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

Abstract

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. K E Y W O R D SAbelson, activities of daily living, alpha-synuclein, dementia with Lewy bodies, dopamine Highlights• Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrier• Bosutinib is safe and tolerated in individuals with dementia with Lewy bodies• Bosutinib engages its target via inhibition of Abl and Src• Bosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamine • Bosutinib improves activities of daily living in dementia with Lewy bodiesThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

“…A follow-up study involving analysis of CSF in these patients with PDD or DLB previously treated with nilotinib [ 50 , 54 ] showed that nilotinib altered CSF microRNAs that regulate autophagy genes [ 55 ]. A further study from the same group randomised 26 participants with DLB to receive bosutinib 100mg orally or placebo for 12 weeks [ 56 ]. It showed that bosutinib was safe and well tolerated, penetrated the BBB to inhibit Abelson kinase and reduce CSF α-synuclein and dopamine catabolism.…”

“…It showed that bosutinib was safe and well tolerated, penetrated the BBB to inhibit Abelson kinase and reduce CSF α-synuclein and dopamine catabolism. Secondary clinical outcome analyses showed that the bosutinib group had improved activities of daily living as measured with the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) but had no improvements in all other clinical, cognitive, neuropsychiatric and motor outcomes tested [ 56 ].…”

Outcome Measures for Dementia With Lewy Body Clinical Trials

“…Interventions (from both sources) included donepezil (8),10–17 memantine (8),18–25 rivastigmine (4),26–29 levodopa (4),30–33 nelotanserin (3),34–36 intepirdine (3),37–39 yokukansan (3),40–42 armodafinil (2),43,44 deep brain stimulation (2),45,46 nilotinib (2),47,48 and 1 each of galantamine,49 olanzapine,50 quetiapine,51 ramelton,52 zonisamide,53 tacrine,54 citalopram,55 feru-guard,56 tryptophan depletion,57 treadmill walking,58 cognitive rehabilitation,59 cognitive stimulation,60 and electroconvulsive therapy/transcranial magnetic therapy 61. The comparators were placebo (26),8,14–18,20–22,25,26,32,33,35,36,45,48–51,55,60–65 treatment as usual,59,60 sham stimulation (2),45,46 relaxation therapy (1),59 risperidone,55 and different doses of donepezil (1),17 nelotanserin (1),36 and intepirdine (1) 39. In all 4 levodopa studies, comparisons were made to patients with PD and/or PDD 30–33.…”

Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

“…Bosutinib, another tyrosine kinase inhibitor approved for chronic myeloid leukemia, was associated with less worsening in CDR-SB and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) performance in an open label study with 15 AD and 16 PDD patients after 1 year of treatment [18]. A phase 2 clinical trial was recently completed in DLB showing adequate safety and tolerability, reduction of CSF a-synuclein and dopamine catabolism, and functional improvement in activities of daily living [19].…”