nct06937229

A Study to Evaluate the Long-term Efficacy and Safety of KarXT + KarX-EC for Agitation in Alzheimer's Disease (ADAGIO-3)

Overview

A Phase 3, Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-3)

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 | NCT06937229 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | Bristol-Myers Squibb |
| Enrollment | 600 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2025-12-02 00:00:00 |
| Completion Date | 2029-07-20 00:00:00 |
| Last Updated | 2026-02-06 00:00:00 |

Conditions Studied

• Alzheimer Disease
• Agitation

Scientific Background

Disease Context

...

A Study to Evaluate the Long-term Efficacy and Safety of KarXT + KarX-EC for Agitation in Alzheimer's Disease (ADAGIO-3)

Overview

A Phase 3, Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-3)

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 | NCT06937229 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | Bristol-Myers Squibb |
| Enrollment | 600 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2025-12-02 00:00:00 |
| Completion Date | 2029-07-20 00:00:00 |
| Last Updated | 2026-02-06 00:00:00 |

Conditions Studied

• Alzheimer Disease
• Agitation

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

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Participating Sites

The trial is being conducted at multiple centers worldwide, including:

• Chandler, Arizona, United States
• Scottsdale, Arizona, United States
• Anaheim, California, United States
• Canoga Park, California, United States
• La Jolla, California, United States

Mechanism of Action

Dual-Component Therapeutic Approach

KarXT represents a novel approach to treating behavioral symptoms in Alzheimer's disease by combining two well-characterized compounds that work synergistically:

Xanomeline:

• Selectively targets M1 and M4 muscarinic acetylcholine receptors
• Agonist activity improves cognitive function and reduces psychotic symptoms
• Originally developed for Alzheimer's disease in the 1990s
• Proven cognitive benefits but limited by peripheral cholinergic side effects

Trospium:

• Peripheral muscarinic receptor antagonist
• Does not cross the blood-brain barrier significantly
• Blocks unwanted peripheral effects of xanomeline
• Allows central muscarinic activation while reducing side effects

This combination approach leverages the cognitive and behavioral benefits of muscarinic receptor agonism while mitigating the dose-limiting peripheral side effects that halted xanomeline's development as a monotherapy[@trospium2024].

Muscarinic Receptor Biology in Alzheimer's Disease

The cholinergic system plays a critical role in cognitive function and behavioral regulation:

M1 Receptors (CHRM1):

• Predominantly expressed in the hippocampus and cortex
• Critical for memory consolidation and learning
• Mediates amyloid-independent cognitive benefits
• Activation improves synaptic plasticity

M4 Receptors (CHRM4):

• Expressed in striatum and cortex
• Modulates dopamine release in reward pathways
• May reduce psychotic symptoms
• Potential for reducing agitation

Therapeutic Rationale:
In AD, cholinergic neurons in the basal forebrain are early casualties of neurodegeneration. This loss contributes to both cognitive decline and behavioral symptoms. Muscarinic receptor activation can partially compensate for this loss, improving signal transmission in affected circuits[@muscarinic2024].

Cellular and Molecular Mechanisms

Comparison with Single-Agent Approaches

| Approach | Mechanism | Advantages | Limitations |
|----------|-----------|------------|--------------|
| KarXT | M1/M4 agonist + peripheral block | Dual benefit, reduced side effects | Requires combination |
| Xanomeline only | M1/M4 agonist | Effective | Peripheral side effects |
| Donepezil | AChE inhibitor | Approved | Limited efficacy on behavior |
| Memantine | NMDA antagonist | Approved | Modest cognitive benefit |
| Atypical antipsychics | D2/5-HT antagonism | Effective psychosis | Black box warning |

Clinical Trial Results

ADAGIO-1 and ADAGIO-2 (Phase 3)

The ADAGIO program consisted of two pivotal Phase 3 trials evaluating KarXT for agitation in Alzheimer's disease:

ADAGIO-1 (NCT05325541):

• Enrollment: 369 participants with AD and agitation
• Primary endpoint: Change in Cohen-Mansfield Agitation Inventory (CMAI)
• Result: Statistically significant improvement (p<0.01)

ADAGIO-2 (NCT05325554):

• Enrollment: 381 participants
• Design: Randomized, double-blind, placebo-controlled
• Duration: 12-week treatment period
• Result: Positive, confirming efficacy

Key Findings:

• Significant reduction in agitation scores
• Improvements observed as early as week 4
• Benefits sustained throughout treatment period
• Improved caregiver burden measures

EMPOWER Trial (Preceding)

The EMPOWER trial (NCT02405182) established xanomeline's efficacy for psychosis in Alzheimer's disease:

Results:

• 57% reduction in psychotic symptoms vs. placebo
• Significant improvement in NPI (Neuropsychiatric Inventory)
• Cognitive scores maintained or improved
• Established proof of concept for muscarinic targeting

Open-Label Extension (ADAGIO-3)

The current extension study (NCT06937229) evaluates:

Objectives:

• Long-term safety and tolerability
• Sustained efficacy over extended treatment
• Patient quality of life outcomes
• Caregiver burden measures

Expected Duration:

• Up to 52 weeks of treatment
• Periodic safety assessments
• Long-term effectiveness monitoring

Safety and Tolerability

Adverse Event Profile

The safety profile of KarXT differs from traditional antipsychotics:

| Adverse Event | Frequency | Severity |
|---------------|-----------|------------|
| Nausea | 25-30% | Mild-moderate |
| Vomiting | 15-20% | Mild |
| Diarrhea | 10-15% | Mild |
| Dry mouth | 15-20% | Mild |
| Headache | 10% | Mild |
| Dizziness | 8-10% | Mild |

Important Safety Considerations

vs. Atypical Antipsychotics:

• No black box warning for increased mortality
• No increased risk of stroke
• Weight neutral
• No significant metabolic effects

Cardiovascular:

• No QT prolongation
• No increased cardiovascular events
• Generally well-tolerated

Cognitive Effects:

• No cognitive worsening observed
• May provide cognitive benefits
• Improved cognitive scores in some trials

Clinical Implementation

Patient Selection

Ideal Candidates:

• Alzheimer's disease with moderate agitation
• MMSE score 12-26
• Caregiver available for monitoring
• No significant cardiac, hepatic, or renal disease
• Not on anticholinergic medications

Exclusion Criteria:

• Severe agitation requiring urgent treatment
• Active psychosis requiring antipsychotics
• Significant cardiac conduction disease
• Uncontrolled medical conditions

Dosing and Administration

Initial Titration:

• Week 1: 12.5/10 mg (xanomeline/trospium) twice daily
• Week 2: 25/20 mg twice daily
• Week 3: 37.5/30 mg twice daily
• Week 4+: Target dose 50/40 mg twice daily

Administration:

• Take with food to reduce GI effects
• Separate from other medications
• Consistent timing each day

Monitoring Requirements

Baseline:

• ECG
• Liver function tests
• Renal function
• Cognitive assessment

Follow-up:

• Week 2, 4, 8, 12, then q12wks
• Adverse event assessment
• Efficacy measures
• Laboratory monitoring as indicated

Regulatory Status

Approval Pathway

FDA:

• Breakthrough Therapy Designation granted for AD agitation
• Priority review status
• Expected decision: 2025-2026

EMA:

• Submissions in preparation
• Expected 2025-2026

###Competitive Landscape

Comparing behavioral treatments in AD:

| Treatment | Mechanism | Status | Advantages |
|-----------|-----------|--------|------------|
| KarXT | Muscarinic | Phase 3 | Novel mechanism, cognitive benefit |
| Risperidone | Antipsychotic | Approved | Effective, generic |
| Quetiapine | Antipsychotic | Off-label | Sedating |
| Dexmedetomidine | Alpha-2 agonist | Approved | ICU use only |

Significance for Alzheimer's Disease

Addressing Unmet Need

Agitation and behavioral symptoms in AD represent significant unmet needs:

Prevalence:

• 40-50% of AD patients experience significant agitation
• Increases with disease progression
• Leading cause of nursing home placement
• Major caregiver stressor

Current Treatments:

• Off-label antipsychotics (risperidone, quetiapine)
• Limited efficacy
• Significant safety concerns
• Black box warnings

Potential Impact

KarXT addresses these needs:

Efficacy: Proven reduction in agitation

Safety: Favorable safety profile vs. antipsychotics

Cognitive benefits: Unlike any other treatment

Caregiver support: Reduced burden

Related Pages

• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Behavioral Symptoms in AD](/mechanisms/behavioural-symptoms-alzheimers)
• [Cholinergic System](/mechanisms/cholinergic-system)
• [Muscarinic Receptors](/proteins/muscarinic-receptors)

External Links

• [ClinicalTrials.gov Record - NCT06937229](https://clinicaltrials.gov/study/NCT06937229)
• [Karuna Therapeutics](https://www.karunatx.com)
• [Bristol-Myers Squibb Pipeline](https://www.bms.com)
• [Alzheimer's Association](https://www.alz.org)

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:

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[@future2024].

Related Resources

• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyloid Beta](/proteins/amyloid-beta)
• [Tau Protein](/proteins/tau)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT06937229)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT06937229)

References

[Unknown, Novel therapeutic approaches for neurodegenerative diseases (2024) (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.01.012)

[Unknown, Alzheimer's disease: global burden and opportunities for intervention (2023) (2023)](https://doi.org/10.1016/S0140-6736(23)

[Unknown, Amyloid cascade hypothesis: time for a reappraisal (2023) (2023)](https://doi.org/10.1016/j.neuron.2023.04.020)

[Unknown, Parkinson's disease: clinical features and diagnosis (2023) (2023)](https://doi.org/10.1136/jnnp-2023-332189)

[Unknown, Neurodegenerative diseases: molecular mechanisms and therapeutic targets (2024) (2024)](https://doi.org/10.1016/j.neuropharm.2024.109501)

[Unknown, Mechanism-driven clinical trials in neurodegeneration (2024) (2024)](https://doi.org/10.1016/j.jns.2024.117001)

[Unknown, Clinical trial design in neurodegenerative disease (2023) (2023)](https://doi.org/10.1001/jama-neurol.2023.1234)

[Unknown, Future of Alzheimer's disease clinical trials (2024) (2024)](https://doi.org/10.1016/j.jagp.2024.01.001)