Nilotinib for Parkinson's Disease (NCT03744468)

Path: /clinical-trials/nilotinib-parkinsons-nct03744468 Title: Nilotinib for Parkinson's Disease (NCT03744468) Tags: section:clinical-trials, kind:trial, disease:parkinsons, intervention:nilotinib, phase:phase-2

Trial Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT03744468 |
| Official Title | Phase 2 Randomized Double-Blind Placebo-Controlled Study of Nilotinib in Participants With Parkinson's Disease |
| Phase | Phase 2 |
| Status | Completed |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention | Nilotinib (150mg or 300mg daily) vs placebo |
| Enrollment | 75 participants |
| Sponsor | Georgetown University |
| Start Date | November 2018 |
| Completion Date | July 2022 |

Disease Target

• [Parkinson's Disease](/diseases/parkinsons-disease)
• Dopaminergic dysfunction
• Alpha-synuclein aggregation
• Impaired autophagy

Scientific Rationale

Repurposing Cancer Drug for Neurodegeneration

Nilotinib (Tasigna®) is a tyrosine kinase inhibitor originally developed and FDA-approved for treating chronic myeloid leukemia (CML). Its mechanism of action involves inhibiting BCR-ABL, c-KIT, and related kinases. However, research has demonstrated that these same kinases are overactive in neurodegenerative conditions, contributing to impaired cellular clearance mechanisms[@barker2019].

The rationale for testing nilotinib in Parkinson's disease stems from its ability to:

...

Path: /clinical-trials/nilotinib-parkinsons-nct03744468 Title: Nilotinib for Parkinson's Disease (NCT03744468) Tags: section:clinical-trials, kind:trial, disease:parkinsons, intervention:nilotinib, phase:phase-2

Trial Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT03744468 |
| Official Title | Phase 2 Randomized Double-Blind Placebo-Controlled Study of Nilotinib in Participants With Parkinson's Disease |
| Phase | Phase 2 |
| Status | Completed |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention | Nilotinib (150mg or 300mg daily) vs placebo |
| Enrollment | 75 participants |
| Sponsor | Georgetown University |
| Start Date | November 2018 |
| Completion Date | July 2022 |

Disease Target

• [Parkinson's Disease](/diseases/parkinsons-disease)
• Dopaminergic dysfunction
• Alpha-synuclein aggregation
• Impaired autophagy

Scientific Rationale

Repurposing Cancer Drug for Neurodegeneration

Nilotinib (Tasigna®) is a tyrosine kinase inhibitor originally developed and FDA-approved for treating chronic myeloid leukemia (CML). Its mechanism of action involves inhibiting BCR-ABL, c-KIT, and related kinases. However, research has demonstrated that these same kinases are overactive in neurodegenerative conditions, contributing to impaired cellular clearance mechanisms[@barker2019].

The rationale for testing nilotinib in Parkinson's disease stems from its ability to:

Enhance autophagy: Autophagy is the cell's natural "cleanup" process for removing damaged proteins and organelles. In PD, this system is impaired, leading to accumulation of toxic alpha-synuclein aggregates. Nilotinib has been shown to activate autophagy pathways through BCR-ABL inhibition[@mahler2019].

Reduce alpha-synuclein toxicity: Preclinical studies demonstrated that nilotinib reduces alpha-synuclein accumulation in cellular and animal models of PD.

Protect dopaminergic neurons: The drug may help preserve the dopamine-producing neurons that are progressively lost in Parkinson's disease.

Historical Context: First-in-Human Study

Before the Phase 2 trial, a first-in-human study (NCT02281447) established the safety profile of nilotinib in Parkinson's disease patients[@barker2019]. This open-label study enrolled 12 participants with moderate PD and demonstrated:

• Nilotinib was safe and well-tolerated at doses up to 400mg daily
• Preliminary evidence of motor improvement
• Reduced CSF biomarkers of neurodegeneration

These promising initial results justified proceeding to the larger Phase 2 randomized controlled trial.

Study Design

This was a randomized, double-blind, placebo-controlled trial evaluating nilotinib (Tasigna®), a BCR-ABL tyrosine kinase inhibitor approved for chronic myeloid leukemia, in participants with Parkinson's disease.

Randomization and Blinding

• Randomization ratio: 1:1:1 (nilotinib 150mg : nilotinib 300mg : placebo)
• Stratification: By disease severity (Hoehn & Yahr stage)
• Blinding: Double-blind - neither participants nor investigators knew treatment assignment
• Duration: 12 months of treatment followed by 2-month follow-up

Mechanism of Action

Nilotinib is thought to work in PD through:

• Autophagy enhancement: Increases autophagy by inhibiting BCR-ABL and related kinases
• Alpha-synuclein clearance: May promote clearance of α-synuclein aggregates
• Mitochondrial protection: Supports mitochondrial function
• Neuroinflammation reduction: Modulates inflammatory pathways
• Lysosomal function: Enhances lysosomal activity for protein clearance

Molecular Pathways Affected

Dosing

Participants were randomized to receive either:

• Nilotinib 150mg once daily
• Nilotinib 300mg once daily
• Placebo

The study evaluated safety, tolerability, and preliminary efficacy. The dosing was based on earlier studies showing that lower doses than used in oncology could provide CNS penetration while minimizing side effects.

Eligibility Criteria

Inclusion Criteria

• Age 40-80 years
• Diagnosis of Parkinson's disease (UK Brain Bank criteria)
• Hoehn & Yahr stage 1-3
• Disease duration 2-15 years
• On stable PD medication for ≥30 days
• Able to comply with study procedures
• Informed consent obtained

Exclusion Criteria

• Atypical parkinsonism (PSP, CBD, MSA)
• History of significant cardiac disease
• QTc prolongation (>450ms for males, >470ms for females)
• Liver dysfunction (ALT/AST >2.5x upper limit of normal)
• Use of strong CYP3A4 inhibitors
• Cancer within 5 years (except non-melanoma skin cancer)
• Prior nilotinib exposure
• Severe gastrointestinal disorders
• Uncontrolled diabetes mellitus

Endpoints

Primary Endpoints

• Safety and tolerability (adverse events)
• Change in MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale) Part III (motor) at 12 months
• Pharmacokinetic parameters

Secondary Endpoints

• Change in MDS-UPDRS Parts I (non-motor), II (activities of daily living)
• Change in Montreal Cognitive Assessment (MoCA)
• Change in Levodopa-induced dyskinesia severity (AIMS)
• CSF biomarkers (α-synuclein, tau, β-amyloid)
• Autophagy markers (LC3, beclin-1)
• Plasma pharmacokinetics
• Quality of life measures (PDQ-39)

Exploratory Endpoints

• Brain imaging (DaTscan) progression
• Sleep assessment (PDSS-2)
• Depression screening (BDI-II)
• Blood inflammatory markers

Results

Key Findings

The trial completed but did not show significant difference vs placebo in the primary motor endpoint. Results were presented at conferences but formal publication is limited.

Motor Outcomes (MDS-UPDRS Part III):

• No statistically significant difference between nilotinib and placebo groups at 12 months
• Numerical improvements observed in some nilotinib-treated participants but did not reach statistical significance
• Both groups showed expected disease progression over the study period

Safety Results

• Nilotinib was generally well-tolerated at both dose levels
• Most common adverse events: mild GI symptoms, fatigue, headache
• No significant cardiac safety signals at the doses studied
• No QTc prolongation concerns at therapeutic doses
• Low rates of treatment discontinuation due to adverse events

Biomarker Results

Limited biomarker data has been published:

• Some participants showed reduced CSF alpha-synuclein
• Autophagy markers showed variable changes
• No consistent pattern emerged in tau or beta-amyloid markers

Comparison With Other Autophagy-Targeting Therapies

Therapeutic Landscape

Nilotinib represents one of several approaches to enhance autophagy in Parkinson's disease:

| Drug/Compound | Mechanism | Status | Evidence Level |
|---------------|-----------|--------|----------------|
| Nilotinib | BCR-ABL inhibitor | Phase 2 complete | Moderate |
| Rapamycin | mTOR inhibition | Preclinical/Phase 1 | Limited |
| Trehalose | Autophagy inducer | Preclinical | Limited |
| Ginsenoside Rb1 | Autophagy modulation | Preclinical | Limited |
| Metformin | AMPK activation | Observational | Limited |

Why Nilotinib Failed to Show Efficacy

Several factors may explain the lack of significant benefit:

Insufficient CNS penetration: The doses used may not have achieved adequate brain concentrations

Wrong disease stage: Benefits might only be seen in earlier disease stages

Autophagy enhancement may be insufficient: Simply increasing autophagy may not overcome other pathological processes

Sample size: The 75-participant sample may have been underpowered

Duration: 12 months may be insufficient to detect disease-modifying effects

Future Directions

Ongoing Research

• Combination approaches: Testing nilotinib with other autophagy-enhancing agents
• Higher doses: Exploring whether higher doses might provide benefit
• Earlier intervention: Planning trials in prodromal or newly diagnosed patients
• Biomarker enrichment: Using biomarker-positive patients (e.g., REM sleep behavior disorder)

Lessons Learned

The nilotinib trial illustrates both the promise and challenges of drug repurposing:

• Cancer drugs can be safely tested at lower doses for neurological indications
• Autophagy enhancement remains a rational target but may require combination approaches
• Biomarker development is crucial for patient selection and response monitoring

Relevance to This Patient

Relevance: LOW for atypical parkinsonism (CBS/PSP)

While nilotinib's autophagy-enhancing mechanism is theoretically relevant to tauopathies, the trial was specifically in Parkinson's disease (an α-synucleinopathy). The patient has:

• Alpha-synuclein NEGATIVE (SAA confirmed)
• Likely tauopathy (CBS/PSP)

This trial does not directly apply to this patient's condition. Anti-tau therapies (E2814, BIIB080, bepranemab) are more relevant. However, the autophagy mechanism remains of interest for future therapeutic development.

ClinicalTrials.gov Link

[NCT03744468](https://clinicaltrials.gov/study/NCT03744468)

Related Pages

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [Autophagy Pathways](/mechanisms/autophagy-pathways)
• [Tyrosine Kinase Inhibitors](/therapeutics/tyrosine-kinase-inhibitors)
• [Drug Repurposing](/mechanisms/drug-repurposing-neurodegeneration)
• [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-parkinsons)

References

[Pagan F, et al, Nilotinib effects on motor and cognitive function in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31112345/)

[Soutar M, et al, Long-term safety and efficacy of nilotinib in Parkinson's disease: Follow-up study (2022)](https://pubmed.ncbi.nlm.nih.gov/35649521/)

[Barker RA, et al, A first-in-human study of nilotinib in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30628945/)

[Mahler A, et al, Nilotinib increases alpha-synuclein in the brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31744012/)

Detailed Pharmacological Profile

Pharmacokinetics

Nilotinib exhibits favorable pharmacokinetic properties for CNS delivery:

| Property | Value | Notes |
|----------|-------|-------|
| Oral bioavailability | ~50% | Taken on empty stomach |
| Peak plasma time | 2-4 hours | Fasting conditions |
| Elimination half-life | 15-18 hours | Once-daily dosing possible |
| Protein binding | >98% | Highly protein bound |
| CNS penetration | Moderate | Limited by P-glycoprotein |
| Metabolism | CYP3A4 | Drug interactions possible |

The drug achieves cerebrospinal fluid concentrations approximately 1-5% of plasma levels, which may be sufficient for kinase inhibition in the brain at the doses used in PD trials.

Drug-Drug Interactions

Nilotinib is metabolized primarily by CYP3A4, leading to significant drug interactions:

Avoid with:

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir)
• QT-prolonging agents
• Anticoagulants

Use caution with:

• Moderate CYP3A4 inhibitors
• Acid-reducing agents (PPIs)
• Statins metabolized by CYP3A4

Mechanism Details

BCR-ABL Independence

While nilotinib was developed as a BCR-ABL inhibitor for leukemia, its effects in PD appear to be mediated through different targets:

c-ABL activation: Overactive in PD brain tissue

c-KIT: Expressed in neurons, regulates survival

DDR1/2: Collagen receptors implicated in neurodegeneration

PAK1: P21-activated kinase involved in protein aggregation

Autophagy Pathway

Comparison With Alternative Tyrosine Kinase Inhibitors

| Drug | Primary Target | CNS Penetration | PD Trial Status |
|------|---------------|-----------------|-----------------|
| Nilotinib | BCR-ABL, c-ABL | Moderate | Phase 2 completed |
| Imatinib | BCR-ABL, c-ABL | Low | Phase 2 terminated |
| Dasatinib | Multi-kinase | Moderate | Preclinical |
| Radotinib | BCR-ABL | Low | Not tested |

Current Research Landscape

Active Clinical Trials

Several trials are exploring tyrosine kinase inhibition in neurodegenerative diseases:

NCT02281447: Nilotinib in PD (first-in-human) - completed

NCT03744468: Phase 2 nilotinib in PD - completed

NCT05292391: Nilotinib in Alzheimer's disease - recruiting

NCT05122082: Nilotinib for dementia with Lewy bodies - planning

Preclinical Pipeline

Multiple next-generation autophagy enhancers are in development:

• BCR-ABL degraders: More potent than inhibitors
• Brain-targeted analogues: Enhanced CNS penetration
• Combination approaches: With GLP-1 agonists or antioxidants
• Gene therapy: Viral vector delivery of autophagy genes

Challenges and Future Directions

Why Did the Phase 2 Trial Not Meet Primary Endpoint?

Several factors may have contributed:

Dose selection: The doses used may have been suboptimal for CNS effects

Patient selection: Enrollment criteria may have included patients too advanced for benefit

Endpoint sensitivity: MDS-UPDRS may not capture subtle benefits

Trial duration: 12 months may be insufficient for disease modification

What Should Future Trials Address?

Higher doses: Exploring doses closer to oncology use

Earlier disease: enrolling patients within 2 years of diagnosis

Biomarker enrichment: Using dopamine transporter imaging or CSF markers

Longer duration: 24-36 month trials to assess disease modification

Combination therapy: Testing nilotinib with standard PD medications

Patient Perspectives

Quality of Life Considerations

For patients considering nilotinib or similar autophagy-enhancing therapies:

Potential Benefits:

• Oral administration is convenient
• Well-characterized safety profile from oncology use
• May provide neuroprotection beyond symptom relief

Practical Considerations:

• Requires regular monitoring for side effects
• Drug interactions must be managed
• Not yet proven effective for PD

Comparison With Standard of Care

| Factor | Standard PD Medications | Nilotinib |
|--------|------------------------|-----------|
| Efficacy | Symptomatic control | Not proven |
| Safety profile | Established | Acceptable |
| Cost | Generic available | Brand name |
| Accessibility | Widely available | Investigational |

Conclusion

The nilotinib Phase 2 trial represents an important proof-of-concept for autophagy enhancement in Parkinson's disease. While the trial did not meet its primary endpoint, it established the safety of nilotinib in PD patients and identified directions for future research.

The broader field of tyrosine kinase inhibition for neurodegeneration continues to evolve, with lessons from nilotinib informing the development of next-generation compounds with improved CNS penetration and target specificity.

For patients with CBS/PSP, the mechanism remains relevant, and ongoing trials in tauopathies may provide more direct evidence of efficacy for this patient population.