Session Information
Date: Thursday, June 23, 2016
Session Title: Parkinson's disease: Clinical trials, pharmacology and treatment
Session Time: 12:00pm-1:30pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: The objective was to determine whether Nilotinib crosses the blood brain barrier (BBB).
Background: Parkinson’s disease (PD) involves death of dopamine producing neurons in the Substantia Nigra Nigra pars compacta. Accumulation of alpha-Synuclein within intracellular inclusions known as Lewy bodies (LBs) is the pathological hallmark of Synucleinopathies, including PD, Lewy body dementia (LBD) and Multiple system atrophy (MSA). As PD progresses, Tau and beta-amyloid (Abeta) pathologies coincide with the onset of dementia, reminiscent of Alzheimer’s disease (AD).
Methods: Nilotinib concentration was measured in plasma and cerebrospinal fluid (CSF) at baseline, 2 months (interim) and 6 months. Pharmacodynamics analysis was performed to determine target engagement via measurement of CSF phosphorylated Abl (activity) in addition to neurodegeneration biomarkers, including α- Synuclein, dopamine breakdown by-product homovanillic acid (HVA), Total Tau and pTau181/231, Aβ42 and Aβ40. Cell death biomarkers, including CSF neuron specific enolase (NSE) and glial and neuronal marker S100B were measured.
Results: Nilotinib significantly reverses loss of CSF α-Synuclein and restores its plasma level to baseline. Nilotinib significantly increases the concentration of CSF homovanillic acid, suggesting an increase in central dopamine stores despite reduction of L-Dopa therapy. Nilotinib significantly alters CSF levels of total Tau and hyper-phosphorylated (p-Tau)231 and pTau181 and Aβ42 and Aβ40. Nilotinib significantly reduces CSF cell death markers, including neuron specific enolase (NSE) and S100B.
Conclusions: Pre-clinical data indicate that the tyrosine kinase Abl (Abelson) inhibitor Nilotinib penetrates the brain and induces autophagic clearance of alpha-Synuclein, hyper-phosphorylated Tau (p-Tau) and Abeta. The results of phase-I open label clinical trial of 12 participants taking 150mg and 300mg Nilotinib show a significant alteration in CSF biomarkers and increase of endogenous dopamine. Additionally, the apparent motor and cognitive outcomes may be attributed to reduction of neurotoxic proteins and/or the increase of endogenous dopamine via mesolimbic signaling to pre-frontal cortex. The data provide feasibility for multicenter, randomized, placebo-controlled, double blind studies in PD and other neurodegenerative diseases.
To cite this abstract in AMA style:
C. Moussa, E. Valadez, Y. Torres-Yaghi, A. Keys, R. Falconer, S. Rogers, B. Wilmarth, M. Hebron, F. Pagan. Nilotinib significantly alters CSF biomarkers and increases endogenous dopamine in open-label phase I clinical trial in Parkinson’s disease with dementia and Lewy body dementia [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/nilotinib-significantly-alters-csf-biomarkers-and-increases-endogenous-dopamine-in-open-label-phase-i-clinical-trial-in-parkinsons-disease-with-dementia-and-lewy-body-dementia/. Accessed June 15, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/nilotinib-significantly-alters-csf-biomarkers-and-increases-endogenous-dopamine-in-open-label-phase-i-clinical-trial-in-parkinsons-disease-with-dementia-and-lewy-body-dementia/