Objective: To investigate the safety, biomarkers effects and determine the lowest effective dose of Bosutinib
in Dementia with Lewy Bodies (DLB)
Background: The effects of bosutinib, a dual Abelson (Abl)/Src inhibitor, were investigated in Dementia with Lewy Bodies (DLB). Bosutinib (Bosulif, Pfizer) is FDA approved at 500mg oral daily dose for leukemia. We investigated bosutinib, 100mg, which is equivalent to the lowest effective intraperitoneal daily dose (5mg/kg) in pre-clinical studies. Bosutinib was investigated in several models of neurodegeneration and it was shown to facilitate clearance of alpha-synuclein and other neurotoxic proteins via autophagy, protect dopaminergic neurons and improve motor and cognitive behavior in animals.
Method: A single center, Phase 2, randomized, double-blind, placebo-controlled study primarily investigated the safety and pharmacokinetics of 12-week oral treatment of bosutinib,100mg. Biomarkers and clinical outcomes were exploratory.
Results: Approximately 120 subjects were approached, 39 were screened, 13 did not meet inclusion criteria and 26 were randomized and included male and female (12:1) in bosutinib and male (13) in placebo with average age 72.94±8.8 (year±SD). There was no serious adverse events (SAEs) and no difference in AEs and no dropouts. Bosutinib, 100mg, was detected in the cerebrospinal fluid (CSF) and inhibited both Abl and Src in plasma. Bosutinib significantly reduced CSF alphasynuclein and the ratio of CSF/plasma alpha-synuclein compared to placebo. Bosutinib significantly (p=0.034) improved activities of daily living (ADCS-ADL-MCI) compared to placebo.
Conclusion: This study showed that bosutinib is safe and enters the brain. Bosutinib, 100mg, inhibited Abl/Src indicting dual target engagement, reduced brain alpha-synuclein and improved activities of daily living, suggesting that this is lowest effective dose (100mg) in DLB. This study is underpowered (by design) but the data will guide adequately powered future studies of a higher dose range of bosutinib (100-400mg) over longer time (6 months) in DLB.
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To cite this abstract in AMA style:F. Pagan, Y. Torres-Yaghi, M. Hebron, R. Turner, B. Wilmarth, S. Matar, D. Ferrante, J. Ahn, C. Moussa. Safety, Target Engagement and Effects of Bosutinib in Dementia with Lewy Bodies [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/safety-target-engagement-and-effects-of-bosutinib-in-dementia-with-lewy-bodies/. Accessed December 7, 2023.
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