NILOTINIB IN PATIENTS WITH ADVANCED PARKINSONS DISEASE: A RANDOMIZED PHASE 2A STUDY (NILO-PD)

Background: Nilotinib, a tyrosine kinase Abelson inhibitor, exhibits neuroprotective effects in preclinical Parkinson disease (PD) models. Methods: This Phase 2A double-blind placebo-controlled study in moderate/advanced PD randomized participants 1:1:1 to placebo:150:300 mg nilotinib once daily for 6 months. The primary outcomes were safety and tolerability, the latter defined as ability to complete the study on assigned dose. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), Part 3 OFF/ON). Exploratory outcomes included serum and cerebrospinal fluid (CSF) pharmacokinetic (PK) profile, and CSF dopamine metabolites. Findings: The study screened 125 and enrolled 76 participants (39% screen failure) between November 2017 and December 2018 at 25 US sites. At baseline, mean (standard deviation) age was 64.6 years (7.5), disease duration 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score 66.4(19.3) and ON score 48.4(16.2), Montreal Cognitive Assessment (MoCA) score 27.1(2.2). Tolerability was 21(84%):19 (76%):20 (77%) in placebo:150:300 mg arm, respectively. Both active doses were safe. The most common reasons for drug suspension were dose dependent elevations of amylase and/or lipase. There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between the groups (p=0.17). CSF/serum PK ratio was 0.2-0.3%. There was no evidence of treatment-related elevation of dopamine metabolites. Interpretation: Both doses of nilotinib were safe and tolerable. There was no evidence of any symptomatic benefit of nilotinib. The drug had low CSF exposure and failed to change dopamine metabolites. These findings do not warrant further testing of nilotinib in PD. Funding: The study was funded by Funded by Michael J Fox Foundation for Parkinsons Research / The Cure Parkinson Trust / Van Andel Institute. Clinicaltrials.gov NCT03205488