Safety, target engagement, and biomarker effects of bosutinib in dementia with Lewy bodies.

Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB).
Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes.
Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism.
Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB.
Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies.
Competing Interests: Charbel Moussa is an inventor on a Georgetown University (GU) US and International Patent to use bosutinib in neurodegenerative diseases, including alpha‐synucleinopathies. GU exclusively licensed bosutinib use patent to KeifeRx LLC. Charbel Moussa and Fernando Pagan are founders and shareholders of KeiferX LLC, and Charbel Moussa and Jaeil Ahn are paid consultants to KeifeRX LLC. All other authors declare no conflict with this manuscript.
(© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)