Vodobatinib Fails To Slow Early Parkinson Disease In Phase 2 Trial

Key Takeaways

• Neither vodobatinib dose showed benefit over placebo on the week-40 MDS-UPDRS Part III primary endpoint.
• Several secondary measures also favored placebo, including shorter time to significant worsening in the high-dose group.
• Discontinuation increased with dose, cerebrospinal fluid exposure exceeded the in vitro c-Abl IC50, and serum neurofilament light chain rose in both active-treatment groups.

In the phase 2 PROSEEK trial, vodobatinib did not improve the week-40 primary motor outcome versus placebo in early Parkinson disease. Among 513 randomized participants, median time to significant worsening was 20.0 weeks with 384 mg versus 41.1 weeks with placebo, and plasma and cerebrospinal fluid exposure increased with dose during treatment. Overall, the efficacy pattern did not show benefit for either vodobatinib dose.

PROSEEK was a phase 2, randomized, double-blind, placebo-controlled study in early Parkinson disease. At 73 sites in six countries, 513 participants were assigned in a 1:1:1 ratio to vodobatinib 384 mg, vodobatinib 192 mg, or placebo. Eligible participants were at least 50 years old, had Parkinson disease diagnosed within 3 years, had modified Hoehn and Yahr stage 2 or less, had confirmatory DaT-SPECT findings, and had no dopaminergic therapy except stable MAO-B inhibitor use. Part 1 lasted 40 weeks, Part 2 was an optional 36-week extension with placebo participants switching to high-dose treatment, and the primary endpoint was change from baseline to week 40 in MDS-UPDRS Part III total score.

At week 40, observed mean change in MDS-UPDRS Part III was 1.0 ± 7.6 with 384 mg, 1.5 ± 8.8 with 192 mg, and -1.0 ± 8.1 with placebo. In the prespecified repeated-measures analysis, treatment differences versus placebo were 2.3 points for 384 mg and 2.1 points for 192 mg. The corresponding 90% confidence intervals were 0.4 to 4.2 and 0.4 to 3.8, with one-sided p values of 0.977 and 0.980. Combined MDS-UPDRS Parts II and III and combined Parts I through III moved in the same direction, favoring placebo, and the high-dose hazard ratio for significant worsening versus placebo was 1.8. Together, the broader efficacy results did not support clinical benefit.

Among 511 treated participants, 300 completed Part 1, and withdrawal increased with dose. Discontinuation rates were 62% in the high-dose group, 33% in the low-dose group, and 28% with placebo. Adverse events occurred in 87%, 77%, and 74% of those groups, while discontinuations due to adverse events were 31.8%, 15.2%, and 7.8%, respectively. Gastrointestinal disorders were reported in 34.0% of vodobatinib-treated participants versus 24.0% with placebo, including diarrhea in 11.0% versus 4.2% and nausea in 10.5% versus 6.0%; serious adverse events occurred in 4.0%, 8.2%, and 3.0%, and one death in the low-dose arm was judged unrelated to study drug. Overall, tolerability was worse at the higher dose.

For vodobatinib, plasma and cerebrospinal fluid exposure increased with dose, and day-252 cerebrospinal fluid concentrations reached 8.4 nM with 192 mg and 16.5 nM with 384 mg. Those levels exceeded the in vitro c-Abl IC50, yet serum neurofilament light chain increased significantly in both active groups compared with placebo. Median week-40 increases were 1.51 pg/mL with placebo, 3.92 pg/mL with 192 mg, and 5.70 pg/mL with 384 mg. A cerebrospinal fluid synSAA substudy did not alter the overall efficacy direction, and one Slovakian site was excluded from efficacy analyses because of data integrity concerns, although site audits did not identify systemic study-conduct problems.

The authors interpreted the findings as supporting inefficacy in this early Parkinson disease population and as highlighting a translational gap between preclinical and clinical results, while noting high differential dropout and limited worsening among placebo completers.