What are the right endpoints to assess the effectiveness of new treatments for IgAN?

Immunoglobulin A nephropathy (IgAN) is a glomerular disease associated with a rapid estimated glomerular filtration rate (eGFR) decline, especially in the presence of severe proteinuria. The change in proteinuria and eGFR slope are accepted surrogate endpoints in clinical trials to establish the efficacy of new interventions for patients with IgAN. Proteinuria is an established surrogate marker for disease progression, with higher levels correlating with worse long-term outcomes. Meta-analyses have demonstrated that treatment effects on proteinuria over 6-9 months correlate with treatment effects on eGFR slope. The eGFR slope, particularly over 2-3 years, provides an indicator of renal function decline and long-term prognosis. Studies have demonstrated robust associations between treatment effects on eGFR slope and clinical kidney outcomes. Based on these studies, recent regulatory considerations support proteinuria change and eGFR slope as clinical trial endpoints for accelerated approval in IgAN trials, allowing for earlier assessment of treatment efficacy. Future trials can leverage these markers to streamline drug development, providing robust and timely evaluations of novel therapies. This review summarizes recent advances in the validation of clinical trial endpoints in IgAN and concludes with new developments in this area.