A targeted-release formulation of budesonide—designed to deliver drug to the distal ileum—reduces proteinuria in patients with IgA nephropathy who don’t respond to first-line treatment, reports a trial in The Lancet.
The phase 2b NEFIGAN trial included patients with confirmed IgA nephropathy and persistent proteinuria at 62 European nephrology clinics. All patients were on optimized renin-angiotensin system (RAS) blockade, which continued throughout the study. After stratification by baseline urine protein creatinine ratio (UPCR), patients were randomly assigned to TRF-budesonide, 8 or 16 mg/d, or placebo. The main efficacy outcome was change in UPCR from baseline to 9 months of treatment.
On planned interim efficacy analysis in 149 patients, the combined TRF-budesonide groups had a mean 24.4% reduction in UPCR, compared to an increase of 2.7% in the placebo group. The 16 mg/d dose group had a significant 27.3% reduction in UPCR, while the 21.5% reduction in the 8 mg/d group fell short of significance.
The reduction in proteinuria was associated with changes in 24-hour urine protein and albumin excretion and urine/albumin creatinine ratio. These changes were sustained throughout the study, including a 3-month follow-up phase. The researchers write, “This persistence of effect following cessation of treatment suggests a disease-modifying effect.”
On safety analysis in 150 patients, the overall incidence of adverse events was similar across groups. Of 13 serious adverse events, 2 were considered possibly associated with TRF-budesonide: one patient had deep vein thrombosis and another had unexplained decline in renal function.
For patients with IgA nephropathy who have persistent proteinuria despite optimized RAS blockade, high-dose systemic corticosteroids are the recommended treatment. The pathogenesis of IgA nephropathy is thought to involve mucosal B-lymphocyte activation and proliferation in Payer’s patches. The TRF-budesonide evaluated in NEFIGAN targets the distal ileum, which has a high density of Payer’s patches.
At a 16 mg/d dose, TRF-budesonide added to optimized RAS blockade reduces persistent proteinuria in patients with IgA nephropathy. The researchers conclude: “TRF-budesonide has the potential to become the first disease-specific treatment for IgA nephropathy, with a risk-benefit profile supportive of its use early in the course of disease” [Fellström BC, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial. Lancet 2017; DOI: http://dx.doi.org/10.1016/S0140-6736(17)30550-0].
