Background

Bosutinib is an oral inhibitor of Abl and Src tyrosine kinases that has been approved since 2012 for the treatment of chronic myeloid leukemia. At the therapeutic dose of 500 mg/day, its common side effects are diarrhea, nausea, and vomiting. The drug can also cause myelosuppression.

Bosutinib and another Abl inhibitor, nilotinib, are candidates for repurposing to treat the α-synucleinopathies Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and other neurodegenerative conditions. The inhibitors promote autophagy, which facilitates clearance of neurotoxic protein aggregates in neurons.

In preclinical work, bosutinib reduced levels of α-synuclein in mice expressing the human A53T α-synuclein pathogenic mutation. Bosutinib was reported to enhance dopaminergic neuron survival, and modulated the immune response to α-synuclein (Lonskaya et al., 2013; Hebron et al., 2014).

In other mouse models, bosutinib treatment facilitated α-amyloid and tau clearance, changes in immune markers, and cognitive improvement (Lonskaya et al., 2013; Lonskaya et al., 2015; Hebron et al., 2018). The drug also protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenqiang et al., 2014). 

In cell and animal models of amyotrophic lateral sclerosis, bosutinib enhanced survival and function of motor neurons (Imamura et al., 2017; Osaki et al., 2018).

Findings

In September 2016, a Phase 1, open-label study began to evaluate bosutinib’s tolerability in people with mild cognitive impairment or dementia. The single-center study at a private neurological practice in Santa Monica, California, has enrolled 71 volunteers between age 45 and 89 with a Clinical Dementia Rating from 0.5 to 2. Participants start out on 100 mg bosutinib daily, with the dose increasing monthly to a top dose of 300 mg as tolerated. Total treatment time is one year, and the primary outcome is the number of patients who discontinue treatment due to side effects. A publication describes results of dementia evaluation on 31 participants who completed one year of treatment and one year of follow-up (Mahdavi et al., 2021). The patients had probable AD dementia or Parkinson's dementia. During the year of treatment, participants declined less according to the Quick Dementia Rating System and the Repeatable Battery Assessment of Neuropsychological Status, than expected from population estimates. No difference was found on the MoCA. Sixteen patients reached one year of follow-up; as a group, their worsening was no different than the population-based estimate. The trial will run through December 2023.

In April 2019, a Phase 2 trial began testing bosutinib in people with DLB. The single-center study at Georgetown University, Washington, D.C., would enrolled 26 patients for a 12-week regimen of 100 mg drug or placebo per day, followed by a four-week follow-up. The primary outcome was safety and tolerability. Secondary measures included plasma and CSF bosutinib levels and changes in a panel of plasma and CSF biomarkers including dopamine metabolites, Aβ, total and phosphorylated tau, oligomeric α-synuclein, as well as additional markers of cell death and inflammation. The trial finished in August 2021, and results were published after peer review (Pagan et al., 2022). Among the 25 men and one woman in the trial, there were no serious adverse events and no dropouts. CSF drug concentrations reached 2 percent of plasma, and were adequate to inhibit the kinase. Treatment reduced phosphorylation of the Abl protein in CSF compared to placebo, and lowered CSF α-synuclein. Plasma markers of dopamine breakdown were reduced. Exploratory efficacy assessments revealed improvement in activities of daily living after 12 weeks of treatment, but no change in cognitive measures.

An open-label Phase 1 study in ALS patients is underway in Japan. In March 2019, Kyoto University investigators began recruiting 24 patients to compare treatment with 100, 200, 300, or 400 mg/day bosutinib for 12 weeks, with a four-week follow-up (Imamura et al., 2019). The primary outcome is the occurrence of dose-limiting toxicity during treatment or follow-up. The trial will also measure change from baseline in lung function and grip strength, and blood levels of neurofilament proteins. The study will finish in 2022. 

Bosutinib is also being evaluated in other types of cancer. For details on bosutinib trials, see clinicaltrials.gov.