Analysis of the NefIgArd Part A Study Population Confirms Nefecon Reduces Levels of Dietary Antigen-Specific IgA in Patients with IgA Nephropathy

Background: Nefecon, the targeted-release formulation of budesonide, is delivered to the gut-associated lymphoid tissue (GALT) of the terminal ileum, a major site of immunoglobulin A (IgA) production. The Phase 3, double-blind, randomized controlled clinical trial NefIgArd tested the efficacy of Nefecon in patients with IgA nephropathy (IgAN) at high risk of progressive kidney disease despite optimized supportive care. The trial comprised 9 months of treatment with either placebo or Nefecon 16 mg/day, and a 3-month (Part A) or 15-month (Part B) off-drug observational follow-up period. Treatment with Nefecon 16 mg/day significantly reduced proteinuria after 9 months of treatment compared with placebo (p=0.0003) and this effect was maintained, along with preservation of estimated glomerular filtration rate (p<0.0001), over the 15-month off-drug observational follow-up period. The aim of this study was to determine the effect of Nefecon treatment on circulating levels of dietary antigen-specific IgA, secretory IgA, and a marker of gut permeability, fatty acid-binding protein 2 (FABP2). Methods: Circulating levels of anti-gliadin IgA, anti-casein IgA, secretory IgA and FABP2 were measured in baseline serum samples and 3, 6, and 9 months after randomization during Part A of the NefIgArd trial using enzyme-based immunosorbent assays. Comparisons between placebo and Nefecon-treated groups were made at each study time point using unpaired t-tests, with a significance level of p<0.05. Results: Treatment with Nefecon 16 mg/day significantly reduced levels of anti-gliadin IgA at 3 months (p=0.044), 6 months (p=0.029), and 9 months (p=0.027), and levels of anti-casein IgA at 9 months (p=0.023), compared with antibody levels at baseline. These data are consistent with Nefecon 16 mg/day results obtained in the Phase 2b NEFIGAN clinical trial. No significant changes were seen in levels of secretory IgA or FABP2. Conclusions: Reductions in IgA antibodies against mucosally encountered antibodies confirm a local mucosal effect of Nefecon in IgAN. This effect is likely mediated by a direct action on GALT B cell IgA production rather than an effect on gut permeability and increased antigen exclusion.