POS-830 NEFECON FOR THE TREATMENT OF IgA NEPHROPATHY IN PATIENTS AT RISK OF PROGRESSING TO END-STAGE RENAL DISEASE: THE NEFIGARD PHASE 3 TRIAL RESULTS

Abstract

Peyer’s patches located within the gut-associated lymphoid tissue have been identified as a major source of poorly O-galactosylated immunoglobulin A (IgA)1, which triggers the formation of nephritogenic immune complexes in IgA nephropathy (IgAN). The therapeutic potential of targeting Peyer’s patches in patients with IgAN was demonstrated in the Phase 2 NEFIGAN trial, which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON), designed to deliver budesonide to the Peyer’s patches in the ileum. Patients treated for 9 months with NEFECON 16 mg/day demonstrated a significant (~30%) reduction in urine protein-to-creatinine ratio (UPCR) compared with placebo, and stabilization of estimated glomerular filtration rate (eGFR). Based on these data, the Phase 3 NefIgArd trial is a two-part design: Part A evaluates proteinuria reduction as a surrogate of the effect of NEFECON on long-term kidney function preservation. NefIgArd is a randomized, double-blind, placebo-controlled clinical trial recruiting a total of 360 patients across 155 nephrology clinics in 20 countries. Patients must be aged ≥18 years with biopsy-confirmed primary IgAN, proteinuria >1 g/24 h and eGFR 35–90 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Patients are randomized on a 1:1 ratio to NEFECON 16 mg/day or placebo. The primary endpoint, based on the first 199 patients, is the percentage decrease in proteinuria (UPCR) after 9 months of treatment. The secondary objectives include the difference in kidney function between NEFECON-treated subjects and those on placebo, as measured using eGFR, and the urine albumin-to-creatinine ratio (UACR) at 9 months compared with baseline. Between September 2018 and October 2020, 657 subjects were screened. Of these, 306 patients were randomized and 199 with 9 months of follow-up were included in the efficacy analyses of Part A of the study. At 9 months, the geometric mean UPCR was reduced by 27% in the NEFECON group compared with the placebo group (p=0.0005). At 9 months, the NEFECON group provided a statistically significant 7% (3.87 mL/min/1.73m2) treatment benefit on eGFR (p=0.0029), compared with placebo. There was a similar overall incidence of adverse events in the two treatment groups. The NefIgArd study met its primary endpoint and demonstrated a favorable safety profile. These results are indicative of a clinically meaningful reduced risk of future progression to end-stage renal disease in patients with IgAN treated with NEFECON. This trial will continue in order to validate UPCR reduction as a surrogate of long-term renal function preservation.