Abstract: FR-PO859
Impact of Nefecon on Complement Pathways in IgA Nephropathy: An Analysis of Lectin, Alternative, and Terminal Pathways
Session Information
- IgA Nephropathy: Clinical, Outcomes, and Therapeutics
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Nawaz, Nadia, University of Leicester College of Life Sciences, Leicester, United Kingdom
- Thomas, Roisin Clare, University of Leicester College of Life Sciences, Leicester, United Kingdom
- Barratt, Jonathan, University of Leicester College of Life Sciences, Leicester, United Kingdom
Background
Complement system activation is increasingly recognized as a critical factor mediating glomerular damage in immunoglobulin A (IgA) nephropathy (IgAN), and can be a predictor of poor outcomes. Nefecon, a targeted-release formulation of budesonide for the treatment of IgAN, targets the gut-associated lymphoid tissue of the distal ileum. In the Phase 3 NefIgArd trial, 9 months of Nefecon 16 mg/day treatment significantly reduced proteinuria and slowed kidney function decline compared with placebo. In the Phase 2b NEFIGAN trial, biomarker analyses supported a role for Nefecon in modulating complement activation in IgAN. In this analysis, we investigated the effects of Nefecon on complement pathways in the NefIgArd trial.
Methods
Patients with IgAN received Nefecon 16 mg/day or placebo for 9 months on top of supportive care, followed by a 15-month observational period off study drug. Commercially available enzyme-linked immunosorbent assays were used to measure serum levels of mannan-binding lectin serine protease 2 (MASP2; lectin pathway), Factor B (alternative pathway) and complement 5 (C5; terminal pathway) at 3, 6, 9, 12, and 18 months (Nefecon group, n=110; placebo group, n=113). Unpaired t-tests were used to compare groups at each timepoint (significance threshold of p<0.05).
Results
Nefecon 16 mg/day treatment for 9 months resulted in a significant and sustained reduction in serum levels of factor B (3 months, p<0.0001; 6 months, p<0.0001; 9 months p<0.0001; 18 months p=0.04) vs placebo. By contrast, Nefecon treatment did not change serum levels of MASP2 or C5 at any timepoint.
Conclusion
The effect of Nefecon on complement pathways was analysed by examining representative proteins of the lectin, alternative, and terminal pathways. Nefecon specifically and significantly reduced serum levels of the alternative pathway protein, Factor B. This effect is likely to impact positively on reducing glomerular inflammation and provides additional support for the kidney-protective action of Nefecon in IgAN. This effect was specific for Factor B, as no significant effect was observed on critical lectin and terminal pathway proteins. We are currently investigating the mechanisms responsible for this specific modulation of the alternative pathway, which may obviate the need for additional complement inhibition for the treatment of IgAN.
Funding
- Commercial Support – Calliditas Therapeutics AB