Objective: To evaluate if 3 newfound genetic subgroups represent differing aspects of disease biology in PD by determining if subgroup participants have differing responses to treatment in Phase 3 trials.
Background: PD may be considered to result from different biological mechanisms, but which converge on a clinical diagnosis of Parkinson’s Disease .
Method: A Bayesian approach analysed genetic data to capture heterogeneity in PD. WGS and pharmacokinetic data from two disease-modifying Phase 3 trials, where testing of isradipine (STEADY-PD3) or inosine/urate (SURE-PD3) did not show efficacy in early-stage PD, were modelled for treatment and exposure effects for multiple clinical outcomes in each of the 3 subgroups.
Results: We sought to identify Parkinson’s disease-relevant genetic signatures and identified a unique signal in two independent PD case-control cohorts that stratified PwP into three distinct subgroups (A/B/C). In STEADY-PD3 data we found subgroup C had better clinical outcomes across a number of clinical measures: C participants on isradipine showed a delayed time to requiring antiparkinson therapy, required less symptomatic treatment and progressed less rapidly in UPDRS I-III total scores (primary outcome) than C participants on placebo. These isradipine-dependent better outcomes were not seen in subgroups A and B. In SURE-PD3, subgroup A participants who achieved target urate levels (≥7.1mg/dL serum urate) had better clinical outcomes than A participants with below target levels, with an increased time until requiring antiparkinson therapy, less cumulative symptomatic treatment and a reduced mean change in MDS-UPDRS I-III total scores. Subgroup B and C participants did not show better outcomes.
Conclusion: Treatments that address the heterogeneity and complexity of PD are the most likely to benefit patients. We have identified a genetic signature, relevant to PD, that stratifies PwP into three subgroups. When applied to clinical data from two previously conducted Phase 3 clinical trials, it was evident that participants with differing genetic signatures responded differently to the trial therapeutic both within and between trials.
To cite this abstract in AMA style:
K. Hill, J. Cooper, J. Kozlowska, N. Olsen, R. Sultana, J. Surmeier, R. Wyse, N. Humphryes-Kirilov, A. Cooper. Genetic signatures stratify PwP into three subgroups with differing responses in two disease-modifying Phase 3 trials and indicate multiple disease biology pathways to Parkinson’s Disease [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/genetic-signatures-stratify-pwp-into-three-subgroups-with-differing-responses-in-two-disease-modifying-phase-3-trials-and-indicate-multiple-disease-biology-pathways-to-parkinsons-disease/. Accessed October 7, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-signatures-stratify-pwp-into-three-subgroups-with-differing-responses-in-two-disease-modifying-phase-3-trials-and-indicate-multiple-disease-biology-pathways-to-parkinsons-disease/