Specificity of Nefecon in Targeting Pathogenic IgA in IgA Nephropathy While Preserving Systemic Humoral Immunity

Background: Nefecon, an FDA- and EMA-approved targeted-release formulation of budesonide, is recognized for its efficacy in treating immunoglobulin (Ig) A nephropathy (IgAN) by specifically targeting the gut-associated lymphoid tissue (GALT). In the Phase 2b NEFIGAN trial, Nefecon 16 mg/day significantly reduced levels of pathogenic galactose-deficient IgA1 (Gd-IgA1) and IgA-containing immune complexes (IgA-IC) vs placebo, but not IgA1, total IgA, or total IgG. Subsequently, an interim analysis of the larger Phase 3 NefIgArd trial confirmed that Gd-IgA1 (p<0.0001) and IgA-IC (p=0.0169) were significantly reduced by 9 months of Nefecon 16 mg/day treatment vs placebo. The trial also showed significant proteinuria reduction and kidney function benefit over 2 years with Nefecon vs placebo. Here, we assess the effect of Nefecon on total serum Ig levels in NefIgArd. Methods: In NefIgArd, 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. Enzyme-linked immunosorbent assays (ELISAs) were used to measure serum levels of IgA1, total IgA, and anti-tetanus toxoid antibodies (Nefecon group, n=110; placebo group, n=113), as well as serum levels of total IgG (Nefecon, n=32; placebo, n=38 [at 9 months]). An in-house ELISA was used to measure serum anti-tetanus toxoid Igs; commercial ELISAs were otherwise used. Serum Ig levels were compared between groups at baseline, 3, 6, 9, 12, and 18 months, using unpaired t-tests (significance level p<0.05). Results: There was no significant change from baseline in anti-tetanus toxoid Igs, total IgA, or total IgG levels following Nefecon 16 mg/day treatment for 9 months. There was a slight reduction from baseline in IgA1 at 3 months with Nefecon (p=0.02), with no reductions at any other timepoint. Conclusion: The ability of Nefecon to specifically modulate pathogenic Gd-IgA1 production in the GALT, while leaving systemic IgA responses and total IgA and IgG levels unchanged, supports its use as a generally well tolerated, targeted, locally-acting treatment option for IgAN. Unlike other B cell−directed therapies currently in development for IgAN, Nefecon does not impair systemic humoral immunity and, therefore, offers a therapeutic advantage by selectively reducing pathogenic Gd-IgA1 while preserving overall serum Ig levels. Funding: Commercial Support - Calliditas Therapeutics AB