Risvodetinib Phase 2 Trial: Safety and Skin‑Biopsy Changes in pSer129 α‑synuclein

Results from the randomized, double-blind phase 2a 201 Trial of risvodetinib in early, untreated Parkinson disease were reported with two parallel emphases: the trial’s primary safety and tolerability outcomes and an exploratory tissue biomarker readout from skin biopsies.

The biomarker analysis focused on phosphorylated Ser129 α-synuclein in cutaneous neurons (intra-axonal deposits), framed as a window into pathological α-synuclein deposition outside the central nervous system. Feasibility is described in terms of participant consent and completion of paired baseline and week-12 biopsies, alongside a longitudinal imaging-based assay that enabled within-participant comparisons in peripheral tissue. Overall, the report pairs trial conduct and safety reporting with an exploratory tissue signal measured in cutaneous neurons.

For the primary outcomes, the authors describe safety and tolerability over a 12-week dosing period with an additional 2-week safety follow-up, reporting that 95% of participants completed the regimen. They report that the fraction of participants experiencing at least one treatment-emergent adverse event and the average number of adverse events per person were similar between the risvodetinib and placebo groups. In that context, the safety dataset is presented as supporting the practical execution of study visits and assessments across the dosing interval, without extending those observations beyond the reported timeframe. The authors summarize safety and tolerability as comparable between groups during the period analyzed.

The exploratory skin-biopsy component is described as voluntary, with sampling at baseline and again at week 12 to enable longitudinal comparisons. Approximately 40% of randomized participants agreed to skin biopsy, and 36 participants had complete paired baseline and week-12 sample sets. Tissue was analyzed with immunofluorescence coupled to confocal microscopy, with quantification directed at phosphorylated Ser129 α-synuclein deposition in cutaneous neurons. The report describes presenting change at the participant level as fractional change relative to baseline, emphasizing directionality over time within each individual rather than relying solely on cross-sectional measurement. In this framing, the exploratory workflow centers on longitudinal within-participant comparisons using the specified imaging-based assay.

Within the exploratory dataset, the article reports 36 longitudinal skin-biopsy sample sets distributed across groups (10 placebo, 10 at 50 mg, 5 at 100 mg, and 11 at 200 mg). The authors describe a dose-graded pattern in which the proportion of participants showing reduced pathological α-synuclein increased with dose, reported as 30%, 60%, and 64% at 50 mg, 100 mg, and 200 mg, respectively, while also noting that differences versus placebo were not statistically significant. The report presents these findings as suggestive of a dose-related increase in the fraction with reduced pathology that did not meet statistical significance in this sample.

The authors also note several constraints on interpreting the biopsy findings as presented. Because biopsies were voluntary, the longitudinal biopsy sample set is described as limited in size and not necessarily representative of all randomized participants. The report further highlights variability in baseline pathological α-synuclein and heterogeneity in apparent responses across individuals, including the presence of participants without detectable deposition at both timepoints.

Finally, the study duration is characterized as short for drawing broader inferences from an exploratory pathology readout. In aggregate, the article positions the skin-biopsy signal as exploratory and bounded by the dataset’s scale, self-selection, and variability.

Key Takeaways:

• The article reports primary safety/tolerability outcomes over 12 weeks with an additional 2-week safety follow-up, with similar treatment-emergent adverse-event patterns and average adverse events per person between risvodetinib and placebo.
• An exploratory, voluntary baseline-to-week-12 skin-biopsy program used immunofluorescence and confocal microscopy to quantify pSer129 α-synuclein in cutaneous neurons, reporting within-participant fractional change.
• In the reported biopsy sample, higher dose aligned with a higher proportion of participants showing reduced pathological α-synuclein, while group differences versus placebo were not statistically significant and the authors noted limitations related to sample size, variability, and duration.