Objective: To investigate the safety and tolerability of nilotinib, an FDA-approved drug for leukemia, in individuals with Huntington’s disease (HD).

Background: Previous clinical studies in neurodegeneration demonstrated that the tyrosine kinase inhibitor nilotinib is safe and well-tolerated, it achieves pharmacologically adequate CSF concentration to inhibit discoidin domain receptor (DDR)-1 and alters the levels of dopamine metabolites, including Homovanillic acid (HVA) suggesting an increase in brain dopamine. HD is a hereditary neurodegenerative disease caused by mutations in the Huntingtin’s (HTT) gene and characterized by motor and behavioral symptoms that are associated with dopamine receptors activation. We explored the effects of a low dose of nilotinib (150mg) on behavioral and motor symptoms in manifest HD patients.

Method: A single center, Phase 1b, open label study primarily investigated the safety and tolerability of 12-week oral treatment of niloitnib,150mg and explored its effects on biomarkers of disease, including HTT.

Results: Approximately 15 subjects were approached, 10 screened, 4 did not meet inclusion criteria and 6enrolled: male and female (2:1), average age 55.33±6.18 (year±SD). There were no serious adverse events (SAEs) and no dropouts. Nilotinib, 150mg, did not worsen or induce chorea and did not result is any behavioral changes, although it significantly reduced dopamine catabolism via attenuation of HVA levels. There was no significant change in HTT and no change in CSF inflammatory markers via immunoassays. Next generation whole miRNA genome sequencing of the CSF revealed significant longitudinal changes in miRNAs controlling specific genes associated with autophagy, inflammation, microglial activity and basal ganglia neurotransmitters, including dopamine and serotonin.

Conclusion: This study showed that nilotinib,150mg, is safe and tolerated in HD, despite the potential increase in dopamine levels. Changes in miRNAs are indicative of longitudinal alterations in autophagy and glial activity and point to strong inflammatory and bioenergetics changes, consistent with the clinical and neurodegenerative manifestations of HD. This study is small with no placebo and short duration of treatment, suggesting that the epigenomics changes may be due to disease progression or nilotinib effects. Larger, placebo-controlled studies are needed to determine the effects of nilotinib over a longer treatment period.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-and-tolerability-of-nilotinib-in-patients-with-huntingtons-disease/