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Safety and effects of bosutinib in Lewy body dementia

Presented By
Dr Fernando Pagán, Georgetown University Hospital, DC, USA
Presented by
Fernando Pagán MedStar Georgetown University Hospital
AAN 2022

A phase 2 study assessed the safety pharmacokinetics and biomarker effects of 12-week oral treatment with bosutinib in dementia with Lewy bodies (DLB). Bosutinib 100 mg inhibited Abl/Src in plasma, reduced brain alpha-synuclein, and improved activities of daily living. These outcomes will guide adequately powered larger studies in DLB.

Bosutinib is a dual Abl/Src tyrosine kinase inhibitor which is already approved at a daily oral dose of 400–600 mg for the treatment of chronic myeloid leukaemia (CML), with manageable side effects [1,2]. In preclinical studies, bosutinib (1–10 mg/kg) reduced neuropathological processes, including accumulation of neurotoxic proteins [3]. Bosutinib also increased brain dopamine levels (by >60%) in models of alpha-synucleinopathies [4]. Bosutinib has been shown to penetrate the brain, promote autophagic degradation of neurotoxic proteins, and improve motor and cognitive behaviour in Alzheimer’s disease (AD) and Parkinson’s disease (PD) models [5].

Dr Fernando Pagán (Georgetown University Hospital, DC, USA) and colleagues evaluated the safety and pharmacokinetics of 12-week oral treatment of bosutinib 100 mg [6]. Their single-centre, double-blind, placebo-controlled, phase 2 study enrolled 26 patients (25 male) with mild-to-moderate DLB. Average age of participants was 73 years. Randomisation was preceded by an open-label pharmacokinetics study, in which the 26 participants were randomised to a single dose of bosutinib 100 mg, 200 mg, or placebo. Both single doses of bosutinib resulted in a dose-dependent increase in plasma and CSF bosutinib levels.

The most important observation in the main study was that multiple dosing (during 12 weeks) of 100 mg bosutinib resulted in a dose-dependent effect: a more than 2-fold elevation in plasma and 9-fold elevation in CSF. The volume of distribution was large, suggesting that bosutinib was distributed extensively into tissues with low bioavailability. Bosutinib also exhibited high protein binding of 94%.

Bosutinib achieved a sufficiently high level to directly inhibit both Abl and Src in plasma, indicating dual target engagement. Bosutinib inhibited Abl/Src at IC50=1.2 nM. Bosutinib significantly reduced CSF alpha-synuclein (P=0.023) and the ratio of oligomeric/total alpha-synuclein (P=0.045) compared with placebo. Plasma oligomeric alpha-synuclein (P=0.04) and ptau181/Aβ42 (P=0.03) also significantly decreased. Finally, bosutinib significantly (P=0.034) improved activities of daily living (ADCS-ADL-MCI). There were no serious adverse events.

These results suggest that bosutinib 100 mg may be (or nearly be) the lowest effective dose to inhibit CSF Abl in DLB. More adequately powered studies are needed to further explore the effects of bosutinib.

  1. Cortes JE, et al. Blood. 2011;118(17):4567–76.

  2. Khoury HJ, et al. Blood. 2012;119(15):3403–12.

  3. Boschelli F, et al. Eur J Cancer. 2010;46(10):1781–9.

  4. Lonskaya I, et al. EMBO Mol Med. 2013;5(8):1247–62.

  5. Hebron ML, et al. Autophagy. 2013;9(8):1249–50.

  6. Pagan F, et al. Safety, Target Engagement and Effects of Bosutinib in Dementia with Lewy Bodies. S20.010, AAN 2022, 02–07 April, Seattle, USA.

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