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 mid-to-advanced PD with dementia (PDD) and Dementia with Lewy Bodies
(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 suggests that Nilotinib
penetrates the brain and inhibits CSF Abelson (Abl) activity via reduction of phosphorylated
Abl in agreement with pre-clinical data. Several studies suggest that CSF alpha-Synuclein and
Abeta42 are decreased and CSF total Tau and p-Tau are increased in PD and DLB. The
investigators data shows 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 a by-product of dopamine metabolism, 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, the Unified Parkinson's Disease Rating Scale (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 an open label proof-of-concept study in patients with
HD.