Change in Soluble Biomarker Levels in Patients with IgAN: Analysis of the Phase 2 Trial of Ravulizumab (SANCTUARY)

Background: Complement activation plays an important role in the pathophysiology of IgA nephropathy (IgAN), leading to inflammation and progressive kidney damage. In a phase 2 trial, clinically meaningful proteinuria reduction was observed with the complement C5 inhibitor, ravulizumab (RAV).1 Here, we evaluated change over time in soluble biomarkers in patients (pts) treated with RAV vs placebo (PBO). Methods: In SANCTUARY (NCT04564339), 66 adults with IgAN were randomized (2:1) to RAV (IV q8w) or placebo (PBO) for 26 weeks (wks). Spot urine was collected pre-dose on days 1, 15, 71, 127, and 183. Evaluable data were available from 60 pts. Validated immunoassays were performed on spot urine and soluble biomarker levels were normalized to urine creatinine (Cr). Longitudinal changes in biomarker levels were reported using descriptive statistics and a mixed model for repeated measures (MMRM) to compare RAV with PBO. Results: With RAV, there was early (by Day 15), sustained, and marked reduction in sC5b-9/Cr and Ba/Cr (complement pathway products) (Figure). Sustained reduction in CD163/Cr (macrophage renal infiltration marker) was observed starting at day 71. MMRM analysis of change from baseline to wk26 showed significant reduction in sC5b-9/Cr, Ba/Cr, CD163/Cr, and KIM-1/Cr (proximal tubule injury marker) with RAV vs PBO (Figure). Conclusion: In pts treated with RAV, there was an early and sustained reduction in biomarkers of complement activation and reduction in markers of macrophage renal infiltration and tubular injury. These results suggest reduced inflammation and kidney damage in response to C5 (terminal complement) inhibition and are consistent with the observed proteinuria reduction in SANCTUARY.1 1. Lafayette R, et al. J Am Soc Nephrol. 2025;36(4):645–656. Funding: Commercial Support - Alexion, AstraZeneca Rare Disease, Boston, MA, United States