Sibeprenlimab in IgA Nephropathy — Final Phase 3 Trial Analysis

BackgroundSibeprenlimab, a humanized monoclonal antibody, selectively inhibits the cytokine A proliferation-inducing ligand (APRIL), a key driver of IgA nephropathy. Preliminary trial results with regard to the primary end point of the 24-hour urinary protein-to-creatinine ratio at 9 months after treatment as compared with baseline have been reported, but secondary end points, including outcomes regarding estimated glomerular filtration rate (eGFR), have not. MethodsWe randomly assigned adults with IgA nephropathy to receive subcutaneous sibeprenlimab (at a dose of 400 mg) or placebo every 4 weeks. The key secondary end point was the annualized slope of the eGFR over 24 months. Other secondary end points included the change in eGFR from baseline to 24 months, a composite kidney end point of kidney-function decline or kidney failure, and pharmacodynamic and safety end points. ResultsA total of 510 patients underwent randomization — 259 to receive sibeprenlimab and 251 to receive placebo. The annualized eGFR slope over 24 months was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], −0.4 to 0.9) with sibeprenlimab and −4.2 ml per minute per 1.73 m2 per year (95% CI, −4.9 to −3.6) with placebo (between-group difference, 4.5 ml per minute per 1.73 m2 per year; 95% CI, 3.6 to 5.4; P<0.001). The least-squares mean treatment difference for the change in eGFR from baseline to 24 months was 9.2 ml per minute per 1.73 m2 (95% CI, 7.1 to 11.4; P<0.001). A composite kidney end-point event occurred in 1 patient (0.4%) in the sibeprenlimab group and in 28 patients (11.2%) in the placebo group (adjusted difference, −10.8 percentage points; hazard ratio, 0.029; 95% CI, 0.004 to 0.214; P<0.001). Adverse events occurred in 235 patients (90.7%) in the sibeprenlimab group and 226 patients (90.0%) in the placebo group; serious adverse events occurred in 21 patients (8.1%) and 32 patients (12.7%), respectively; and serious infections in 5 patients (1.9%) and 10 patients (4.0%). No deaths were reported. ConclusionsAmong patients with IgA nephropathy, treatment with sibeprenlimab stabilized the eGFR slope over 24 months, a finding consistent with a reduced risk of kidney-function decline. (Funded by Otsuka Pharmaceutical Development and Commercialization; VISIONARY ClinicalTrials.gov number, NCT05248646.)