Proteinuria as a Surrogate Endpoint for Disease Progression in IgA Nephropathy: Predicting Long-Term Treatment Effects of Sparsentan

Abstract

IgA nephropathy (IgAN) is a rare, life-limiting disease for which there is significant unmet need. Until recently, drug development for IgAN had been impeded by the requirement for large-scale, long-term clinical trials to measure clinical outcomes. However, the recent establishment of ‘reduction in proteinuria’ as a surrogate endpoint to predict clinical outcomes in IgAN, as a basis for accelerated drug approval, has transformed the field. At the 60th European Renal Association (ERA) Congress in June 2023, two oral poster presentations focused on the use of early reduction in proteinuria as an endpoint for clinical studies in IgAN. Alex Mercer, Consultant in Clinical Drug Development at JAMCO Pharma Consulting in Stockholm, Sweden, presented data estimating the long-term clinical outcome of reductions in proteinuria (clinically meaningful extensions in time to kidney failure or death), which could help predict the future protective effect of any new intervention on kidney function. Following this, Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, and Honorary Consultant Nephrologist at Leicester General Hospital, UK, described findings from the prespecified interim analysis of the Phase III PROTECT study of sparsentan (a novel dual endothelin angiotensin receptor antagonist) in IgAN, which included reduction in proteinuria as a primary endpoint. In patients with IgAN at high risk of disease progression, sparsentan produced a rapid and significant reduction in proteinuria of a level that, according to the study data presented by Mercer, would correspond to a substantially lowered risk of kidney failure or death. Long-term data to confirm this predicted clinical outcome on disease progression are anticipated.