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Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis and a major cause of chronic kidney disease and kidney failure worldwide. Recent data on long-term outcomes from a large cohort of patients with IgAN have highlighted that patients with proteinuria <0.88 g/g have high rates of kidney failure within 10 years. This means IgAN cannot be considered benign even when proteinuria is <1 g/day. Early intervention with disease-modifying therapies may be particularly effective early in the natural history of IgAN, before the onset of irreversible kidney fibrosis.
Nefecon, a novel, oral, targeted-release budesonide formulation, is specifically designed to treat IgAN by inhibiting galactose-deficient-IgA1 formation in the Peyer’s patch-rich distal ileum. In the phase III, multicenter, randomized, double-blind NefIgArd clinical trial, we demonstrated that Nefecon treatment for 9 months led to a significant reduction in the average decline in estimated glomerular filtration rate (eGFR) over 2 years in patients with primary IgAN, which was preserved during a 15-month follow-up period off drug. The benefit of Nefecon was consistent across subgroups, including patients with baseline urine protein–creatinine ratio (UPCR) above and below 1.5 g/g. Here we extended the analysis to those with baseline UPCR levels above and below 0.8 g/g to further explore potential benefits of Nefecon.
Patients aged ≥18 years with primary IgAN, eGFR of 35–90 mL/min/1.73 m2, persistent proteinuria with a high risk of kidney failure, defined as either UPCR ≥0.8 g/g or proteinuria ≥1 g/24 h or both, despite optimized renin–angiotensin system blockade, were considered eligible. Patients received a 9-month treatment course of Nefecon 16 mg/day or placebo in addition to supportive care, followed by a 15-month observational period off study drug. In this analysis, the change in eGFR (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula [CKD-EPI]) was measured at multiple timepoints over 2 years and compared with baseline, for those patients with UPCR <0.8 g/g or ≥0.8 g/g.
In the full analysis set of 364 patients, 72 had a baseline UPCR <0.8 g/g (despite having a baseline total proteinuria measure ≥1 g/24 h) and 292 had a baseline UPCR ≥0.8 g/g. Over the 2-year study period, the mean change in eGFR remained higher in the Nefecon arm vs placebo arm regardless of baseline UPCR. Relative to baseline, there was an eGFR benefit with Nefecon treatment for those with baseline UPCR <0.8 g/g which remained beneficial for up to 18 months following treatment initiation, despite treatment cessation at Month 9 (Figure 1). There was a significant difference between the Nefecon and placebo arms in the ratio of geometric least-squares means for eGFR-weighted average over 2 years for patients with UPCR <0.8 g/g (p=0.0026) and ≥0.8 g/g (p<0.0001); the absolute change in eGFR favored Nefecon over placebo by 4.4 and 5.1 mL/min/1.73 m2 in those with UPCR <0.8 g/g and ≥0.8 g/g, respectively (Table 1).
These findings support that the eGFR benefit from 9 months of Nefecon treatment is also seen and is clinically meaningful in patients with UPCR <0.8 g/g.