The PARASOL (Proteinuria and GFR as Clinical Trial Endpoints in Focal Segmental Glomerulosclerosis) working group, a collaborative international effort involving academics and regulators, convened a scientific workshop in Washington DC on October 7-8, 2024, to discuss the use of proteinuria-based endpoints for accelerated and traditional marketing approval in FSGS kidney disease. The workshop's findings, presented on October 25, 2024, suggest that broader proteinuria endpoints may be acceptable for FDA approval of drugs targeting FSGS.
Preliminary Analysis of Pooled Observational Data
The PARASOL project team presented a preliminary analysis of pooled, globally available observational data of FSGS patients at the American Society of Nephrology meeting in San Diego. This dataset includes a wide range of demographics, ages, and regions, and is not limited to randomized trial data, unlike the Dimerix ACTION3 Phase 3 clinical trial. The analysis confirmed the strong correlation between improvement in estimated glomerular filtration rate (eGFR) and the clinical endpoint of reduced risk of end-stage kidney disease. eGFR is currently the primary endpoint in Dimerix's ACTION3 Phase 3 clinical trial.
Implications for Proteinuria Thresholds
Workshop participants recognized that FSGS patients often have residual kidney scarring, preventing them from reaching the low levels of proteinuria seen in other kidney diseases. The PARASOL dataset demonstrated that higher proteinuria thresholds, including 0.7 g/g, 1.0 g/g, and up to 1.5 g/g, showed significant benefit in reducing the risk of progression to renal failure. These findings provide a range of potential proteinuria targets for drug candidates targeting FSGS, pending confirmation with the FDA.
FDA Perspective and Future Steps
The FDA indicated general agreement that the PARASOL working group has likely provided sufficient data to support the relationship between a reduction in proteinuria and decreased risk of kidney disease progression. The FDA may now have sufficient data to grant approval based on proteinuria endpoints, either as an alternative to eGFR alone or in combination with eGFR. However, each company will likely need to justify its proposed proteinuria threshold to the FDA, considering the drug candidate's safety profile and mechanism of action.
Dimerix's Strategy
For Dimerix and its ACTION3 Phase 3 clinical trial, these developments suggest that a range of proteinuria endpoints could be acceptable as a primary endpoint for FDA approval, subject to FDA agreement. Dimerix anticipates no changes to the ACTION3 study, as both eGFR and proteinuria data are being collected for two years. The company plans to request a meeting with the FDA to reach an agreement on appropriate proteinuria endpoints for DMX-200 in the ACTION3 Phase 3 clinical trial.
