Nilotinib May Hold Promise as Parkinson Disease Treatment


The results pave the way for a potential phase 3 trial to examine the effects of nilotinib in patients with Parkinson disease.

Dr Fernando L Pagan

Fernando. L. Pagan, MD, of the Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center

Fernando. L. Pagan, MD

Results of a phase 2 study examining the safety and pharmacokinetics of nilotinib demonstrated an alteration of exploratory biomarkers, as well as reasonable safety in patients with Parkinson disease (PD).1

The FDA previously approved nilotinib (Tasigna; Novartis) for adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia,2 however, several studies have found that the drug degrades alpha-synuclein and tau in animal models of neurodegeneration, and may increase dopamine metabolism, potentially treating motor and nonmotor symptoms.

Investigators included Fernando. L. Pagan, MD, of the Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, and colleagues. This single-center, double-blind, placebo-controlled measured the impact of low dose nilotinib on safety, tolerability, pharmacokinetics, and biomarkers in PD.

In total, 75 patients were randomized 1:1:1 to 150-mg of nilotinib, 300-mg, or placebo. Patients were administered daily for 12 months, followed by a 3-month washout period, and criteria for those enrolled included those on a stable dose of 800-mg Levadopa daily for at least 4 weeks prior to the trial who were medically stable, between the ages of 40-90. Additionally, participants had Montreal Cognitive Assessment scores ≥22 and a Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)-III motor score of 20—40.

Patients administered with 150-mg of nilotinib showed an increase in cerebrospinal fluid (CSF) levels of the dopamine metabolites homovanillic acid (159.80 nM; 90% CI, 7.04—312.60 nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87 nM; 90% CI, 1.51—8.23 nM; P = .01), compared to the 300-mg nilotinib group which experienced a raise in 3,4-dihydroxyphenylacetic acid (7.52 nM; 90% CI, 2.35—12.69 nM; P = .01). Only those in the 300-mg group showed a reduction of α-synuclein oligomers (−0.04 pg/mL; 90% CI, −0.08 to 0.01 pg/mL; P = .03).

Investigators also observed significant reductions in hyperphosphorylated tau levels in both 150-mg of nilotinib (−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).

Investigators recorded 71, 57 and 65 total adverse events (AEs) in the nilotinib 150-mg, 300-mg, and placebo groups, respectively. Falls occurred in 13 patients in each nilotinib group, making it the most common AE observed in the study. Other common AEs observed included musculoskeletal (placebo: n = 10 [40%]; nilotinib 150 mg: n = 16 [64%]; nilotinib 300 mg: n = 9 [36%]), respiratory (placebo: n = 11 [44%]; 150 mg: n = 9 [36%]; 300 mg: n = 7 [28%]), and skin and subcutaneous disorders (placebo: n = 9 [36%]; 150 mg: n = 9 [36%]; 300 mg: n = 8 [32%]).

There were a reported 22 total serious AEs in the 3 dose groups. Twelve (48%) patients in the nilotinib 300-mg group reported serious AEs, compared to 6 (24%) in the 150-mg nilotinib group and 4 (16%) in the placebo group. Renal and urinary tract, gastrointestinal disorders such as cancer, general disorders, and musculoskeletal and connective tissue disorders were among some of the SAEs observed in the trial. Disease progression, drowning, and pneumonia were the 3 known SAEs that led to death in 3 patients during the washout stage, with each group reporting 1 death, though none were deemed related to the study drug.

The follow-up to the study ended August 10, 2019, and the official estimated completion date is July of 2020. Pagan and colleagues concluded that the data extracted from this study will be pivotal for a future phase 3 study to evaluate the effects of nilotinib therapy in patients with PD.

“Exploratory biomarkers were altered in response to nilotinib treatment, and future phase 3 studies may identify dopamine metabolites, including HVA and DOAPC, as biomarkers of dopamine metabolism. Taken together, our results will guide the future development of a definitive phase 3 study to evaluate the effects of nilotinib as a disease-modifying drug in PD,” they concluded.


1. Pagan FL, Hebron ML, WIlmarth B, et al. Nilotinib effects on safety, tolerability, and potential biomarkers in parkinson disease. JAMA Neurol. Published online December 16, 2019. doi: 10.1001/jamaneurol.2019.4200

2. FDA approves nilotinib for pediatric patients with newly diagnosed or resistant/intolerant Ph+ CML in chronic phase [news release]. Silver Spring, MD: FDA; Published March 3, 2019. Accessed December 17, 2019.

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