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Abstract: FR-OR37

Nefecon® (Budesonide) Selectively Reduces Circulating Levels of BAFF (BLyS) and Soluble BCMA and TACI in IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Molyneux, Karen, Mayer IgA Nephropathy Laboratory, University of Leicester, UK, Leicester, Leicester, United Kingdom
  • Barratt, Jonathan, Mayer IgA Nephropathy Laboratory, University of Leicester, UK, Leicester, Leicester, United Kingdom
  • Wimbury, David Harry John, Mayer IgA Nephropathy Laboratory, University of Leicester, UK, Leicester, Leicester, United Kingdom
Background

Evidence supports a pivotal role for gut-associated lymphoid tissue (GALT) as a major source of poorly O-galactosylated immunoglobulin A (IgA) 1 in patients with IgA nephropathy (IgAN). IgA synthesis in GALT is regulated by B-cell activating factor (BAFF) [B-lymphocyte stimulator (BLyS)] and A PRoliferation-inducing ligand (APRIL). BAFF and APRIL bind to specific cell-surface receptors: transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI), B-cell maturation antigen (BCMA), and the BAFF receptor. Elevated levels of BAFF and APRIL have been linked to worse clinical outcomes in IgAN. The therapeutic potential of targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the efficacy of a novel targeted-release formulation of budesonide (Nefecon®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. The trial comprised 6-month run-in, 9-month treatment, and 3-month follow-up phases: 48 patients received Nefecon® 16 mg/day, 51 patients received Nefecon® 8 mg/day, and 50 patients received placebo. As a result, Nefecon® 16 mg/day, added to optimised renin–angiotensin system blockade, reduced proteinuria and stabilized estimated glomerular filtration rate in patients with IgAN. This study investigated whether Nefecon® treatment altered serum levels of BAFF and APRIL and their receptors.

Methods

Serum levels of BAFF, APRIL, BCMA, and TACI were measured using Luminex technology. Changes in the levels of each biomarker with treatment were compared using a one-way analysis of variance. Significance was set as p<0.05.

Results

A significant, dose-dependent reduction in serum BAFF levels was seen with Nefecon®, which reversed on cessation of Nefecon®. There were similar significant reductions in the levels of soluble BCMA and TACI with treatment, but no effect was seen on circulating levels of APRIL. These changes were mirrored by parallel changes in soluble CD27 levels and were consistent with our previous reports on dose-dependent reductions in circulating IgA–IgG immune complexes, secretory IgA, and galactose-deficient IgA levels with Nefecon®.

Conclusion

Delivering budesonide to the GALT-rich distal ileum modulates key regulators of GALT B-cell maturation and IgA class switch recombination in patients with IgAN.

Funding

  • Commercial Support