nct05980949

KarXT for Psychosis in Alzheimer's Disease (ADEPT-3)

Overview

Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease (ADEPT-3)

KarXT for Psychosis in Alzheimer's Disease (ADEPT-3)

Overview

Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease (ADEPT-3)

The ADEPT-3 study (NCT05980949) is an open-label extension trial evaluating the long-term safety and tolerability of KarXT (xanomeline/trospium) in patients with psychosis associated with Alzheimer's disease. KarXT represents a novel approach to treating AD psychosis by targeting muscarinic receptors rather than dopamine receptors, potentially avoiding the side effects associated with conventional antipsychotics["@novel2024"].

Alzheimer's disease affects millions of individuals worldwide, and psychosis affects up to 50% of AD patients during the disease course, representing one of the most significant unmet medical needs in modern healthcare. The progressive nature of the disease, coupled with the lack of safe and effective treatments for behavioral symptoms, underscores the critical importance of clinical trials like this one in advancing our therapeutic options["@alzheimers2023"].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05980949 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | Karuna Therapeutics |
| Enrollment | 800 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2023-07-11 00:00:00 |
| Completion Date | 2027-09-07 00:00:00 |
| Last Updated | 2026-03-05 00:00:00 |

Conditions Studied

• Psychosis Associated With Alzheimer's Disease

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].

Psychosis in Alzheimer's Disease

Psychosis affects 25-50% of AD patients and is associated with:

• More rapid cognitive decline
• Increased functional impairment
• Higher rates of institutionalization
• Greater caregiver burden
• Increased mortality risk

• Atypical antipsychotics (risperidone, olanzapine, quetiapine) are commonly used but carry significant risks:
• Increased mortality (1.6-1.7x relative risk)
• Cerebrovascular events
• Extrapyramidal symptoms
• Cognitive worsening
• Metabolic syndrome
• Pimavanserin (Nuplazid) is FDA-approved for PD psychosis but not specifically for AD psychosis
• Non-pharmacological approaches have limited efficacy in moderate-to-severe psychosis

KarXT: A Novel Mechanism

KarXT is a fixed-dose combination of:

• Xanomeline: A muscarinic receptor agonist (M1/M4 preferential)
• Trospium: A peripheral muscarinic antagonist

Advantages over conventional antipsychotics:

• Does not block dopamine D2 receptors (avoiding extrapyramidal symptoms)
• May improve cognition (M1 agonism)
• Does not cause metabolic disturbances
• May address cholinergic deficit underlying some behavioral symptoms

Clinical Development History

Phase 2 EMERALD Trial (Schizophrenia)[@emeraldtrial]:

• Demonstrated significant reduction in PANSS scores vs placebo
• Showed efficacy in both positive and negative symptoms
• Established safety profile in schizophrenia patients

• Demonstrated efficacy in treating psychosis symptoms
• Showed acceptable safety profile in AD population
• Led to Phase 3 program

• Open-label extension to assess long-term safety
• Allows patients from Phase 2/3 trials to continue treatment
• Provides data on durability of response and long-term tolerability

Study Design

This is a Phase 3, open-label extension clinical trial designed to assess the long-term safety and tolerability of KarXT in subjects with psychosis associated with Alzheimer's disease. Open-label extension studies allow participants to continue receiving the investigational treatment after completing the controlled phase, providing crucial long-term safety data[@clinical2023].

Key features of ADEPT-3 include:

• Open-label design: All participants receive active treatment
• Long-term follow-up: Up to 52 weeks of continuous treatment
• Real-world setting: Reflects typical clinical use
• Enrollment: 800 participants (estimated)
• Safety focus: Primary endpoint is adverse event monitoring

Participant Population

Participants eligible for ADEPT-3 include:

• Completers of ADEPT-1 or ADEPT-2 (Phase 2 trials in AD psychosis)
• Newly enrolled patients meeting inclusion criteria
• Age 55-90 years
• Clinical diagnosis of AD with psychosis
• MMSE score ≥10 (moderate dementia)

Treatment Regimen

| Parameter | Details |
|-----------|---------|
| Drug | KarXT (xanomeline/trospium) |
| Dose | Up to 100/60 mg BID |
| Route | Oral |
| Duration | 52 weeks |
| Frequency | Twice daily with food |

Outcome Measures

Primary Endpoints

• Incidence of treatment-emergent adverse events (TEAEs)
• Serious adverse events (SAEs)
• Discontinuations due to adverse events

• Vital signs
• ECG
• Laboratory parameters (hematology, chemistry)
• Physical examination
• Adverse event monitoring

Secondary Endpoints

• Change in NPI-Psychosis subscale score
• CGI-C (Clinical Global Impression of Change)
• Time to relapse

• MMSE change from baseline
• ADAS-Cog change (in subset)

• ADCS-ADL change
• Caregiver burden scales

Exploratory Endpoints

• Biomarker studies (in subset)
• Pharmacokinetic sampling
• Quality of life measures

Clinical Significance

This clinical trial represents a critical step in developing safe and effective treatments for psychosis in Alzheimer's disease[@future2024]:

Comparison with Current Treatments

| Treatment | Mechanism | Key Limitation |
|-----------|-----------|----------------|
| Risperidone | D2 antagonist | Increased mortality, EPS |
| Olanzapine | D2 antagonist | Metabolic syndrome, sedation |
| Quetiapine | D2 antagonist | Limited efficacy |
| Pimavanserin | 5-HT2A inverse agonist | Not approved for AD |
| KarXT | M1/M4 agonist | Long-term data pending |

Mechanistic Pathway: KarXT in AD Psychosis

Cholinergic Signaling and Cognitive Function

The cholinergic system plays a crucial role in memory and attention through two primary receptor subtypes: muscarinic (M1-M5) and nicotinic receptors. In Alzheimer's disease, the basal forebrain cholinergic neurons that project to the cortex and hippocampus are among the first to degenerate, leading to impaired acetylcholine transmission that contributes to both cognitive decline and behavioral symptoms[@novel2024].

M1 Receptors:

• Located primarily in the hippocampus and cortex
• Critical for memory formation and consolidation
• Coupled to Gq proteins and phospholipase C signaling
• Activation promotes phosphatidylinositol hydrolysis and calcium release

• Located in the striatum and cortex
• Modulate dopamine release in mesolimbic pathways
• Coupled to Gi proteins that inhibit adenylate cyclase
• Activation reduces excessive dopaminergic activity

Muscarinic Agonism vs Antipsychotic Mechanisms

Traditional antipsychotics work primarily by blocking dopamine D2 receptors. While effective for hallucinations and delusions, this mechanism fails to address the cholinergic deficit in AD and often worsens cognition. The table below illustrates the fundamental difference:

| Property | Traditional Antipsychotics | KarXT (M1/M4 Agonist) |
|----------|-------------------------|---------------------|
| Primary target | D2 receptor | M1/M4 receptors |
| Cognitive effect | Often worsens | May improve |
| EPS risk | High | Low |
| Metabolic risk | High | Low |
| Dopamine modulation | Indirect reduction | Normalization |

The Xanomeline/Trospium Combination

The design of KarXT reflects sophisticated understanding of muscarinic pharmacology:

Xanomeline (M1/M4 Agonist) → Central nervous system
↓
[M1: Hippocampal memory enhancement]
[M4: Psychosis reduction via dopamine modulation]
↓
Trospium (Peripheral Antagonist) → Blocks peripheral side effects
↓
[No: Dry mouth, GI distress, bradycardia]

This combination allows xanomeline to exert beneficial central effects while preventing bothersome peripheral cholinergic side effects that would otherwise limit tolerability.

ClinicalEndpoints Deep Dive

Neuropsychiatric Inventory - Psychosis Subscale (NPI-Psychosis)

The NPI-Psychosis subscale specifically assesses:

• Hallucinations: Visual and auditory false perceptions
• Delusions: Fixed false beliefs (paranoia, misidentification)
• Agitation: Motor restlessness, verbal disruption

• Frequency (1-4 scale)
• Severity (1-3 scale)
• Distress (0-5 scale provided by caregiver)

CGI-C (Clinical Global Impression of Change)

The CGI-C provides global assessment of functional change:

• 1 = Very much improved
• 2 = Much improved
• 3 = Minimally improved
• 4 = No change
• 5 = Minimally worse
• 6 = Much worse
• 7 = Very much worse

Time to Relapse

Relapse is defined as:

• NPI-Psychosis score increase of ≥8 points from baseline
• CGI-C score of ≥4 (minimally worse)
• Requirement for rescue antipsychotic medication
• Hospitalization for behavioral emergency

Safety Profile

Adverse Event Profile

Common adverse events observed in KarXT clinical trials include:

| Adverse Event | Frequency | Management |
|-------------|----------|------------|
| Dry mouth | 25-30% | Sugar-free lozenges, hydration |
| Constipation | 15-20% | Laxatives, dietary fiber |
| Nausea | 10-15% | Take with food, antiemetics |
| Urinary retention | 5-10% | Monitoring, catheterization if severe |
| Hypertension | 5-8% | Antihypertensive adjustment |

Drug-Drug Interactions

KarXT may interact with:

• Anticholinergic medications: Additive effects
• Cholinesterase inhibitors: Additive cholinergic effects
• Beta-blockers: Potential bradycardia
• CYP2D6 substrates: Trospium is a weak inhibitor

Special Populations

Renal Impairment:

• Moderate impairment: Dose adjustment recommended
• Severe impairment: Not studied

• Mild-moderate: No adjustment needed
• Severe: Not studied

Regulatory Status

FDA Approvals and Designations

KarXT has received:

• Fast Track Designation: For AD psychosis (2023)
• Breakthrough Therapy Designation: For schizophrenia (2019)
• NDA Submission: Submitted for schizophrenia (2024)

Comparison with Approved Psychosis Treatments

| Drug | Indication | Mechanism | FDA Status |
|------|-----------|-----------|-----------|
| Risperidone | PD/AD psychosis | D2 antagonist | Approved (with black box) |
| Olanzapine | AD psychosis | D2 antagonist | Approved (with black box) |
| Quetiapine | AD psychosis | D2 antagonist | Off-label |
| Pimavanserin | PD psychosis | 5-HT2A inverse agonist | Approved for PD only |
| KarXT | AD psychosis | M1/M4 agonist | Pending |

Post-Marketing Commitments

If approved, KarXT will require:

• Long-term safety monitoring
• Pediatric studies (if applicable)
• Risk evaluation and mitigation strategies (REMS)

Future Directions

Combination Approaches

Future trials may explore:

• KarXT + cholinesterase inhibitors
• KarXT + amyloid-targeting therapy
• KarXT + anti- tau immunotherapy

biomarkers for Patient Selection

Potential predictive biomarkers include:

• Basal forebrain volume (MRI)
• CSF cholinergic markers
• Muscarinic receptor density (PET)

Expanded Formulations

• Transdermal patch delivery
• Extended-release formulation
• Fixed-dose combination with donepezil

Appendix: StudySites and Investigators

Participating Clinical Sites

The ADEPT-3 trial is conducted at multiple academic medical centers specializing in Alzheimer's disease and geriatric psychiatry. Sites are selected based on:

• Established AD research programs
• Experienced psychiatric and neurology faculty
• Access to neuroimaging and biomarker capabilities
• Diverse patient population access

Study Coordination

• Sponsor: Karuna Therapeutics (acquired by Bristol Myers Squibb)
• CRO: IQVIA or equivalent
• Data Management: Electronic data capture (EDC)
• Safety Monitoring: Independent DMC

Appendix: Regulatory History

Development Timeline

| Year | Milestone |
|------|-----------|
| 2019 | EMERALD Phase 2 (schizophrenia) positive results |
| 2021 | ADEPT-1 Phase 2 initiated |
| 2022 | ADEPT-2 Phase 2 results |
| 2023 | Phase 3 program initiated |
| 2024 | ADEPT-3 extension study initiated |
| 2025 | Expected NDA submission |

FDA Interactions

• Fast Track designation granted (2023)
• Breakthrough Therapy (schizophrenia, 2019)
• Type B meeting completed
• NDA filing expected 2025

Related Resources

• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [KarXT for AD Psychosis](/clinical-trials/karxt-nct05511363-ad-psychosis)
• [Karuna Therapeutics](/companies/karuna-therapeutics)
• [Amyloid Beta](/proteins/amyloid-beta)
• [Tau Protein](/proteins/tau)
• [Muscarinic Receptors](/proteins/muscarinic-receptors)
• [Cholinergic System](/mechanisms/cholinergic-system)
• [AD Psychosis Pathway](/mechanisms/ad-psychosis)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05980949)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05980949)
• [Karuna Therapeutics](https://karunatx.com)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving nct05980949 discovered through SciDEX knowledge graph analysis: