Background

Vodobatinib is a third-generation c-Ableson tyrosine kinase inhibitor. It is structurally similar to the commercial anticancer agents Dasatinib and Ponatinib (Antelope et al., 2019). Abl kinase inhibitors induce autophagy, leading to the death of rapidly dividing cells (Salomoni and Calabretta, 2009). 

Some drugs in this class have been proposed for repurposing as a disease-modifying treatment for synucleinopathies including Parkinson’s disease and dementia with Lewy bodies (e.g., see nilotinib, bosutinib, risvodetinib). The rationale is based on the finding that activated Abl kinase contributes to pathogenesis by phosphorylating α-synuclein and promoting its aggregation and toxicity, and by inhibiting neuroprotective effects of the parkin protein (e.g., Ko et al., 2010). In cells, nilotinib promoted α-synuclein degradation by autophagy (Mahul-Mellier et al., 2014). Abl kinase inhibitors prevented loss of dopaminergic neurons in mouse models of Parkinson's disease (Karuppagounder et al., 2014; Imam et al., 2013; Hebron et al., 2013).

No preclinical work is published to date for Vodobatinib. The company claims it is neuroprotective in two mouse and one rat model of PD (Sep 2019 investor presentation, slides 25-28). K0706 has a reported IC50 for c-Abl of 0.9 nM.

Findings

From 2017-2019, the company conducted three Phase 1 studies relevant to the PD indication. A bioavailability study compared different formulations in healthy adults. A second study compared two weeks of daily doses from 6 to 384 mg or placebo in 60 people with Parkinson’s disease. Another Phase 1 study in 2018-2019 assessed brain penetration of the drug, by measuring CSF drug levels after seven days of 48, 192, or 384 mg daily in 18 healthy men. According to results presented at the 2019 AAN meeting, no serious adverse events were observed in the PD patients (Goldfine et al., 2019). Blood levels increased with dose and reached estimated therapeutic levels based on PD animal models. Observed blood and CSF drug concentrations guided the choice of dose for subsequent Phase 2 trials. Phase 1 data were published after peer review (Walsh et al., 2023).

In February 2019, the company began a Phase 2 study in Parkinson’s disease, called PROSEEK. It planned to enroll 504 people with early Parkinson’s who were not taking dopamine therapy, and randomizing them to 192 mg or 384 mg K0706, or placebo, once a day for 40 weeks. The primary outcome was change from baseline on the MDS-UPDRS Parts 2 and 3, although that was later changed to only Part 3. Secondary outcomes were change in MDS-UPRDS all parts, time to start symptomatic medication, health-related quality of life, clinical impression of change, and autonomic symptoms. Exploratory outcomes include DAT-Spec brain dopamine scans, blood and CSF drug levels, and α-synuclein deposition in skin. The trial, at 77 sites in the U.S., Hungary, India, Poland, Slovakia, and Spain, was to run through March 2023. In an April 10, 2024 press release, the company announced that PROSEEK had failed to meet its primary endpoint. Vodobatinib at either dose did not change the MDS-UPDRS Part 3 total score, and the study was terminated.

In September 2019, a single-center investigator-initiated Phase 2 study at Georgetown University Hospital began testing vodobatinib in dementia with Lewy bodies. The plan was to randomize 45 participants to 96 or 192 mg K0706 or placebo daily for 12 weeks. The primary outcome is adverse events; secondaries are pharmacokinetics, and CSF and plasma biomarkers of kinase inhibition. The study will also assess cognition, behavioral symptoms, and motor function using standard scales, with a planned end date of October 2023. As of January 2025, the status of this trial is unknown. In 2024, vodobatinib for DLB was removed from the company pipeline.

K0706 is also being tested for chronic and acute myeloid leukemia. The drug reportedly was well tolerated at doses up to 204 mg in a Phase 1 study in people with chronic AML (meeting abstract), and a larger Phase 1/2 trial is ongoing.

For details on K0706 trials, see clinicaltrials.gov.