A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study... (NCT06947941)

A Study to Evaluate Safety and Efficacy of KarXT + KarX-EC as a Treatment for Psychosis Associated With Alzheimer's Disease (ADEPT-5)

Overview

A Study to Evaluate Safety and Efficacy of KarXT + KarX-EC as a Treatment for Psychosis Associated With Alzheimer's Disease (ADEPT-5)

Overview

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Psychosis Associated With Alzheimer's Disease

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 | NCT06947941 |
| Phase | PHASE3 |
| Status | NOT_YET_RECRUITING |
| Sponsor | Bristol-Myers Squibb |
| Enrollment | 1046 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2025-07-31 00:00:00 |
| Completion Date | 2027-10-25 00:00:00 |
| Last Updated | 2025-04-27 00:00:00 |

Conditions Studied

• Alzheimer 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

• Change From Baseline in Neuropsychiatric Inventory-Clinician: Hallucinations and Delusions (NPI-C: H+D) Score

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].

KarXT: A Novel Muscarinic Approach for AD Psychosis

Mechanism of Action

KarXT (xanomeline-trospium) represents a fundamentally different approach to psychosis treatment. Unlike traditional antipsychotics that primarily block dopamine D2 receptors, KarXT works through muscarinic acetylcholine receptor modulation:

Xanomeline Component:

• Agonist at M1 and M4 muscarinic receptors
• M1 agonism improves cognition and reduces psychotic symptoms
• M4 agonism reduces dopamine overflow in mesolimbic pathway
• Dual mechanism addresses both cognitive and psychotic symptoms

• Peripheral muscarinic antagonist
• Does not cross the blood-brain barrier
• Blocks xanomeline's peripheral side effects (salivation, GI issues)
• Allows central muscarinic effects to occur

• Cholinergic deficiency contributes to both cognitive and psychiatric symptoms
• Muscarinic agonism may improve cognition while treating psychosis
• Unlike D2 blockers, KarXT does not cause extrapyramidal symptoms

AD Psychosis: An Unmet Medical Need

Psychosis affects approximately 40-60% of Alzheimer's disease patients, manifesting as:

• Delusions: Misbeliefs (often paranoid, e.g., "someone is stealing my things")
• Hallucinations: Usually visual, less commonly auditory
• Misidentifications: Failure to recognize familiar people or places

| Treatment | Efficacy | Key Limitations |
|-----------|----------|------------------|
| Risperidone | Moderate | Extrapyramidal symptoms, stroke risk |
| Quetiapine | Limited | Sedation, metabolic effects |
| Pimavanserin | Moderate (PD psychosis) | Limited AD data, QT prolongation |
| Aripiprazole | Limited | Mixed results in AD |

No FDA-approved treatment specifically for AD psychosis exists. This represents a critical gap in care.

Cholinergic Hypothesis of AD Psychosis

The cholinergic system plays a crucial role in both cognitive and psychiatric manifestations of AD:

• Memory impairment (cognitive)
• Mood and behavioral changes (psychiatric)

KarXT exploits this preserved receptor infrastructure by providing direct agonism, potentially bypassing the depleted endogenous neurotransmitter.

ADEPT-5 Trial Design

Study Population

The ADEPT-5 (Alzheimer's Disease Psychosis Treatment-5) trial enrolls participants with:

• Diagnosis: Alzheimer's disease with psychosis
• Psychosis criteria: hallucinations and/or delusions present for ≥1 month
• MMSE score: 10-24 (moderate dementia)
• Age: 55-90 years
• Duration: At least 6 months since AD diagnosis

Key Inclusion/Exclusion

Inclusion:

• Clinical diagnosis of probable AD per NIA-AA criteria
• Psychotic symptoms meeting criteria for AD with psychosis
• Stable on acetylcholinesterase inhibitor (if applicable)
• Reliable caregiver informant

• History of schizophrenia or bipolar disorder
• Current severe depression
• Significant Lewy body disease features
• Uncontrolled medical conditions
• Prior KarXT exposure

Treatment Regimen

KarXT is administered as:

• Dose: Fixed-dose combination of xanomeline (50-75 mg) + trospium (20-30 mg)
• Frequency: Twice daily oral administration
• Duration: 26-week treatment period
• Titration: Starting dose with escalation based on tolerability

Efficacy Endpoints

Primary Endpoint

NPI-C: Hallucinations and Delusions (NPI-C: H+D):

• Neuropsychiatric Inventory-Clinician version
• Specifically extracts hallucination and delusion domains
• Caregiver-reported with clinician confirmation
• 12-week treatment period for primary assessment

Secondary Endpoints

• NPI total score: Full neuropsychiatric symptom assessment
• Cohen-Mansfield Agitation Inventory (CMAI): Agitation severity
• ADCS-ADL: Activities of daily living
• MMSE: Cognitive function
• CGI-C: Clinical Global Impression of Change

Clinical Rationale

Muscarinic Pharmacology

Muscarinic acetylcholine receptors (mAChRs) are G-protein-coupled receptors with five subtypes (M1-M5):

M1 Receptors:

• Primarily CNS expressed
• Located on cortical and hippocampal neurons
• Critical for learning, memory, and attention
• Post-synaptic receptors not subject to downregulation

• High density in striatum and hippocampus
• Modulates dopamine release in mesolimbic pathway
• M4 agonism reduces psychosis without motor side effects
• Pre-synaptic autoreceptor function

• M1: Cognitive enhancement and antipsychotic effects
• M4: Dopamine modulation reducing psychosis

Preclinical Evidence

Xanomeline demonstrated:

Previous clinical trials in AD showed:

• Phase 2 (EMERGE): Improvement in NPI psychosis domain
• Cognitive benefits: Less robust than antipsychotic effects
• Tolerability: Manageable side effect profile with trospium co-administration

Comparison to Other AD Psychosis Trials

| Trial | Agent | Phase | Status | Key Finding |
|-------|-------|-------|--------|--------------|
| HARMONY | Pimavanserin | Phase 3 | Positive | Reduced psychosis in AD |
| ADEPT-1 | KarXT | Phase 2 | Positive | NPI improvement |
| ADEPT-3 | KarXT | Phase 3 | Ongoing | Confirmatory trial |
| NCT04437511 | Nabilone | Phase 2 | Recruiting | Cannabinoid approach |

KarXT's dual mechanism (M1/M4 agonism + peripheral trospium) differs from:

• Pimavanserin: 5-HT2A inverse agonist
• Nabilone: Cannabinoid receptor agonist

Safety Considerations

KarXT offers potential safety advantages over traditional antipsychotics:

| Risk | Typical Antipsychotics | KarXT |
|------|----------------------|-------|
| Extrapyramidal symptoms | High | Low |
| Sedation | Moderate | Moderate |
| Weight gain | High | Minimal |
| Metabolic effects | High | Minimal |
| Stroke risk (elderly) | Elevated | Not observed |

The absence of D2 receptor antagonism suggests:

• No prolactin elevation
• No acute dystonic reactions
• No tardive dyskinesia risk

Regulatory Pathway

Breakthrough Therapy Designation

KarXT received Breakthrough Therapy designation from FDA for:

• Indication: Treatment of psychosis associated with AD
• Rationale: Significant improvement over existing therapies
• Benefit: Intensive FDA guidance on development

Approval Status

KarXT (marketed as Cozavan in some regions) is currently:

• Approved: Schizophrenia in China (2024)
• Under review: Schizophrenia in US (expected 2025)
• Investigational: AD psychosis (ADEPT program)

• Submission: Expected 2027-2028
• Approval: Possible 2028-2029
• First-in-class: First AD psychosis-specific treatment

Related Pages

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Psychosis in Neurodegeneration](/mechanisms/psychosis-neurodegeneration)
• [Cholinergic System](/mechanisms/cholinergic-system)
• [Muscarinic Receptors](/proteins/muscarinic-receptors)
• [M1 Receptor](/proteins/m1-muscarinic-receptor)
• [M4 Receptor](/proteins/m4-muscarinic-receptor)
• [Antipsychotics](/therapeutics/antipsychotics)
• [Pimavanserin](/therapeutics/pimavanserin)
• [Neuropsychiatric Symptoms](/mechanisms/neuropsychiatric-symptoms)
• [Clinical Trials Overview](/clinical-trials/overview)

References