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Abstract Details

Nilotinib is a Multi Kinase Inhibitor that Alters Cerebrospinal Fluid (CSF) Biomarkers and Increases TREM2 Levels in Individuals with Parkinson Disease.
Movement Disorders
S10 - Biomarkers in Movement Disorders (4:36 PM-4:47 PM)
007

Nilotinib is a broad-based tyrosine kinase inhibitor with highest affinity to inhibit Abelson (c-Abl) and Discoidin Domain Receptors (DDR1/2). Preclinical evidence indicate that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson’s disease (PD). We previously showed that Nilotinib penetrates the blood-brain-barrier (BBB) and potentially improves clinical outcomes in individuals with PD and Dementia with Lewy Bodies (DLB).

We performed a physiologically-based population pharmacokinetics/pharmacodynamics (popPK/PD) study to determine Nilotinib effects in a cohort of 75 PD participants.

 

 Participants were randomized (1:1:1:1:1) into 5 groups (n=15) and received open label random single dose (RSD) 150:200:300:400mg Nilotinib versus placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3 and 4 hours after Nilotinib administration.

The results show that Nilotinib enters the brain in a dose-independent manner and 200mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and Homovanillic Acid (HVA), suggesting alteration of dopamine metabolism. Nilotinib appears to significantly reduce CSF oligomeric:total alpha-synuclein ratio and plasma total alpha-synuclein. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect.

Nilotinib penetrates the BBB and is detected in the CSF in a concentration independent manner. An optimal dose of 200mg Nilotinib potentially induces a concurrent change of dopamine metabolism, reduction of oligomeric alpha-synuclein and elevation of TREM2 levels in the CSF. Long-term effects of Nilotinib will be demonstrated in an ongoing phase II, randomized, double-blinded placebo controlled study in which patients will be treated for 12 months.

Authors/Disclosures
Charbel E. Moussa, PhD, MB (Georgetown University)
PRESENTER
Dr. Moussa has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for KeifeRX LLC. Dr. Moussa has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sun Pharmaceuticals Research Industry. Dr. Moussa has received stock or an ownership interest from Orphan Therapeutics. The institution of Dr. Moussa has received research support from NIA. The institution of Dr. Moussa has received research support from Sun Pharmaceuticals Research Industry. The institution of Dr. Moussa has received research support from Alzheimer's Association . Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received publishing royalties from a publication relating to health care. Dr. Moussa has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with DG Information Technology. Dr. Moussa has received personal compensation in the range of $0-$499 for serving as a Peer Reviews with National Institutes of Health.
Fernando L. Pagan, MD, FAAN (Georgetown University Hospital Dept of Neurology) Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Acorda. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Adamas. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merz. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kyowa Kirin. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for US World Meds. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Adamas. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurocrine. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Parkinsonism and related Disorders. Dr. Pagan has stock in Keiferx. The institution of Dr. Pagan has received research support from US World Meds. The institution of Dr. Pagan has received research support from Novartis.
No disclosure on file
No disclosure on file
Yasar A. Torres-Yaghi, MD Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Torres-Yaghi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amneal. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbott. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Kyowa Kirin. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Teva. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sunovion .
Abigail C. Lawler, MD (Inova neurology) No disclosure on file
Elizabeth E. Mundel, MD (MedStar Georgetown University Hospital) No disclosure on file
Nadia Yusuf, MD No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file