The October 10 sessions of the PARASOL kickoff meeting for APOL1 kidney disease and membranous nephropathy (MN) projects continued the conversation between leading nephrologists, clinical trialists, and researchers on strategies to address regulatory biomarkers and endpoints in APOL1 kidney disease, and primary membranous nephropathy. The mission of the PARASOL initiative is to accelerate the development of effective therapies and improve outcomes for patients with rare and complex kidney diseases. Its new membranous nephropathy project will explore the potential for aPLA2R to be used as a surrogate endpoint in clinical trials and a qualitative marker for monitoring disease severity, as well as expanding the data-driven understanding of other potential proteinuria-based endpoints for PMN trials. The focus of the APOL1 kidney disease project is to advance understanding of potential proteinuria-based surrogate endpoints for use in clinical trials in APOL1 kidney disease.
The day began with a deep dive into the biology and disease logic of primary membranous nephropathy and APOL1 kidney disease, with Tobias B. Huber (UKE Hamburg) and Kirk Campbell (University of Pennsylvania) reviewing the latest research and current understanding of each condition from genetic, epidemiologic, and mechanistic perspectives. Dr. Huber discussed the biological plausibility of PLA2R as a marker of disease activity in MN, supported by animal models and clinical data, and the potential implications of these findings for clinical trial design and regulatory acceptance. Dr. Campbell's presentation highlighted the need for more granular data, international collaboration, and targeted therapies, as well as the challenges in defining APOL1 as a disease versus a disease modifier.
The APOL1 breakout session emphasized the need for a breadth of data from multiple diverse datasets and international collaboration to validate surrogate clinical trial endpoints in APOL1. Participants surveyed available and potential datasets and explored the strengths and limitations of various potential endpoint elements in the context of APOL1 kidney disease, as well as the heterogeneous nature of APOL1 kidney disease and its consequences for potential trial design approaches. The biostatistics team, led by Abigail Smith (Northwestern University) and Margaret Helmuth (University of Michigan) is tasked with translating these insights into an initial analysis plan in the coming weeks.
In the MN/PLA2R breakout session, Brad Rovin (Ohio State University) and colleagues reviewed historical data and previous work establishing proteinuria thresholds for different glomerular diseases. The group discussed the pathogenic role of PLA2R antibodies, the need for standardized assays, and the potential for personalized treatment strategies based on PLA2R levels and epitope spreading. The session concluded with a call for more shared data to analyze PLA2R as a potential surrogate endpoint, while recognizing the challenges of assay variability and the desire for global consensus.
Throughout the day, participants addressed the anticipated challenges of data collection, inclusion and exclusion criteria, and the need for comprehensive genetic and clinical data. The discussions underscored the importance of including multiple, inclusive datasets to identify meaningful subgroups and inform future clinical trials and treatment strategies. In closing, the meeting reinforced the necessity of international collaboration, data sharing, and standardized protocols to advance APOL1 and MN research. The next steps will include expanding the working groups, developing analytic plans and engaging with registries and cohorts to collect the necessary data. The PARASOL team invites participation from interested parties with relevant patient-level longitudinal data from cohorts of any size. In the words of Laurel Damashek (International Society of Glomerular Disease), "One of the lessons from PARASOL FSGS that we're carrying into the future is that no dataset is too small when we all work together to answer these big questions."
For more information or to participate in the project, please contact parasol@is-gd.org.