Abstract: PUB222
Soluble Biomarkers in IgAN: Analysis of Baseline Data from the Phase 2 Trial of Ravulizumab (SANCTUARY)
Session Information
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Cammett, Tobin J., Translational Research, Alexion, AstraZeneca Rare Disease, New Haven, Connecticut, United States
- Millman, Ellen E., Translational Research, Alexion, AstraZeneca Rare Disease, New Haven, Connecticut, United States
- Luna, Julio Cesar, Translational Research, Alexion, AstraZeneca Rare Disease, New Haven, Connecticut, United States
- Rice, Kara, Biostatistics, Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
- Garlo, Katherine, Clinical Development, Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
- Kateifides, Andreas, Clinical Development, Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
- Nolan, Stephen, Clinical Development, Alexion, AstraZeneca Rare Disease, Dublin, Ireland
- Williams, Cory, Clinical Development, Alexion, AstraZeneca Rare Disease, New Haven, Connecticut, United States
- Lafayette, Richard A., Stanford Glomerular Disease Center, Stanford University Medical Center, Stanford, California, United States
- Barratt, Jonathan, University of Leicester, Leicester, United Kingdom
- Farag, Youssef MK, Clinical Development, Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
Background
In IgA nephropathy (IgAN), immune complex formation and deposition leads to complement activation, culminating in complement terminal pathway-mediated inflammation and kidney damage. Validated soluble biomarkers of disease activity and pathophysiology are needed in IgAN. This analysis aimed to characterize biomarkers using baseline data from the ph2 trial (NCT04564339) of ravulizumab (RAV) (a complement C5 inhibitor) and from healthy adult normal donors (ND).
Methods
Soluble biomarker levels in 60 pts with IgAN at baseline in SANCTUARY and from a validation cohort of up to 25 ND were compared. Biomarkers were measured from spot urine samples: sC5b-9 and factor Ba (complement pathway products), CD163 (macrophage renal infiltration marker), KIM-1 (specific marker of renal proximal tubule injury), and NGAL (marker of renal tubule injury). A stringent sample collection protocol was implemented for all samples and immunoassays were developed and validated to FDA guidance (Bioanalytical Method Validation, 2018). Biomarkers were normalized to urine creatinine (Cr).
Results
Baseline levels of 4 of 5 urine biomarkers were significantly elevated in pts with IgAN vs ND: sC5b-9/Cr, Ba/Cr, CD163/Cr, and KIM-1/Cr (p<0.0001 for all) (Table). These 4 biomarkers were also elevated above the upper limit of normal (observed mean for ND + 2 SD) in >50% of pts with IgAN, at baseline: sC5b-9 elevated in 93% of pts, CD163 in 82%, Ba in 65%, and KIM-1 in 62%.
Conclusion
Soluble urine biomarkers of complement activation, inflammation, and proximal tubule injury were detected at significantly higher levels in this cohort of patients with IgAN vs ND, and the vast majority (56/60) had elevated terminal complement activation (urine sC5b-9). These results provide insights into the pathophysiology of IgAN and suggest the potential clinical utility of soluble biomarkers in this heterogenous disease.
Funding
- Commercial Support – Alexion, AstraZeneca Rare Disease, Boston, MA, United States