Nilotinib is an approved therapy for chronic myeloid leukemia. Several cell and animal model studies suggest that nilotinib may be neuroprotective for dopamine neurons in Parkinson’s disease (PD) via c-Abl inhibition

We completed a Phase 2a randomized, double-blind, placebo-controlled, parallel group study (NILO-PD) in moderate to advanced PD with the primary objectives to evaluate safety and tolerability of nilotinib, and secondary/exploratory objectives to monitor clinical efficacy outcomes, serum pharmacokinetics (PK), cerebrospinal fluid (CSF) drug concentrations, and biomarkers of c-Abl modulation and monoamine neurotransmission in the CSF and/or plasma. Here we report the pre-specified analyses of PK and biomarkers at 3 months after treatment initiation.

76 participants were randomized 1:1:1 to a once daily dose of placebo:nilotinib (150 mg):nilotinib (300 mg) for 6 months. Mean (standard deviation) serum concentrations (ng/mL) at ~Tmax (2 h) for 150 and 300 mg arms were, respectively, 465 (198) and 569 (161); the corresponding CSF concentrations were 0.91 (0.53) and 1.69 (0.94). Thus the CSF/serum concentration ratios were 0.0020 (0.0007) and 0.0029 ( 0.0013) for 150  and 300 mg doses, respectively. None of the 17 monoamines and their metabolites examined in the CSF showed a significant drug-induced change or correlation with serum nilotinib levels. Our results did not replicate the previously reported increases in dopamine metabolites, DOPAC or HVA in response to either dose of nilotinib.

The rigorous study design and use of validated analytical methods indicate that nilotinib at 150 mg or 300 mg daily dose has poor brain penetration (0.2-0.3%) and does not affect monoamine biomarkers three months after initiation of nilotinib. Analyses are underway for clinical outcomes and markers of c-Abl inhibition.