#2642 Effects of Nefecon on hits 1, 2, and 3 of the pathogenic cascade of IgA nephropathy: a full NefIgArd analysis

Abstract Background and Aims The pathogenesis of immunoglobulin A nephropathy (IgAN) is commonly described as a multi-hit paradigm characterized by an increase in circulating levels of poorly O‑galactosylated IgA1 (Gd-IgA1) (referred to as “Hit 1”), which leads to the presence of IgA and IgG antibodies that bind to the Gd-IgA1 (“Hit 2”), and the formation of circulating IgA-containing immune complexes (IgA-IC) (“Hit 3”). These immune complexes have a propensity to accumulate in the mesangium, driving inflammation and scarring in the kidneys (“Hit 4”), leading to progressive nephron loss. To avoid kidney failure in the lifetime of patients with IgAN, there is a pressing need for disease-modifying therapies capable of targeting these pathogenic Hits, inhibiting mesangial IgA-IC accumulation and kidney damage. The gut-associated lymphoid tissue (GALT) is considered to be a major site for Gd-IgA1 production in patients with IgAN; Nefecon is an oral, targeted‑release formulation of budesonide that is designed to inhibit Gd-IgA1 production in the GALT. NefIgArd (NCT03643965) was a Phase 3, double-blind, randomized, placebo-controlled clinical trial in patients with IgAN at high risk of disease progression despite optimized supportive care. Patients received 9 months of treatment with either placebo or Nefecon 16 mg/day, before entering a 15-month off-drug observational period. Nefecon stabilized estimated glomerular filtration rate decline and was associated with a significant and durable reduction in proteinuria versus placebo. Here, we present data for all of the exploratory biomarker time points (baseline, 3, 6, 9, 12, and 18 months) from all consenting patients in the NefIgArd trial, looking in detail at changes in markers of Hits 1, 2, and 3 of the IgAN pathogenic cascade with Nefecon versus placebo. Method Gd-IgA1, IgG anti-IgA antibody, and IgA-IC levels were measured using serum samples collected at baseline and at 3, 6, 9, 12, and 18 months from 216 consenting NefIgArd participants (n = 108 per treatment group). Gd-IgA1 levels were assessed using a commercial assay, while IgG anti-IgA antibody and IgA-IC levels were measured using in‑house sandwich enzyme-linked immunosorbent assays. Comparisons between the placebo and Nefecon-treated groups were made using robust regression with multiple imputations, and with a significance threshold set at P < 0.05. Results Statistically significant reductions in circulating Gd-IgA1 levels were observed with Nefecon versus placebo at 3, 6, 9, and 12 months; however, levels were not significantly different at 18 months (Fig. 1A). Nefecon was also associated with significant reductions versus placebo in IgG anti-IgA antibodies at 3, 6, and 9 months of treatment, with levels approaching baseline by 12 months (i.e., 3 months post-treatment) and remained non‑significant at the 18-month time point (Fig. 1B). Additionally, treatment with Nefecon resulted in a significant reduction versus placebo in IgA-IC levels at 3 months, with numerical reductions maintained at 6 and 9 months in the Nefecon group (Fig. 1C). Conclusion Nefecon 16 mg/day was the first fully approved treatment for IgAN based on the Phase 3 NefIgArd trial findings. The 18-month NefIgArd biomarker data represent the most complete analysis to date of the effects of a drug on the IgAN pathogenic cascade, showing clear reductions in markers of Hits 1, 2, and 3 with Nefecon compared with standard of care alone. These findings, coupled with other previously published data, demonstrate that treatment with Nefecon has a direct disease-modifying effect in IgAN.