#2808 A mechanistic biopsy study of the effect of iptacopan on immunopathology in patients with IgA nephropathy (IgAN)

Abstract Background and Aims Overactivation of the complement system via the alternative pathway (AP) is a key driver of immunoglobulin A nephropathy (IgAN) pathophysiology. This mechanistic study aims to evaluate the effects of iptacopan, a selective oral complement factor B inhibitor, on the underlying immunopathology in patients with IgAN. Method This Phase IIa multicenter, single-arm, open-label, repeat-biopsy study will enroll up to 20 adult patients with biopsy-proven IgAN, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, proteinuria ≥0.8 g/g or 1 g/day, and receiving a maximally tolerated and/or stable dose of supportive care treatment (angiotensin converting enzyme inhibitor or angiotensin receptor blocker and sodium-glucose co-transporter 2 inhibitors) for ≥90 days before baseline (Fig. 1). Patients will receive iptacopan 200 mg bid for 9 months, with kidney biopsies at baseline and study end. The primary objective is to quantify changes in mesangial complement 3c (C3c) and its C3c-containing fragment deposition from baseline to 9 months. The secondary objectives are to describe the histopathological changes after iptacopan treatment, changes in CD68+ cells and immunoglobulins from baseline at 9 months. The exploratory objectives include evaluating the histopathological changes in complement biomarkers after iptacopan treatment, changes in the MEST-C scores from baseline at 9 months; describing changes in urine protein–creatinine ratio (UPCR; log-transformed ratio to baseline of UPCR), hematuria (change from baseline in dipstick and red blood cell per high power field [RBC/HPF] at 9 months), and eGFR (change from baseline at 9 months); and exploring the correlation of histopathological changes with UPCR and eGFR changes. Results Conclusion This study will explore the impact of iptacopan on IgAN immunopathology by assessing glomerular complement activation together with renal histopathology, kidney function, and key biomarkers. The findings will enhance understanding of iptacopan's mechanistic effects on IgAN and potential kidney protective benefits.