EFFICACY AND SAFETY OF A TARGETED-RELEASE FORMULATION OF BUDESONIDE (HR19042 CAPSULES) IN PATIENTS WITH PRIMARY IgA NEPHROPATHY: A RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO-CONTROLLED PHASE 2/3 TRIAL

IgA nephropathy (IgAN) is a chronic, immune-mediated glomerular disease and a leading cause of kidney failure worldwide. Increasing evidence implicates the gut-associated mucosal immune system in its pathogenesis. HR19042 is a novel oral, targeted-release formulation of budesonide designed to deliver the drug to the distal ileum, where gut-associated lymphoid tissue is most abundant. This phase 2/3 trial evaluated the efficacy and safety of HR19042 in adults with primary IgAN.

In this randomized, double-blind, placebo-controlled, multicenter phase 2/3 trial (ClinicalTrials.gov identifier NCT05016323), adults (≥18 years) with biopsy-confirmed primary IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m², and persistent proteinuria (urine protein–creatinine ratio [UPCR] ≥ 0.5 g/g or proteinuria ≥ 0.75 g/24 h) despite at least 3 months of optimized renin–angiotensin system blockade were enrolled at 49 sites across China. After a ≥3-month run-in period, patients were randomly assigned (1:1:1) via an interactive response technology system, stratified by baseline UPCR (>0.9 g/g vs ≤0.9 g/g), to receive HR19042 capsules 12 mg/day, 16 mg/day, or matching placebo for 9 months, followed by a 2-week tapering period, a 2.5-month safety follow-up, and an optional 12-month long-term extension. Optimized supportive therapy was maintained throughout. The co-primary endpoints were the ratio of change in UPCR from baseline to Month 9 and the change in eGFR from baseline to Month 12.

A total of 316 patients were randomized and received at least one dose of study treatment (HR19042 12 mg, n = 106; HR19042 16 mg, n = 105; placebo, n = 105). The median age was 36 years (range, 18–68), and 55.1% were female. The geometric mean baseline UPCR was 1.06 g/g, and the mean (SD) eGFR was 78.94 (25.81) mL/min/1.73 m²; 70.9% of patients had an eGFR greater than 60 mL/min/1.73 m². At Month 9, the least-squares geometric mean (LSGM) percentage change in UPCR from baseline versus placebo was −40.9% (95% CI, −51.3% to −28.1%) for HR19042 12 mg and −47.7% (95% CI, −56.9% to −36.4%) for HR19042 16 mg, both representing statistically significant reductions (one-sided P < 0.0001; Figure 1A). At Month 12, the least-squares (LS) mean difference in change in eGFR from baseline versus placebo was 3.30 mL/min/1.73 m² ((95% CI, 0.50 to 6.10; one-sided P = 0.0105) for HR19042 12 mg and 5.22 mL/min/1.73 m² (95% CI, 2.44 to 7.99; one-sided P = 0.0001; Figure 1B), demonstrating a significantly smaller decline in eGFR compared with placebo. Treatment-emergent adverse events (TEAEs) occurred in 93.4%, 94.3%, and 85.7% of patients in the HR19042 12 mg, 16 mg, and placebo groups, respectively. Serious adverse events were reported in 8.5%, 10.5%, and 3.8%, respectively. TEAEs leading to treatment discontinuation occurred in 0.9%, 3.8%, and 1.0%. The incidence of steroid-specific side effects (e.g., moon face, buffalo hump) was low and generally mild. No deaths were reported.

Nine months of treatment with targeted-release HR19042 capsules produced a clinically meaningful reduction in proteinuria and slowed eGFR decline compared with placebo, indicating a potential disease-modifying effect in patients with IgA nephropathy. HR19042 was generally well tolerated, with a safety profile consistent with locally acting oral budesonide.