ABLi Therapeutics announced breakthrough results from its Phase 2 "201 Trial" evaluating risvodetinib in patients with untreated Parkinson's disease, marking the first time an experimental treatment has demonstrated reduction in alpha-synuclein pathology, widely recognized as the underlying cause of the neurodegenerative condition. The results were presented as the "Clinical Breakthrough Lecture" during the keynote session at the 2025 Movement Disorders Society Annual Congress.
The multicenter, double-blind, placebo-controlled trial (NCT05424276) evaluated 126 participants randomized to receive either 50 mg, 100 mg, or 200 mg of risvodetinib or placebo once daily for 12 weeks. The study represents the first long-term dosing trial of the selective, brain-penetrant c-Abl kinase inhibitor as a monotherapy in untreated Parkinson's disease patients.
Safety Profile Exceeds Expectations
Risvodetinib met its primary endpoint in safety and tolerability, with the fraction of participants experiencing adverse events and the average number of adverse events per person remaining similar to placebo. Notably, 95% of enrolled participants completed the full 12-week dosing regimen with 99% dosing compliance.
Common adverse events including nausea, diarrhea, vomiting, edema, or cardiovascular events occurred no more frequently in participants receiving any dose of risvodetinib compared to those receiving placebo. The frequency of falling reported as an adverse event was reduced nearly 5-fold for risvodetinib treatment relative to placebo treatment.
"The outcomes of the 201 Trial were wholly unexpected," noted Dr. Milton Werner, Chairman & Chief Executive Officer of ABLi Therapeutics. "We had seen a good safety profile with 7-day dosing, but didn't anticipate the drug would have an adverse event profile similar to placebo at longer dosing durations, with none of the typical side-effects of other drugs in the class."
Functional Improvements Show Promise
The trial demonstrated impact on key secondary endpoints related to Activities of Daily Living, considered the most important metric for evaluating clinical benefit. The MDS-UPDRS Part 1, Part 2, and the Schwab & England Activities of Daily Living (SEADL) scales favored treatment at all doses.
Specifically, the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 2 reached nominal statistical significance at the 100 mg dose, while the Schwab & England Activities of Daily Living Scale (SEADL) achieved nominal statistical significance at the 50 mg dose. An approximate dose-response trend was observed on Part 2 of the MDS-UPDRS, with 13 of 15 secondary outcome assessments showing numerical trends favoring risvodetinib over placebo.
First Demonstration of Alpha-Synuclein Reduction
Perhaps most significantly, exploratory endpoints demonstrated that risvodetinib reduced alpha-synuclein pathology in skin biopsy samples at all doses. This finding represents a potential breakthrough in Parkinson's disease treatment, as no previous experimental therapy has shown the ability to reduce the disease-causing pathology.
"We think the most important measure beyond safety is the confirmation that Risvodetinib can reduce the alpha-synuclein pathology that drives Parkinson's disease," said Dr. Werner. "This outcome is the first measure of an experimental treatment reducing the disease-causing pathology of PD."
The exploratory biomarker data revealed a dose-dependent reduction in cutaneous neuronal alpha-synuclein deposition in a subset of patients, suggesting a potential disease-modifying effect that aligns with the hypothesized mechanism of action and supports earlier preclinical findings linking c-Abl inhibition with clearance of pathological alpha-synuclein aggregates.
Unique Therapeutic Approach
Risvodetinib represents a novel approach to Parkinson's disease treatment as a potent, selective small-molecule inhibitor of non-receptor c-Abl kinases, designed for once-daily oral use. The drug targets the underlying biological mechanisms driving Parkinson's disease initiation and progression, positioning it as a potential disease-modifying therapy.
The compound's human exposure is two-fold to 200-fold higher than any c-Abl inhibitor currently approved for human use, necessitating the 12-week safety evaluation before proceeding to registrational studies. All currently marketed therapeutic approaches for Parkinson's disease help manage symptoms but do not slow or stop the disease's progression.
Future Development Plans
While the trial was not powered to demonstrate definitive efficacy on clinical outcomes, the consistency of motor and nonmotor improvements, combined with the safety profile and reduction in alpha-synuclein, supports continued investigation of risvodetinib as a potential disease-modifying therapy. A larger, longer-term phase 3 trial is anticipated to further assess clinical efficacy and durability of response, as well as confirm the drug's effect on alpha-synuclein burden.
Since the trial's completion, ABLi has utilized new blood-borne biomarkers to establish that the underlying treatment rationale, first elucidated by the company and its collaborators from animal models, is also the active mechanism of neurodegeneration in humans. Risvodetinib currently has intellectual property protection beyond 2036.
