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December 16, 2019

The Narrowing Path for Nilotinib and Other Potential Disease-Modifying Therapies for Parkinson Disease

Author Affiliations
  • 1James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio
  • 2Department of Neurology, University of South Florida, Tampa
  • 3Department of Neurology, University of Florida College of Medicine, Gainesville
JAMA Neurol. 2020;77(3):295-297. doi:10.1001/jamaneurol.2019.3983

Nilotinib hydrochloride, an Abelson tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia, has been in the neurology news since the results of the open-label, phase 1 study in a small group of patients with advanced Parkinson disease (PD) and dementia with Lewy bodies was reported at the Society for Neuroscience in Chicago in October 2015. The extensive media coverage that followed, supported by videos of nilotinib-treated participants getting up and walking from their wheelchairs, suggested that disease modification in PD was within reach with this drug. The corresponding publication documented that, at 150 and 300 mg/d, doses lower than required for treating leukemia, nilotinib was detectable in the cerebrospinal fluid (CSF), increased CSF homovanillic acid levels, seemed to engage the target Abelson, and was relatively safe and well tolerated at 24 weeks.1 Although the authors emphasized that “motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes,”1(p503) the accompanying editorial noted that, owing to the small sample size and lack of a control group, it was impossible to rule out a placebo effect.2

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2 Comments for this article
At what nilotinib dose are the benefits of autophagy attenuated by the harms of neuronal apoptosis?
DAVID KELLER, MD, MS, FACP | Disabled Internist With Advanced Parkinson Disease
The following comment pertains to potential benefits and harms of treating Parkinson's disease (PD) with nilotinib, as suggested by Hebron, Lonskaya, and Moussa (1):

Stimulation of intracellular autophagy by low-dose nilotinib was postulated to break up aggregated fibrils of alpha synuclein (ASN), with the hope of reviving dopaminergic neurons damaged by the harmful effects these fibrils in PD (1).

Higher doses of nilotinib can cause terminal autophagy and apoptosis, a result that is beneficial in the treatment of malignancy, but potentially harmful when treating PD.

A dose-ranging study is critical to determine a nilotinib
dose high enough to stimulate beneficial autophagy in dopaminergic neurons, but low enough to avoid apoptosis of these neurons.

Could incipient apoptosis of dopaminergic neurons explain decreased benefits at higher tested doses, and an attenuated or inverted dose-response effect?


1: Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons
and improves motor behavior via autophagic degradation of α-synuclein in
Parkinson's disease models. Hum Mol Genet. 2013 Aug 15;22(16):3315-28. doi:
10.1093/hmg/ddt192. Epub 2013 May 10. PubMed PMID: 23666528; PubMed Central
PMCID: PMC3723316.
Response to Authors
Charbel Moussa, MD. PhD | Charbel Moussa, Georgetown University
Clinical outcomes:

The editorial cherry picks some outcomes that change within and not between the groups... Although this is a phase II study that does not show differences in clinical outcomes and the changes are not clinically meaningful within each group using MoCA, TUG and UPDRSII, the editorial certainty "walks the street both ways" and ignores the significant change (-2.85pts) in UPDRS III motor in the 150mg (p<0.05) between baseline and 15 months, and the significant decline in total UPDRS I-III (4.5pts) in the placebo group and the clinically significant worsening using PDQ-39 (as a mirror to UPDRS-II)
between 6-12 months respectively... if we apply the same standards then the editorial should have mentioned the effect of nilotinib to slow the decline in motor, non-motor and Quality of life in the drug groups while the placebo group declines. But since this is a phase II study the editorial incorrectly refers to clinical outcomes in a very selective way despite lack of statistical difference between the groups..

Although the authors have a valid point about selecting patients that best show effects of drugs on biomarkers, the reference to biomarkers seems ill-informed. This study evaluated a "kit" of biomarkers, including HVA/DOPAC in the CSF and Plasma (this is a Go/NoGO to phase III), total and oligomeric alpha-synuclein and total and hyper-phosphorylated tau, to reflect possible changes in motor systems in the PD brain. The editorial ignores the effect on tau and p-tau, and selectively focus on oligmeric levels of CSF alpha-synuclein. In fact oligomeric alpha-synuclein is very difficult to detect in normal individuals and the low level of oligomeric alpha-synuclein in the CSF (cannot be detected in the plasma) is indicative of increased and detectable levels in PD patients. This is again statistically significant with 150mg niloitnib using raw p-values, but both DOPAC and pTau remain statistically significant after corrections for multiple comparison, rendering these data statistically stronger.

We absolutely agree with the authors that dopamine metabolites change depending on PD medications. This is true and this is why this trial followed a single SOP in a single center and collected CSF 2 hours after levodopa administration and within 1-4 hours after nilotinib treatment from patients who were NOT treated with MAOB-I. These results confirm previous studies in the same patients who received single dose of nilotinib and showed a time-dependent change in HVA/DOPAC.

Further, the 12-months measurement and comparison between groups show individual patients' level of HVA/DOPAC. What is referred to "outliers" could result from a different level of neurotransmitters at baseline. i.e a low Vs high levels of CSF HVA/DOPAC within the same group may reflect differences in dopamine loss in the brain and not necessarily differences in response to drug.

Further Phase III studies

It is unreasonable to compare other studies to this study as a justification for why further studies should not be done. Since the phase II data (especially as the authors suggest, 150mg nilotinib shows reasonable safety and biomarker effects) show no QTC prolongation and no drug-related AES or SAES, and a host of biomarkers, including pre-specified dopamine metabolism (which is usually not done in phase II) a phase III study should evaluate the effects of nilotinib. The nilotinib group show no worsening compared to placebo and only a phase III trial can show the difference in clinical effects > 6months.
CONFLICT OF INTEREST: Investor in a Georgetown University patent to use niloitnib in neurodegenerative diseases