A Multicenter, Phase III, Randomized, Double Blind, Placebo-Controlled Study ... (NCT05143528)

Migration, Crosslink

📖

A Multicenter, Phase III, Randomized, Double Blind, Placebo-Controlled Study ... (NCT05143528)

active

wiki page Created: 2026-04-02T07:19:03 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-clinical-trials-nct05143528

📖 Wiki Page

clinical2564 wordssynced 2026-04-02

Nilotinib BE for Early Alzheimer's Disease (NILEAD)

Overview

flowchart TD A_Multicenter__Phase_III__Rand["A Multicenter, Phase III, Randomized, Double Bli"] -->|"references"| ULK1["ULK1"] A_Multicenter__Phase_III__Rand["A Multicenter, Phase III, Randomized, Double Bli"] -->|"references"| HDAC["HDAC"] style A_Multicenter__Phase_III__Rand fill:#4fc3f7,stroke:#333,color:#000

A Multicenter, Phase III, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Nilotinib BE in Subjects With Early Alzheimer's Disease (NILEAD)

The NILEAD trial represents a significant advancement in therapeutic development for Alzheimer's disease by investigating nilotinib, a tyrosine kinase inhibitor originally approved for chronic myeloid leukemia, in the context of Alzheimer's disease pathology. This study leverages the growing understanding of the role played by the c-Abl (Abelson tyrosine kinase) pathway in neurodegenerative processes["@novel2024"].

Alzheimer's disease affects approximately 50 million people 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. Despite significant advances in understanding AD pathophysiology, there remain no approved disease-modifying therapies that can halt or reverse the underlying neurodegenerative process["@alzheimers2023"].

Trial Details

...

Nilotinib BE for Early Alzheimer's Disease (NILEAD)

Overview

Mermaid diagram (expand to render)

A Multicenter, Phase III, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Nilotinib BE in Subjects With Early Alzheimer's Disease (NILEAD)

The NILEAD trial represents a significant advancement in therapeutic development for Alzheimer's disease by investigating nilotinib, a tyrosine kinase inhibitor originally approved for chronic myeloid leukemia, in the context of Alzheimer's disease pathology. This study leverages the growing understanding of the role played by the c-Abl (Abelson tyrosine kinase) pathway in neurodegenerative processes["@novel2024"].

Alzheimer's disease affects approximately 50 million people 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. Despite significant advances in understanding AD pathophysiology, there remain no approved disease-modifying therapies that can halt or reverse the underlying neurodegenerative process["@alzheimers2023"].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05143528 |
| Phase | PHASE3 |
| Status | NOT_YET_RECRUITING |
| Sponsor | KeifeRx, LLC |
| Enrollment | 1275 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2022-02-01 00:00:00 |
| Completion Date | 2026-06-01 00:00:00 |
| Last Updated | 2021-12-03 00:00:00 |

Conditions Studied

Alzheimer 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].

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].

c-Abl Activation in Alzheimer's Disease

The c-Abl (Abelson tyrosine kinase) pathway represents an emerging therapeutic target in Alzheimer's disease. Originally studied primarily in the context of cancer biology and Parkinson's disease, recent research has demonstrated that c-Abl is also activated in AD brains and contributes to disease pathogenesis through several mechanisms:

Amyloid-Beta Toxicity: c-Abl is activated by amyloid-beta exposure in neurons, creating a vicious cycle where Aβ promotes c-Abl activation, which in turn exacerbates neuronal dysfunction. This activation contributes to synaptic toxicity and impaired neuronal survival[@hebron2013].

Tau Pathology: c-Abl phosphorylates tau protein at multiple tyrosine residues, potentially promoting tau aggregation and the formation of neurofibrillary tangles. This represents a direct link between c-Abl activation and one of the core pathological hallmarks of AD.

Autophagy Dysfunction: c-Abl hyperactivation impairs autophagy, the cellular recycling process responsible for clearing damaged proteins and organelles. This impairment contributes to the accumulation of toxic protein aggregates, including amyloid-beta and tau[@karim2021].

Synaptic Dysfunction: c-Abl activation disrupts synaptic plasticity and function, contributing to the cognitive decline characteristic of AD. The kinase affects NMDA receptor signaling and dendritic spine morphology.

Nilotinib: Repurposing a Cancer Drug for Neurodegeneration

Nilotinib (Tasigna) is a BCR-Abl tyrosine kinase inhibitor originally developed and approved for the treatment of chronic myeloid leukemia (CML). The drug potently inhibits c-Abl at concentrations significantly lower than those used in oncology, making it suitable for CNS applications[@pagan2020].

Mechanisms of Action in AD:

c-Abl Inhibition: Nilotinib directly inhibits c-Abl kinase activity, reducing tyrosine phosphorylation of substrates involved in neurodegeneration

Autophagy Enhancement: By inhibiting c-Abl, nilotinib promotes autophagy-mediated clearance of toxic proteins including amyloid-beta and tau[@tunc2022]

Mitochondrial Protection: c-Abl inhibition preserves mitochondrial function and reduces oxidative stress

Neuroinflammation Modulation: Nilotinib reduces microglial activation and pro-inflammatory cytokine release

Clinical Development History:

Phase 1/2 studies in Parkinson's disease demonstrated safety and tolerability at doses of 150-300mg daily (significantly lower than the 400-600mg daily dose used in CML)
CSF biomarker studies showed reductions in alpha-synuclein and neurofilament light chain (NfL) in PD patients[@pagan2020]
The successful safety profile in Parkinson's disease has enabled expansion into AD

Therapeutic Rationale for NILEAD

The NILEAD trial tests the hypothesis that nilotinib can slow disease progression in early AD by:

Reducing c-Abl-mediated neurodegeneration

Enhancing clearance of amyloid-beta and tau through autophagy

Protecting synaptic function

Modulating neuroinflammation

This represents a disease-modifying approach that targets a fundamentally different pathway than amyloid-targeting antibodies currently in development.

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 in a 1:1 ratio
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
Duration: 72-week treatment period (approximately 18 months)

Inclusion Criteria

Key inclusion criteria for NILEAD:

Age 60-85 years
Clinical diagnosis of early Alzheimer's disease (MCI due to AD or mild dementia due to AD)
Confirmed amyloid pathology via PET scan or CSF biomarkers
MMSE score of 20-28 (mild cognitive impairment to mild dementia)
Stable on cholinesterase inhibitor medication if already taking
Caregiver available to accompany to visits

Exclusion Criteria

Key exclusion criteria:

Advanced AD (MMSE <20)
Significant psychiatric comorbidity (severe depression, schizophrenia)
History of stroke or significant cerebrovascular disease
Active cancer or cancer within past 5 years
Significant cardiac, hepatic, or renal dysfunction
Prior treatment with nilotinib or other tyrosine kinase inhibitors

Randomization and Blinding

Participants are randomized using a centralized interactive web response system (IWRS) to ensure allocation concealment. The randomization schedule is stratified by baseline disease severity (MCI vs mild dementia) and apolipoprotein E (ApoE) ε4 carrier status to ensure balanced distribution of these prognostic factors across treatment arms.

Outcome Measures

Primary Endpoints

Changes From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 72 [ Time Frame: Baseline, Week 72]

The CDR-SB is a validated global measure of dementia severity that assesses cognitive and functional performance across six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. A higher score indicates greater impairment, and a change of 0.5-1.0 points is considered clinically meaningful in AD trials[@clinical2023].

Secondary Endpoints

ADAS-Cog14 (Alzheimer's Disease Assessment Scale - Cognitive Subscale) at Week 72

Measures memory, language, praxis, and executive function
Sensitive to changes in early AD

ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) at Week 72

Assesses functional abilities in daily activities
Includes both basic and instrumental ADL

Neuropsychiatric Inventory (NPI) at Week 72

Evaluates behavioral and psychological symptoms of dementia
Assesses agitation, depression, anxiety, and other neuropsychiatric features

CSF Biomarkers (in subset of participants)

Amyloid-beta 40 and 42 levels
Total tau and phosphorylated tau
Neurofilament light chain (NfL)

Brain Amyloid PET (in subset of participants)

Centiloid scale change from baseline
Regional amyloid burden

Exploratory Endpoints

MRI brain volume changes (hippocampal atrophy rate)
Blood-based biomarkers (plasma Aβ, tau, NfL)
Pharmacokinetic sampling for nilotinib levels

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[@future2024]:

Advance therapeutic options: Successful results could lead to new treatment paradigms for patients, particularly for disease modification rather than symptomatic relief

Validate c-Abl as a target: The trial provides crucial evidence for the role of c-Abl in AD pathogenesis and validates this pathway as a therapeutic target

Inform precision medicine: Results may help identify patient subgroups who benefit most from c-Abl inhibition, based on biomarker profiles

Establish autophagy enhancement as a strategy: Demonstrating efficacy would validate autophagy enhancement as a viable disease-modifying strategy in AD

Bridge AD and PD research: Positive results would strengthen the link between c-Abl activation in AD and PD, potentially leading to shared therapeutic approaches

Comparison with Other AD Trials

NILEAD occupies a unique position among AD trials by targeting a fundamentally different pathway than amyloid-targeting therapies:

| Trial Type | Target | Examples | Status |
|------------|--------|----------|--------|
| Amyloid antibodies | Aβ plaques | Lecanemab, Donanemab | Approved/Phase 3 |
| Tau vaccines | Tau tangles | ACI-35, Lu AF87903 | Phase 2/3 |
| c-Abl inhibitor | c-Abl kinase | Nilotinib (NILEAD) | Phase 3 |
| Neuroprotective | Multiple | AL-108, Davunetide | Completed |

The success of nilotinib would provide a completely novel mechanism of action and potentially help patients who have not responded to or cannot receive amyloid-targeting therapies.

c-Abl Biology in Detail

c-Abl Structure and Function

The c-Abl (Abelson tyrosine kinase) protein is a non-receptor tyrosine kinase with multiple regulatory domains:

c-Abl Structure:
|---------|---------|---------|---------|
| SH3 | SH2 | SH1 | F-actin |
| | | Kinase | binding |
|---------|---------|---------|---------|
|
Regulatory

Key Domains:

SH3 domain: Protein-protein interactions, autoinhibition
SH2 domain: Phosphotyrosine recognition
SH1 (Kinase) domain: Catalytic activity
F-actin binding: Cytoskeletal functions

Normal Cellular Functions

c-Abl participates in normal cellular processes:

| Function | Mechanism | Outcome |
|----------|-----------|---------|
| Cell adhesion | Integrin signaling | Migration, attachment |
| Actin dynamics | Cytoskeletal regulation | Shape, movement |
| Cell cycle | CDK regulation | Proliferation |
| DNA repair | ATM activation | Genomic stability |
| Autophagy | ULK1 phosphorylation | Protein clearance |

Pathological Activation

In neurodegeneration, c-Abl is activated by:

Amyloid-beta: Direct activation via oxidative stress

Tau pathology: Hyperphosphorylated tau activates c-Abl

α-Synuclein: In PD, contributes to activation

Oxidative stress: ROS directly activate the kinase

DNA damage: ATM-dependent activation

c-Abl Substrates in Neurodegeneration

Key substrate proteins:

| Substrate | Modification | Consequence |
|-----------|--------------|------------|
| Tau | Y394, Y197 | Aggregation |
| α-Synuclein | Y39 | Toxicity |
| parkin | Y143 | Mitochondrial dysfunction |
| APP | Y682 | Amyloid processing |
| PSD-95 | S573 | Synaptic damage |

Autophagy Enhancement Mechanism

The Autophagy Pathway

Autophagy is the cellular recycling process:

mTOR inhibition or ULK1 activation
↓
Phosphatidylinositol 3-phosphate production
↓
Isolation membrane formation
↓
Cargo recognition (p62/SQSTM1)
↓
Autophagosome-lysosome fusion
↓
Degradation and recycling

c-Abl Inhibition Effects

Nilotinib enhances autophagy through:

mTOR inhibition: Indirect pathway activation

ULK1 activation: Direct activation of initiating kinase

Vps34 modulation: PI3K activity enhancement

Lysosomal function: Enhanced cathepsin activity

p62 phosphorylation: Improved cargo recognition

Therapeutic Window

Critical aspect of nilotinib in neurodegeneration:

| Parameter | Cancer Dose | Neurodegeneration Dose |
|-----------|------------|------------------------|
| Daily dose | 400-600 mg | 150-300 mg |
| Cmax | 2-5 μM | 0.2-0.5 μM |
| CSF penetration | Limited | Adequate |
| Duration | Continuous | Intermittent |

The therapeutic rationale:

Sufficient for autophagy enhancement
Below cancer therapeutic threshold
Avoids significant bone marrow toxicity

Clinical Pharmacology

Pharmacokinetics

Absorption:

Tmax: 2-3 hours
Bioavailability: 30%
Food effect: Increased with food

Distribution:

Protein binding: 95%
Vd: 4-6 L/kg
CSF: 10-15% of plasma

Metabolism:

CYP3A4 substrate
No active metabolites
P-gp substrate

Elimination:

Half-life: 17-19 hours
Fecal excretion: 80%
Renal excretion: 20%

Drug Interactions

| Interaction | Effect | Management |
|-------------|-------|------------|
| CYP3A4 inhibitors | Increased levels | Dose reduction |
| CYP3A4 inducers | Reduced levels | Avoid |
| Anticoagulants | Bleeding risk | Monitor |
| Myelosuppressive | Additive | Avoid |

Biomarker Program

CSF Biomarkers

Cerebrospinal fluid biomarkers include:

| Biomarker | Change with Nilotinib | Interpretation |
|-----------|---------------------|----------------|
| Aβ40 | Increase | Enhanced clearance |
| Aβ42 | Increase | Enhanced clearance |
| Total tau | Decrease | Neuroprotection |
| p-tau | Decrease | Reduced pathology |
| NfL | Decrease | Reduced neurodegeneration |
| α-Synuclein | Decrease | Enhanced clearance |

Blood Biomarkers

Blood-based biomarkers under investigation:

| Biomarker | Matrix | Feasibility |
|----------|--------|-------------|
| Total tau | Plasma | High |
| NfL | Plasma | High |
| p-tau181 | Plasma | High |
| Aβ40/42 | Plasma | Moderate |

Imaging Biomarkers

Imaging endpoints include:

Amyloid PET: Centiloid change
FDG-PET: Hypometabolism
MRI: Hippocampal volume
DTI: White matter integrity**

Safety Profile

Adverse Events in PD Trials

| Adverse Event | Frequency | Grade 3/4 |
|---------------|----------|-----------|
| Nausea | 25% | <1% |
| Fatigue | 20% | <1% |
| Headache | 15% | <1% |
| Dry mouth | 12% | <1% |
| Neutropenia | 8% | 2% |
| QT prolongation | 5% | 1% |

Safety Monitoring

Required monitoring in NILEAD:

CBC with differential (monthly)
ECG (baseline, 12 weeks)
LFTs (monthly)
CK (symptomatic)

Contraindications

Excluded conditions:

Active malignancy
QTc >500 ms
Severe hepatic impairment
Recent心血管事件

Comparison with Other Autophagy-Targeting Approaches

Autophagy Modulators in Development

| Drug | Mechanism | Stage | Indication |
|------|-----------|-------|-----------|
| Nilotinib | c-Abl inhibitor | Phase 3 | AD, PD |
| Rapamycin | mTOR inhibitor | Phase 2 | AD |
| Lithium | IMPase inhibitor | Phase 2 | AD |
| Valproic acid | HDAC inhibitor | Phase 2 | AD |
| Trehalose | Autophagy inducer | Preclinical | Multiple |

Advantages of Nilotinib

Clinical safety established in oncology
Good CNS penetration
Multiple mechanisms beyond autophagy
Oral bioavailability

Regulatory Pathway

Accelerated Approval Considerations

NILEAD design supports:

Orphan drug designation for AD
Priority review eligibility
Accelerated approval pathway

Endpoint Considerations

Alternative approval pathways:

Surrogate endpoint (CDR-SB)
Biomarker-based
Condition acceleration

Historical Context

Previous nilotinib indications:

Chronic myeloid leukemia (2010)
Newly diagnosed CML (2013)
Pediatric CML (2018)

Future Directions

Combination Approaches

Potential combinations with nilotinib:

Cholinesterase inhibitors
Amyloid-targeting antibodies
Tau-targeted therapies
Lifestyle interventions

Biomarker-Driven Trials

Future trial designs may:

Enrich for biomarker-positive patients
Use baseline biomarkers for stratification
Evaluate biomarker response as endpoint

Disease Prevention

Broader applications:

Preclinical AD
At-risk populations
Genetic risk carriers

[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)
[Nilotinib for Parkinson's Disease](/therapeutics/nilotinib-parkinsons)
[c-Abl Inhibitors in Neurodegeneration](/therapeutics/tyrosine-kinase-inhibitors-neurodegeneration)
[Autophagy-Enhancing Therapies](/therapeutics/autophagy-enhancing-therapies)
[c-Abl Pathway](/mechanisms/c-abl-pathway)
[Autophagy Pathway](/mechanisms/autophagy-pathway)
[KeifeRx](/companies/keiferx)

External Links

[ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05143528)
[PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05143528)
[KeifeRx NILEAD Trial Information](https://keiferx.com)

References

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

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

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

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

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

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

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

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

[Pagan F, et al., Nilotinib in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32925075/)

[Hebron M, et al., c-Abl activation mediates neurodegeneration (2013)](https://pubmed.ncbi.nlm.nih.gov/23415876/)

[Karim MR, et al., Nilotinib improves autophagy and reduces alpha-synuclein (2021)](https://pubmed.ncbi.nlm.nih.gov/34017051/)

[Tunc C, et al., Autophagy and nilotinib in neurodegenerative disease (2022)](https://pubmed.ncbi.nlm.nih.gov/34514923/)

📖 View canonical wiki page →

Related Entities

clinical-trials-nct05143528

▸Metadataorigin_type: v1_polymorphic_backfill

slug	clinical-trials-nct05143528
kg_node_id	None
entity_type	clinical
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c07a2e1f98fd
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'clinical-trials-nct05143528'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

2107

Outgoing

2137

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

A Multicenter, Phase III, Randomized, Double Blind, Placebo-Controlled Study ... (NCT05143528)

Nilotinib BE for Early Alzheimer's Disease (NILEAD)

Overview

Trial Details

Nilotinib BE for Early Alzheimer's Disease (NILEAD)

Overview

Trial Details

Conditions Studied

Scientific Background

Disease Context

c-Abl Activation in Alzheimer's Disease

Nilotinib: Repurposing a Cancer Drug for Neurodegeneration

Therapeutic Rationale for NILEAD

Study Design

Inclusion Criteria

Exclusion Criteria

Randomization and Blinding

Outcome Measures

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

Clinical Significance

Comparison with Other AD Trials

c-Abl Biology in Detail

c-Abl Structure and Function

Normal Cellular Functions

Pathological Activation

c-Abl Substrates in Neurodegeneration

Autophagy Enhancement Mechanism

The Autophagy Pathway

c-Abl Inhibition Effects

Therapeutic Window

Clinical Pharmacology

Pharmacokinetics

Drug Interactions

Biomarker Program

CSF Biomarkers

Blood Biomarkers

Imaging Biomarkers

Safety Profile

Adverse Events in PD Trials

Safety Monitoring

Contraindications

Comparison with Other Autophagy-Targeting Approaches

Autophagy Modulators in Development

Advantages of Nilotinib

Regulatory Pathway

Accelerated Approval Considerations

Endpoint Considerations

Historical Context

Future Directions

Combination Approaches

Biomarker-Driven Trials

Disease Prevention

Related Resources

External Links

References

💬 Discussion