P0344NEFECON® (BUDESONIDE) SELECTIVELY REDUCES CIRCULATING LEVELS OF BAFF (BLYS) AND SOLUBLE BCMA AND TACI IN IGA NEPHROPATHY
Authors: Molyneux Karen , Wimbury David , Barratt Jonathan 
Published: June 2020

Abstract

Background and Aims
There is increasing evidence to support a pivotal role for the gut-associated lymphoid tissue (GALT) as a major source of the poorly O-galactosylated immunoglobulin A1 (IgA1) that triggers the formation of nephritogenic immune complexes in IgA nephropathy (IgAN). Critical to the regulation of IgA synthesis in GALT are two cytokines, which regulate B-cell maturation, function and survival: BAFF (B-cell activating factor [also known as BLyS (B-lymphocyte stimulator)]) and APRIL (A PRoliferation-inducing ligand). BAFF and APRIL bind to specific cell-surface receptors: TACI (transmembrane activator and calcium modulator and cyclophilin-ligand interactor), BCMA (B-cell maturation antigen) and the BAFF receptor. Several studies have shown elevated levels of BAFF and APRIL in IgAN linked to worse clinical outcomes. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and 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 a 6-month run-in, 9-month treatment and 3-month follow-up phase: 48 patients received NEFECON® 16 mg/day, 51 patients received NEFECON® 8 mg/day and 50 patients received placebo. The headline result of the study was that NEFECON® 16 mg/day, added to optimised renin–angiotensin system blockade, reduced proteinuria and stabilised estimated glomerular filtration rate in patients with IgAN. In this study, we aimed to determine whether NEFECON® treatment altered synthesis of the BAFF and APRIL B-cell maturation modulators.

Method
Serum levels of BAFF, APRIL, BCMA and TACI were measured using Luminex technology. Changes in the levels of each biomarker between randomisation (T0), end of treatment (T1) and the end of study (T2) and between treatments arms were compared using a one-way analysis of variance. Significance was set at p&lt;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 are consistent with our previous reports describing a dose-dependent reduction 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 in IgAN. Although the samples available are not sufficient to determine that the observed changes in serum BAFF, BCMA and TACI levels are due to a direct action on GALT, it is intriguing to note that BAFF-transgenic mice develop an IgAN-like disease, principally due to IgA overexpression in the intestinal lamina propria.