Sibeprenlimab in IgA Nephropathy — Interim Analysis of a Phase 3 Trial

BACKGROUND: The cytokine A proliferation-inducing ligand (APRIL) is considered a key driver of the pathogenesis of IgA nephropathy. Sibeprenlimab, a humanized IgG2 monoclonal antibody, selectively binds to and inhibits APRIL. METHODS: In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned adults with biopsy-confirmed IgA nephropathy in a 1:1 ratio to receive either subcutaneous sibeprenlimab at a dose of 400 mg or placebo administered every 4 weeks for 100 weeks. The primary end point for this interim analysis was the 24-hour urinary protein-to-creatinine ratio at 9 months as compared with baseline. The key secondary end point, to be reported at trial completion, is the annualized slope of estimated glomerular filtration rate over 24 months. Other secondary end points included the change in the level of serum immunoglobulin and safety. Exploratory end points included the change in galactose-deficient IgA1 and APRIL concentrations, the spot 24-hour urinary protein-to-creatinine ratio, hematuria, and remission of proteinuria. RESULTS: A total of 510 patients underwent randomization - 259 to the sibeprenlimab group and 251 to the placebo group. The prespecified interim analysis included the first 320 patients (152 who received sibeprenlimab and 168 who received placebo) who had the opportunity to complete the 9-month evaluation of the 24-hour urinary protein-to-creatinine ratio. At 9 months, a significant reduction in 24-hour urinary protein-to-creatinine ratio was observed with sibeprenlimab (-50.2%) as compared with an increase with placebo (2.1%), corresponding to an adjusted geometric least-squares mean 24-hour urinary protein-to-creatinine ratio that was 51.2% (96.5% confidence interval [CI], 42.9 to 58.2) lower with sibeprenlimab than with placebo (P<0.001). The levels of APRIL and pathogenic galactose-deficient IgA1 at week 48 were reduced from baseline by 95.8% and 67.1%, respectively, with sibeprenlimab. The safety profile appeared to be similar with sibeprenlimab and placebo. No deaths were reported, and the incidence of serious adverse events that occurred during the treatment period was 3.5% with sibeprenlimab and 4.4% with placebo. CONCLUSIONS: Sibeprenlimab resulted in a significant reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Otsuka Pharmaceutical Development and Commercialization. VISIONARY ClinicalTrials.gov number, NCT05248646.).