A 52-Week, Open-Label Extension Study of ACP-204 in Adults With Alzheimer's D... (NCT06194799)

ACP-204 in Adults With Alzheimer's Disease Psychosis Open Label Extension Study

Overview

A 52-Week, Open-Label Extension Study of ACP-204 in Adults With Alzheimer's Disease Psychosis

ACP-204 in Adults With Alzheimer's Disease Psychosis Open Label Extension Study

Overview

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["@novel2024"].

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["@alzheimers2023"].

Trial Details

| 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 |

Conditions Studied

• Alzheimer's Disease Psychosis

Scientific Background

Disease Context

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](/proteins/amyloid-beta) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain[@alzheimers2023].

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[@amyloid2023].

Therapeutic Mechanism

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[@mechanismdriven2024].

Study Design

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[@clinical2023].

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

Outcome Measures

Primary Endpoints

• Treatment-emergent adverse events

Participating Sites

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

Clinical Significance

This clinical trial represents a critical step in the development of new treatments for Alzheimer's disease. The outcomes of this study may:

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[@future2024].

ACP-204: ACADIA's Muscarinic Agonist for AD Psychosis

Background

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

Mechanism of Action

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

• 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

• 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

Relationship to KarXT

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's AD Psychosis Program

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 Extension Study Design

Purpose of OLE Studies

Open-label extensions (OLE) serve multiple purposes in drug development:

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

Study Structure

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

• Prior ACP-204 placebo responders
• Prior ACP-204 treatment responders
• New enrollment in specific protocols

Outcome Measures

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

• NPI psychosis domain scores
• Cognitive assessments (MMSE, ADAS-Cog)
• Functional measures (ADCS-ADL)

Safety Monitoring

Given the AD psychosis population, enhanced safety monitoring includes:

AD Psychosis: Clinical Overview

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)

• Accelerated cognitive decline
• Earlier institutionalization
• Increased mortality risk
• Severe distress for patients and caregivers

• High burden of management
• Psychological distress
• Sleep disruption
• Reduced quality of life

Pathophysiology

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

• Mesolimbic dopamine pathway hyperactivity
• Implicated in delusions and hallucinations
• Traditional antipsychotics target this pathway

• 5-HT2A receptor changes in AD
• May contribute to visual hallucinations
• Pimavanserin targets this mechanism

• 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

ACP-204 Clinical Development

Phase 1 Results

Phase 1 studies established:

• Safety in healthy volunteers
• Pharmacokinetic profile
• Tolerability at multiple dose levels
• Dose selection for Phase 2

Phase 2 Findings

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

• Favorable side effect profile
• Low discontinuation rates
• No significant extrapyramidal symptoms

• Manageable GI effects
• No cognitive worsening
• Sedation less than D2 antagonists

Phase 3 Program

The Phase 3 program includes:

The OLE is designed to support:

• Long-term safety database
• Efficacy maintenance data
• Subgroup analyses

Long-Term Considerations

Sustained Efficacy

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

• Some treatments lose efficacy over time
• Muscarinic agonists theoretically have lower tolerance risk
• OLE data will address this

Safety Profile Evolution

Extended observation may reveal:

Combination Therapy

Future directions may include:

• ACP-204 + cholinesterase inhibitors
• ACP-204 + anti-amyloid antibodies
• ACP-204 + behavioral interventions

Regulatory Considerations

FDA Pathway

For AD psychosis, the regulatory path involves:

Approval Requirements

Successful approval requires:

• Demonstrated efficacy in Phase 3
• Acceptable safety profile
• Positive risk-benefit assessment
• Labeling for appropriate use

Post-Marketing Commitments

Following approval, commitments may include:

• Additional OLE studies
• Pediatric investigation (if applicable)
• Pharmacovigilance monitoring

Competitive Landscape

Muscarinic Agonist Competition

| 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

Market Opportunity

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

Related Pages

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [AD Psychosis](/mechanisms/ad-psychosis)
• [Muscarinic Receptors](/proteins/muscarinic-receptors)
• [M1 Receptor](/proteins/m1-muscarinic-receptor)
• [KarXT](/clinical-trials/nct06947941)
• [Pimavanserin](/therapeutics/pimavanserin)
• [Cholinergic System](/mechanisms/cholinergic-system)
• [Psychosis in Neurodegeneration](/mechanisms/psychosis-neurodegeneration)
• [ACADIA Pharmaceuticals](/companies/acadia-pharmaceuticals)
• [Clinical Trials Overview](/clinical-trials/overview)

Pharmacological Properties of ACP-204

Receptor Binding Profile

ACP-204 is designed as a selective M1 and M4 muscarinic receptor agonist with the following binding characteristics:

M1 Receptor (CHRM1):

• High affinity binding (Ki < 10 nM)
• Agonist activity at central M1 receptors
• [Located in hippocampus, cortex, striatum](/brain-regions/hippocampus)
• [Critical for cognitive function](/genes/nct)

• High affinity binding (Ki < 10 nM)
• [Agonis](/companies/dopamine-d3-d4-selective-agonists)t activity in striatum and limbic regions
• Modulates dopamine release
• Anti-psychotic effects

• M1 > M4 > M2/M3/M5
• Reduced peripheral cholinergic effects
• Designed to minimize cardiovascular effects

Pharmacokinetics

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

• Volume of distribution: 5-10 L/kg
• Brain penetration: Good (logP favorable)
• Protein binding: 80-90%

• Hepatic metabolism primarily via CYP3A4
• Metabolites with reduced activity
• No active metabolites of concern

• Half-life: 12-24 hours
• Renal excretion of metabolites
• Clearance: 30-50 mL/min

Comparison to Other Muscarinic Agonists

| 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 |

Clinical Trial Methodology

Open-Label Extension Design

This 52-week OLE follows participants from prior ACP-204 trials:

Participant Flow:

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)

Assessment Schedule

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)

• Vital signs and weight
• Adverse event collection
• Concomitant medication review
• Efficacy assessments
• Safety laboratory tests periodically

• Comprehensive efficacy assessment
• Safety evaluation
• Physical examination
• Laboratory tests and ECG

Data Management

Source Data Verification:

• Monitoring visits at selected sites
• Query resolution for discrepancies
• Drug accountability verification

• Descriptive statistics for safety
• Change from baseline for efficacy
• Subgroup analyses by prior treatment

Safety Monitoring

Adverse Event Collection

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

• Cognitive changes (MMSE monitoring)
• Cardiovascular events (ECG, vital signs)
• Extrapyramidal symptoms (examination)
• Gastrointestinal effects

Laboratory Monitoring

Hematology:

• Complete blood count at baseline and endpoint
• More frequent if clinically indicated

• Comprehensive metabolic panel at baseline and endpoint
• Liver function tests monitored

• Urinalysis as needed
• Pregnancy testing for women of childbearing potential

ECG Monitoring

Electrocardiograms are performed to assess:

Special Populations

Elderly Patients (≥75 years):

• Enhanced monitoring for cognitive effects
• Cardiovascular surveillance
• Renal function consideration

• Adjusted monitoring based on conditions
• Drug interaction review
• Coordination with other physicians

Efficacy Assessment Details

Neuropsychiatric Inventory (NPI) - Psychosis Domain

The NPI psychosis domain specifically assesses:

Delusions:

• Fixed false beliefs
• Persecutory, grandiose, religious themes
• Frequency and severity rated

• False sensory perceptions
• Visual, auditory, olfactory
• May indicate DLB vs. AD

• Frequency: 1 (occasionally) to 4 (very frequently)
• Severity: 1 (mild) to 3 (marked)
• Domain score: Frequency × Severity (0-12)
• Caregiver distress: 0-5 scale

Clinical Global Impression of Change (CGIC)

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

• Clinician considers all available information
• Caregiver interviews
• Direct patient observation
• Review of other assessments

Mini-Mental State Examination (MMSE)

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

• 30-27: Normal
• 26-24: Mild cognitive impairment
• 23-18: Moderate impairment
• <18: Severe impairment

• Track any cognitive decline
• Distinguish disease progression from drug effect
• Important safety endpoint

ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living)

The ADCS-ADL measures functional abilities:

Domains:

• Basic ADL: Eating, dressing, hygiene
• Instrumental ADL: Cooking, finances, medication management

• 0-78 scale (higher = better function)
• Informant-based (caregiver report)
• Sensitive to change in mild-moderate AD

Statistical Analysis Plan

Sample Size Justification

Enrollment of 752 participants:

• Provides adequate safety database
• Allows subgroup analyses
• Meets regulatory expectations for long-term data

• Not powered for formal hypothesis testing
• Designed to characterize efficacy/safety
• Precision estimates for effect sizes

Efficacy Analyses

Primary Approach:

• Descriptive statistics
• Change from baseline at each visit
• Mean, standard deviation, 95% CI
• Last Observation Carried Forward (LOCF)

• By prior treatment group (active vs. placebo)
• By baseline severity
• By age, gender, disease duration

Safety Analyses

Analyses Planned:

• Treatment-emergent adverse events (TEAEs)
• Serious adverse events (SAEs)
• Discontinuations due to AEs
• Laboratory abnormalities
• Vital sign changes
• ECG changes

• Incidence rates (%)
• Severity assessment
• Relationship to study drug

Regulatory Considerations

Long-Term Safety Database

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

Labeling Implications

OLE data may support:

Post-Marketing Requirements

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

Competitive Positioning

Market Analysis

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

• Off-label antipsychotics dominate
• Limited efficacy, significant side effects
• No FDA-approved agent

• Estimated $2-5 billion potential
• First-mover advantage if approved
• Muscarinic mechanism differentiation

ACP-204 vs. Competition

| 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 |

Strategic Advantages

ACADIA's Position:

• Established CNS expertise from pimavanserin
• Already approved product (Nuplazid)
• Repurposing infrastructure for AD
• Experienced clinical operations team

• Competition from KarXT (BMS resources)
• Need to demonstrate clear advantage
• Market education required

Future Development

Potential Follow-On Studies

Following OLE completion:

Adjacent Indications

The muscarinic mechanism may have utility in:

Other Neuropsychiatric Conditions:

• Schizophrenia (cognitive symptoms)
• Bipolar disorder (manic symptoms)
• Major depression (cognitive aspects)

• Lewy body dementia
• Parkinson's disease psychosis
• Frontotemporal dementia

Combination Approaches

Future trials may explore:

With Anti-Amyloid Therapy:

• Lecanemab or donanemab
• Address multiple aspects of AD
• Sequential or concurrent approaches

• Donepezil, rivastigmine, galantamine
• Complementary mechanisms
• Common combination in practice

References

See Also

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• [Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation](/hypotheses/h-23a3cc07)
• [Ocular Immune Privilege Extension](/hypotheses/h-6a065252)

• [Blood-brain barrier transport mechanisms for antibody therapeutics](/analysis/SDA-2026-04-01-gap-008)
• [Digital biomarkers and AI-driven early detection of neurodegeneration](/analysis/SDA-2026-04-01-gap-012)
• [What are the mechanisms by which gut microbiome dysbiosis influences Parkinson's](/analysis/SDA-2026-04-01-gap-20260401-225155)

• [ER-Golgi Secretory Pathway Dysfunction in PD - Experiment Design](/experiment/exp-wiki-experiments-er-golgi-secretory-pathway-parkinsons)
• [Cytochrome Therapeutics](/experiment/exp-wiki-experiments-lipid-droplet-lysosome-axis-parkinsons)