Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder causing motor and non-motor symptoms. PD is characterized by death of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta and formation of inclusions known as Lewy bodies (LBs) that primarily contain aggregated alpha-Synuclein. Nilotinib (Tasigna®, AMN107, Novartis, Switzerland) is approved by U.S. Food and Drug Administration (FDA) and is well tolerated for CML treatment at oral doses of 600-800mg daily. Nilotinib penetrates the brain and promotes autophagic degradation of alpha-Synuclein and p-Tau, leading to survival of DA neurons and improvement of motor function in PD models. For these studies, Nilotinib (1-10mg/kg daily) was used at significantly less than the clinically approved dose (up to 1200mg daily) in CML.

Based on strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative pathologies, including autophagic clearance of neurotoxic proteins, neurotransmitters (dopamine and glutamate), immunity and behavior, the investigators conducted an open label pilot clinical trial in advanced PD with dementia (PDD) and Dementia with Lewy Body (DLB) (stage 3-4) patients. Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. The investigators' data suggest that Nilotinib penetrates the brain and inhibits CSF Abelson (Abl) activity via reduction of phosphorylated Abl in agreement with pre-clinical data. Several studies show that CSF alpha-Synuclein and Abeta42 are decreased and CSF total Tau and p-Tau are increased in PD and DLB. The investigators' data show attenuation of loss of CSF alpha-Synuclein and Abeta40/42 with 300mg (50% of the CML dose) compared to 150mg Nilotinib after 6 months treatment. CSF homovanillic acid (HVA), which is an end by-product of dopamine, is significantly increased; and CSF total Tau and p-Tau are significantly reduced (N=5, P\<0.05) with 300mg Nilotinib between baseline and 6 months treatment. Despite the reduction of L-Dopa replacement therapies in our study, UDPRS I-IV scores improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6 months and worsened (13.7 points and 11.4 points) after 3 months withdrawal of 150mg and 300mg, respectively. Other non-motor functions e.g. constipation was resolved in all patients and cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) or the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) between baseline and 6 months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. These data are very compelling to evaluate the effects of Nilotinib in a phase II, randomized, double-blind, placebo-controlled trial in patients with PD.