Objective: This is a retrospective biomarker study of an open-label clinical study to examine the safety and efficacy of lower doses (<50% of CML dose) of Nilotinib in human. 

Background:

Parkinson’s disease (PD) is a neurodegenerative disorder that affects motor and non-motor functions. Our pre-clinical data indicate that the tyrosine kinase inhibitor (TKI) Nilotinib improves motor behavior and cognition in several models of neurodegeneration. Nilotinib is FDA-approved for the treatment of chronic myeloid leukemia (CML) at 800mg oral dose twice daily. 

Methods:

We randomized 12 participants with mid-late stage PD with dementia (PDD) or Lewy body dementia (LBD) into 150mg (N=5) or 300mg (N=7) groups, who received oral daily doses of Nilotinib for 6 months. 

Results:

We found that most patients who received 150mg Nilotinib were diagnosed with LBD and treatment resulted in motor improvement as measured by Unified Parkinson Disease Rating Scale (UPDRS)-III and timed-up-and-go. ELISA measurement of CSF oligomeric/monomeric α-synuclein showed a significant increase between baseline and 6 months, but CSF cell death marker (phosphorylated) p-neurofilament was significantly reduced. The change in CSF biomarkers correlated (Pearson’s R) with improvement in UPDRS-III (3 points) and 50% improvement in timed-up-and-go in LBD patients.

Patients who received 300mg Nilotinib were diagnosed with PD or PDD and showed no change in CSF oligomeric α-synuclein between baseline and 6 months treatment but CSF p-neurofilaments were significantly reduced. UPDRS-III was improved (3 points) in these patients but timed-up-and-go was excellent (average 4s/10 feet) at baseline and did not change at 6 months. There was a correlation (Pearson’s R) between reduction in CSF p-neurofilaments and UPDRS-III (3 points) in PD and PDD.

Conclusions:

CSF oligomeric α-synuclein increased at 6 months compared to baseline in LBD and remained stable in PD and PDD. Nilotinib significantly reduced cell death marker p-neurofilaments in CSF in both 150mg (LBD) and 300mg (PDD) groups and this reduction in p-neurofilaments associated with motor improvement, suggesting that p-neurofilaments may correlate better with clinical outcomes. These data indicate that further clinical studies are needed to determine the effects of Nilotinib in PD and differentiate its effects on PD/PDD compared to LBD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nilotinib-differentially-affects-oligomeric-%ce%b1-synuclein-and-reduces-phosphorylated-neurofilaments-and-motor-symptoms-in-parkinsons-disease-with-dementia-and-lewy-body-dementia/