Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies

Abstract

Background: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson’s disease dementia or dementia with Lewy bodies.Objectives: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory.Methods: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks.Results: This study shows that 150 mg and 300 mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson’s disease. Nilotinib is detectable in the cerebrospinal fluid (CSF) and seems to engage the target Abl. Motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes. The CSF levels of homovanillic acid are significantly increased between baseline and 24 weeks of treatment. Exploratory CSF biomarkers were measured.Conclusions: This small proof-of-concept study lacks a placebo group and participants were not homogenous, resulting in baseline differences between and within groups. This limits the interpretations of the biomarker and clinical data, and any conclusions should be drawn cautiously. Nonetheless, the collective observations suggest that it is warranted to evaluate the safety and efficacy of Nilotinib in larger randomized, double-blind, placebo-controlled trials.

c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease

“…A recent clinical study showed that nilotinib reduced the relative level of phosphorylated (active) c-Abl in the cerebrospinal fluid of treated PD patients (Pagan et al, 2016). …”

“…Recently nilotinib was employed in an open-labeled trial to treat 12 patients afflicted by either PD or DLB (Pagan et al, 2016). Since the study lacked proper controls the results are preliminary and should be treated with caution.…”

Could cancer drugs be repurposed for use in Parkinson’s and Alzheimer’s?

“…In human, nilotinib peaks in the plasma and cerebrospinal fluid (CSF) at 2 h (T max ) after dosing with 150 or 300 mg nilotinib. Nilotinib is not detected in the CSF (t 1/2~1 .8) 3 h after dosing suggesting short bioavailability compared to plasma t 1/2 = 12.4 [5]. The CSF:plasma concentration of nilotinib is 12% and 5% after dosing with 300 and 150 mg nilotinib, respectively, but both doses yield similar motor, cognitive and biomarker effects, including 30% inhibition of CNS target [5].…”

“…Furthermore, because cancer drugs may have known targets and biochemical pathways, their use in neurodegeneration may help identify novel biomarkers of drug effects. Measurement of certain molecules as biomarkers of cell death like neuron-specific enolase (NSE) may not have been previously explored in PD or AD, but nilotinib treatment suggests that this molecule may serve as PD-related biomarker as CSF NSE level was significantly reduced after nilotinib treatment in PD patients [5]. HVA and NSE could give an indication of either symptomatic or disease-modifying effects of nilotinib in neurodegenerative diseases.…”

“…Nilotinib is not detected in the CSF (t 1/2~1 .8) 3 h after dosing suggesting short bioavailability compared to plasma t 1/2 = 12.4 [5]. The CSF:plasma concentration of nilotinib is 12% and 5% after dosing with 300 and 150 mg nilotinib, respectively, but both doses yield similar motor, cognitive and biomarker effects, including 30% inhibition of CNS target [5]. Taken together these data suggest that low brain concentration and short CNS bioavailability of cancer drugs may be advantageous as some cancer drugs may induce vasogenic edema, accelerate cell loss, and exacerbate inflammation.…”