Objective: Risvodetinib was evaluated in a randomized, double-blind, placebo controlled Phase 2 trial at three doses to determine the safety and tolerability in patients with early untreated Parkinson’s disease.

Background: Risvodetinib is a brain-penetrant, selective inhibitor of the non-receptor kinases c-Abl1 and c-Abl2.  C-Abl has been implicated in the initiation and progression of Parkinson’s disease.  In animal models of slowly-progressive, inherited or sporadic disease, risvodetinib, at the same doses administered to humans, halted disease progression, restored lost neuronal function in the brain and GI tract, suppressed microglial activation and drove clearance of alpha-synuclein deposition in the central and enteric nervous systems.

Method: The 201 Trial (NCT05424276) was a 12-week, randomized, double-blind, placebo- controlled trial evaluating 50 mg, 100 mg and 200 mg once daily oral doses of risvodetinib in early untreated PD. The primary endpoints were safety and tolerability. Secondary endpoints included MDS-UPDRS Parts 1, II and III alone and in combination, Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Severity (CGI-S), Non-Motor Symptom Score (NMSS), Schwab & England Activities of Daily Living score (SEADL), PDQ-39 summary score, Epworth Sleepiness Scale, and assessments of upper and lower GI function including the Complete Satisfaction of Bowel Movement (CSBM) score. A subset of patients was assessed at initial and final visits for change in tissue-deposited pathological alpha-synuclein.

Results: Risvodetinib exhibited high steady-state plasma exposures with mild-to-moderate adverse events with a frequency and severity similar to placebo.  It was overall safe and well-tolerated, with 95% of enrolled participants completing the 12-week regimen, meeting the study’s primary endpoint. 15 secondary assessments evaluated motor and non-motor features of disease, with MDS-UPDRS Part II and SEADL reaching nominal significance at the 100 mg and 50 mg dose, an approximate dose response to Part 2 and 13 of 15 secondary assessments favored treatment.  Among exploratory outcomes, risvodetinib induced a treatment and dose-dependent reduction in cutaneous neuronal alpha-synuclein deposition.

Conclusion: Risvodetinib met its primary endpoints and functional assessments trended toward clinical benefit supported by a direct effect of treatment on neuronal alpha-synuclein deposition.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-study-of-risvodetinib-in-untreated-parkinsons-disease/