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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pagan reported receiving personal fees and other support from Acadia, AbbVie, Accorda, and Adamas; personal fees from Teva; grants and other from Medtronic; grants, personal fees, and other from US World Meds; grants from the National Institutes of Health National Institute on Aging; grants from Alzheimer's Association and National Institutes of Health as co–principal investigator, and Parkinson Foundation, and personal fees and other from Sunovion and Merz outside the submitted work. Dr Moussa reported having a patent to US 9,474,753 B2 issued and being listed as an inventor on several patent publications to use nilotinib as a potential treatment for neurodegenerative diseases. Dr Moussa and Georgetown University own the intellectual property on the use of nilotinib for neurodegenerative disorders. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

Phase 2, randomized, double-blind, placebo-controlled trial to evaluate nilotinib hydrochloride effects on safety, tolerability, biomarkers, and clinical outcomes in Parkinson disease. For values given as 20-21 in the bottom boxes, biomarkers were analyzed and only those samples who gave a reading were reported. A few samples did not produce a value when analyzed. PI indicates principal investigator; SAE, serious adverse event.

Figure 2.. Data Representing the Pharmacokinetics and Pharmacodynamics Effects of 1-Year Nilotinib Treatment Compared With Placebo in Parkinson Disease

Cerebrospinal fluid (CSF) levels of homovanillic acid HVA (A), 3,4-dihydroxyphenylacetic acid (DOPAC) (B), total α-synuclein (C), oligomeric α-synuclein (D), ratio of oligomeric/total α-synuclein (E), total tau (F), hyperphosphorylated tau (P-tau181) (G), and ratio of p-tau181/total tau (H). Total of 20 to 21 patients per group. aP < .05.