Objective: To compare and contrast nilotinib and vodobatinib regarding efficacy, brain penetration, and safety.

Background: Preclinical evidence suggests that c-Abl is critical for pathogenesis of Parkinson’s Disease (PD). Vodobatinib is a potent, orally bioavailable inhibitor of c-Abl currently being evaluated in patients with PD in the PROSEEK trial. Nilotinib, a multikinase inhibitor of c-Abl, was recently shown to be unsuccessful in slowing PD progression (Simuni et al. 2021). This failure of nilotinib at its maximally permissible dose of 300 mg was attributed to insufficient brain penetration because the concentration of nilotinib in the CSF was found to be 7 fold lower than its IC50 for c-Abl. Here we demonstrate that vodobatinib can adequately penetrate the blood brain barrier to provide potential beneficial effects in PD.

Method: Vodobatinib and nilotinib were evaluated for inhibition of c-Abl enzymatic activity.  Human healthy volunteers were dosed orally at 3 dose-levels of vodobatinib 7 days prior to intrathecal sampling of CSF over 24 hours for drug level measurement.

Results: Vodobatinib (IC50 0.9 nM) is a more potent c-Abl inhibitor than nilotinib (IC50 20 nM).  Oral dosing of vodobatinib for 7 days in three cohorts of healthy adult volunteers (six per cohort) demonstrated that observed steady state levels of 2.9-12 nM of vodobatinib in CSF over 24 hour period exceeded IC50 of c-Abl inhibition. Cmax : IC50 ratio of vodobatinib dosed daily at 384 mg was 13, which greatly exceeded the published ratio of 0.24 for nilotinib dosed at 300 mg. These results suggest that vodobatinib levels in the brain can be maintained over the treatment period to ensure optimal inhibition of c-Abl.

Conclusion: Higher potency and efficient brain penetration of vodobatinib suggest that vodobatinib offers a better opportunity than nilotinib to test whether c-Abl inhibition ameliorates disease progression in PD.

References: n/a

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MDS Abstracts - https://www.mdsabstracts.org/abstract/vodobatinib-a-potent-orally-bioavailable-brain-penetrating-inhibitor-of-c-abl-as-a-potential-neuroprotective-agent-for-the-treatment-of-parkinsons-disease/