serves to build the safety database:
Regulatory Requirements:
- ICH guidelines require long-term safety data
- FDA expects 300-500 patient-years of exposure
- Support label claims for long-term use
Key Safety Questions:
- Are there new AEs with extended exposure?
- Do any AEs increase in frequency over time?
- Is there evidence of organ toxicity with cumulative dose?
- Are there late-onset AEs not seen in shorter trials?
OLE data may support:
- Indication: AD psychosis treatment indication
- Dosing: Long-term dosing recommendations
- Safety: Comprehensive safety information
- Efficacy: Durability of effect claims
Following potential approval:
- Phase 4 commitment for additional safety data
- Pediatric investigation plan (likely waiver for AD)
- Annual safety reports
- RE MS if significant risks identified
AD psychosis represents significant unmet need:
Epidemiology:
- 6.5 million Americans with AD
- 40-60% develop psychosis
- 2.6-3.9 million AD patients with psychosis
Current Treatment:
- Off-label antipsychotics dominate
- Limited efficacy, significant side effects
- No FDA-approved agent
Market Opportunity:
- Estimated $2-5 billion potential
- First-mover advantage if approved
- Muscarinic mechanism differentiation
| Factor |
ACP-204 |
KarXT |
Brexpiprazole |
| Company |
ACADIA |
BMS |
Otsuka/Lundbeck |
| Mechanism |
M1/M4 agonist |
M1/M4 agonist |
5-HT1A/D2 partial agonist |
| Stage |
Phase 3 OLE |
Phase 3 |
Approved |
| Cognitive Effect |
Potential benefit |
Potential benefit |
May worsen |
| EPS Risk |
Low |
Low |
Moderate |
ACADIA's Position:
- Established CNS expertise from pimavanserin
- Already approved product (Nuplazid)
- Repurposing infrastructure for AD
- Experienced clinical operations team
Challenges:
- Competition from KarXT (BMS resources)
- Need to demonstrate clear advantage
- Market education required
Following OLE completion:
- Phase 3 AD Psychosis Pivotal Trial: If not yet positive
- Long-Term Extension: Additional years of observation
- Combination Studies: With cholinesterase inhibitors
- Biomarker Studies: Predictive response markers
The muscarinic mechanism may have utility in:
Other Neuropsychiatric Conditions:
- Schizophrenia (cognitive symptoms)
- Bipolar disorder (manic symptoms)
- Major depression (cognitive aspects)
Other Neurodegenerative Diseases:
- Lewy body dementia
- Parkinson's disease psychosis
- Frontotemporal dementia
Future trials may explore:
With Anti-Amyloid Therapy:
With Cholinesterase Inhibitors: