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Cited by 188Parkinson's Disease Mechanisms and TreatmentsDeep Brain Stimulation and Movement DisordersNuclear Receptors and Signaling

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Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial

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Pagan, Fernando. L., Hebron, Michaeline L., Wilmarth, Barbara, Torres-Yaghi, Yasar, Lawler, Abigail, Mundel, Elizabeth E., Yusuf, Nadia, Starr, Nathan J., Anjum, Muhammad, Arellano, Joy, Howard, Helen H., Shi, Wangke, Mulki, Sanjana, Kurd-Misto, Tarick, Matar, Sara, Liu, Xiaoguang, Ahn, Jaeil, Moussa, Charbel·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2019.4200PMC PMC6990742
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Abstract

Importance: This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease. Objectives: To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. Design, Setting, and Participants: This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease. Interventions: Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period. Main Outcomes and Measures: It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. Results: Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups. Conclusions and Relevance: In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. Trial Registration: ClinicalTrials.gov identifier: NCT02954978.

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Authors
Pagan, F. L., Hebron, M. L., Wilmarth, B., Torres-Yaghi, Y., Lawler, A., Mundel, E. E., Yusuf, N., Starr, N. J., Anjum, M., Arellano, J., Howard, H. H., Shi, W., Mulki, S., Kurd-Misto, T., Matar, S., Liu, X., Ahn, J., & Moussa, C.
Affiliations
  • Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC
  • Georgetown University Medical Center (US)
  • MedStar Georgetown University Hospital (US)
Corresponding author
Moussa, Charbel
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-03-01
Volume
77
Issue
3
Pages
309
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2019.4200
PMC
PMC6990742
OpenAlex
W2995537689
Cited by
185
References
32
Citations by year
2026: 18 · 2025: 18 · 2024: 35 · 2023: 29 · 2022: 28 · 2021: 30 · 2020: 26
FWCI
14.55
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
nilotinib, Parkinson's disease, disease-modifying therapy, safety and tolerability, pharmacokinetics, cerebrospinal fluid biomarkers, homovanillic acid, DOPAC, dopamine metabolism, adverse events, dose comparison, washout
MeSH terms
Aged, Dopamine, Double-Blind Method, Female, Humans, Male, Middle Aged, Parkinson Disease, Pyrimidines, Biomarkers, tau Proteins

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