#3337 The NefXtend trial, investigating extended nefecon treatment beyond 9 months in patients with IgAN

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by excess production of galactose-deficient immunoglobulin A1 predominantly in the gut-associated lymphoid tissue of the distal ileum, resulting in immune complex deposition in the glomeruli. Nefecon is an oral, targeted-release capsule formulation of the glucocorticoid budesonide specifically designed to achieve localized delivery to the mucosal Peyer's patches of the distal ileum. In the Phase 3 NefIgArd trial, nefecon 16 mg/day substantially reduced urine protein–creatinine ratio (UPCR) and stabilized estimated glomerular filtration rate (eGFR) over a 9-month treatment period. During the 15-month observational follow-up period, UPCR and eGFR benefit was maintained up to 2 years post-baseline. However, despite the sustained off-drug treatment benefit, some resumption of eGFR decline could be observed among nefecon recipients, as well as partial rebound in UPCR 15 months after the end of treatment. The NefXtend trial aims to evaluate the efficacy and safety of extended treatment with nefecon to a total of 2 years in patients with IgAN who have completed an initial 9-month course of nefecon 16 mg/day treatment in real-world clinical practice. Method This Phase 4, open-label, multicenter trial is enrolling adult patients with primary IgAN who are receiving 9 months of treatment with nefecon 16 mg/day. After a 1-month screening period during their last month of standard nefecon treatment, participants will seamlessly transition to trial treatment, consisting of a further 6-month treatment period of nefecon 16 mg/day, followed by 9-months of nefecon 8 mg/day. After this, they will enter a 3-month follow-up period, including a 2-week tapering period on nefecon 4 mg/day before complete treatment cessation. Retrospective medical records, including kidney function data, will be collected from the two most recent assessments prior to, and any assessments during the standard 9-month nefecon 16 mg/day treatment period. Inclusion criteria: age ≥18 years old, biopsy-confirmed IgAN, ongoing, tolerated 9-month course of nefecon 16 mg/day treatment (with no substantial interruptions or dose reductions within 8 weeks prior to trial treatment, and no longer than 2 weeks at any point), proteinuria ≥0.5 g/day or UPCR ≥0.3 g/g based on two consecutive measurements, and stable, ongoing renin–angiotensin system inhibitor treatment for at least 8 weeks prior to baseline. Patients on a stable dose of sodium-glucose co-transporter-2 (SGLT2) inhibitors will be eligible. Exclusion criteria include systemic immunosuppressive medications (including systemic glucocorticoids) during the standard nefecon treatment period, other glomerular diseases, current or planned dialysis, previous kidney transplantation, and poorly controlled diabetes or hypertension. Results We plan to enroll up to 60 participants with IgAN across 40 trial sites in the US. The primary endpoint is the ratio of UPCR, based on 24-hour urine collection, at 6 months from start of extended treatment regimen compared to baseline (i.e. study start, after 9 months of standard nefecon 16 mg/day). Secondary endpoints include UPCR at 15 months (i.e. after 6 months of nefecon at 16 mg/day and 9 months at 8 mg/day) versus baseline; eGFR and 24-hour proteinuria at 6 and 15 months versus baseline; UPCR and eGFR at 6 and 15 months, compared to baseline (based on historical records), and the proportion of participants with microhematuria at 6 and 15 months. Safety outcomes include adverse events (AEs), serious AEs, and AEs of special interest (steroid effects, infections). Conclusion This trial is currently recruiting patients and will evaluate whether extending treatment with nefecon to 2 years in total may provide additional and better-sustained proteinuria reduction as well as more complete kidney function preservation in patients with IgAN. Clinical trial registration number: NCT06712407.