To assess the safety, tolerability and exploratory efficacy of nilotinib in moderate/advanced Parkinson’s disease (PD) participants.

Preclinical PD models demonstrate neuroprotective effects of nilotinib, a cAbl inhibitor.

A Phase 2A double-blind placebo-controlled study that aimed to enroll 75 participants with moderate/advanced PD randomized 1:1:1 to placebo:150:300 mg nilotinib in matching capsules once daily for 6 months. The primary outcomes were safety and tolerability. Secondary outcomes included change in PD disability (MDS-UPDRS OFF/ON), and exploratory were cognitive function, quality of life, serum and CSF pharmacokinetic (PK) profile, and CSF dopamine metabolites.

The study screened 125 and enrolled 76 participants (42% screen failure) between November 2017 and December 2018 from 25 sites in US. The last participant completed the study August 2019. Mean (standard deviation) age was 64.6 years (7.5), disease duration 9.9 years (4.7), MDS-UPDRS OFF score 66.4(19.5) and ON score 48.3(16.1), MOCA score 27.1(2.2). Tolerability defined as ability to complete the study on assigned dose 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 elevations of amylase and/or lipase, which were dose-dependent. The 300 mg group had transitory worsening of MDS-UPDRS-3 ON at 1 month (p<0.01), which resolved by 6 months. 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 any dopamine metabolites.

Both doses of nilotinib were safe and tolerable in these participants, who were selected with strict inclusion/exclusion criteria. There was no evidence of any symptomatic effect 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.