Abstract Details

Title Nilotinib significantly alters miRNAs that control genes of the inflammatory, bioenergetics and transport pathways in the CSF of Parkinson’s patients

Topic Movement Disorders

Presentation(s) Movement Disorders Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 166

Objective We analyzed the CSF of Parkinson's Disease patients using next generation whole genome miRNA sequencing.

Background Nilotinib is a tyrosine kinase inhibitor that potently and preferentially inhibits (IC50 1nM) Discoidin domain receptors (DDRs) and is FDA-approved for the treatment of chronic myelogenous leukemia (CML) as an inhibitor of c-Abelson (IC50 >20nM).

Design/Methods We conducted a Phase 2 study that enrolled 75 Parkinson’s patients, who were randomized into a single dose of 100mg, 200mg, 300mg and 400mg nilotinib versus placebo (n=15 per group). These participants were re-randomized into multiple dose of nilotinib, 150mg and 300mg, versus placebo for 12 months (n=25 per group). Following 3 months wash-out, participants were randomized into an open label nilotinib, 150mg and 300mg for 12 months.

Results A total of approximately 2500 miRNAs were detected in the CSF. There was no difference in miRNAs after a single dose. The multiple dose study showed that nilotinib was measured in the CSF in a dose-dependent manner up to (Cmax) 1.8 nM and 3.4 nM in nilotinib, 150mg and 300mg, respectively. Approximately 59 miRNAs significantly changed directionality between placebo and nilotinib, but after adjustment for multiple comparisons significant changes were observed in cellular and molecular pathways that regulate tyrosine kinase signaling, inflammation, angiogenesis, bio-energetics, (de)-ubiquitination, ribosomal and lysosomal pathways.

Conclusions Nilotinib achieves a pharmacologically adequate CSF concentration that would inhibit DDRs and affects multiple tyrosine kinase pathways that are involved in the regulation of inflammation, blood brain barrier (angiogenesis) and protein clearance via ubiquitination and autophagy. These data are in agreement with pre-clinical evidence and suggest that miRNA sequencing in human CSF provides an alternative approach to determine biomarkers based on regulation of molecular pathways relevant to neuropathology. Furthermore, this study suggests that data from Phase 2 studies can be used to predict biomarker and clinical outcomes in lager Phase 3 trials.

Authors/Disclosures
Yasar A. Torres-Yaghi, MD PRESENTER	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 .
Alan Fowler	Mr. Fowler has nothing to disclose.
	No disclosure on file
Fernando L. Pagan, MD, F�鶹��ýӳ�� (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
Charbel E. Moussa, PhD, MB (Georgetown University)	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.

�鶹��ýӳ��

�鶹��ýӳ��