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
| 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 |
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.
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.
-
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.
Before the Phase 2 trial, a first-in-human study (NCT02281447) established the safety profile of nilotinib in Parkinson's disease patients. 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.
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
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
flowchart TD
A["Nilotinib"] --> B["BCR-ABL Inhibition"]
B --> C["mTOR Pathway Modulation"]
C --> D["Autophagy Activation"]
D --> E["Alpha-Synuclein Clearance"]
E --> F["Reduced Protein Aggregation"]
F --> G["Neuroprotection"]
A --> H["c-KIT Inhibition"]
H --> I["Mitochondrial Function"]
I --> J["ATP Production"]
J --> G
style A fill:#e1f5fe,stroke:#333
style G fill:#c8e6c9,stroke:#333
style E fill:#f9c,stroke:#333
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.
- 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
- 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
- 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
- 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)
- Brain imaging (DaTscan) progression
- Sleep assessment (PDSS-2)
- Depression screening (BDI-II)
- Blood inflammatory markers
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
- 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
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
¶ 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 |
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
- 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)
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: 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.
NCT03744468