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.

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.