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    Original Investigation
    December 16, 2019

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

    Author Affiliations
    • 1Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC
    • 2Movement Disorders Clinic, Department of Neurology, MedStar Georgetown University Hospital, Washington, DC
    • 3Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, DC
    JAMA Neurol. Published online December 16, 2019. doi:10.1001/jamaneurol.2019.4200
    Key Points

    Question  Is the use of nilotinib hydrochloride, a drug approved for use in leukemia, safe and effective in patients with Parkinson disease?

    Findings  In this randomized clinical trial of use of nilotinib hydrochloride in 75 patients with Parkinson disease, doses of 150 or 300 mg were reasonably safe and did not inhibit plasma Abelson tyrosine kinase. Twelve months of treatment with nilotinib altered exploratory cerebrospinal fluid biomarkers, including brain dopamine turnover, oligomeric α-synuclein, and hyperphosphorylated tau.

    Meaning  This phase 2 trial met its objectives and nilotinib should be investigated in a phase 3 study as a potential disease-modifying therapy in Parkinson disease.


    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