How VISIONARY's Design Targets APRIL in IgA Nephropathy, With Dana Rizk, MD

The Phase 3 VISIONARY trial enrolled 510 patients with biopsy-proven, high-risk IgA nephropathy (IgAN), making it the largest IgAN trial to date. The global, randomized, double-blind, placebo-controlled study was built to test whether selectively blocking APRIL, a cytokine central to the disease's underlying immune biology, could change the course of a condition typically defined by relentless kidney function decline.

“The VISIONARY trial was a phase three trial. It's a global study that enrolled patients with biopsy-proven IgA nephropathy, primary IgA nephropathy, really from all around the world, so very good representation,” Dana Rizk, MD, professor of medicine in the Division of Nephrology at the University of Alabama at Birmingham, said in an interview with HCPLive.

A High-Risk, Globally Representative IgAN Population

To enroll in VISIONARY, patients needed a biopsy confirming primary IgAN and an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m². Rizk noted the trial built in a timing requirement tied to how preserved a patient's kidney function was at screening.

“They had to have a GFR over 30, and it might be worth mentioning that if their GFR was between 30 and 44, they had to have a biopsy within three years. If it was over 45, so, you know, pretty good preserved GFR, they could have had a biopsy at any point in time,” Rizk said.

Patients also had to meet a proteinuria threshold to qualify as high-risk: > 1 g/day of protein, or a urine protein-to-creatinine ratio > 0.75 g/g, based on a 24-hour collection.

Background Therapy and Randomization

Before randomization, all participants were optimized on background therapy reflecting current standard of care. Patients were maintained on maximum tolerated renin-angiotensin system (RAS) inhibition, and those on sodium-glucose cotransporter-2 (SGLT2) inhibitors had to be on a stable dose for at least 3 months prior to enrollment. Concomitant immunosuppressive medications were not permitted leading up to the study.

Once patients cleared screening, they were randomized to receive sibeprenlimab, 400 mg subcutaneously every 4 weeks, or placebo.

How Anti-APRIL Therapy Targets IgA Nephropathy

Sibeprenlimab is an anti-APRIL therapy, and Rizk walked through why that mechanism was chosen to target IgAN at its immunologic root.

“APRIL is a cytokine that is important in allowing B cells to become IgA-secreting cells, and also is important for the survival of B cells,” Rizk said.

IgAN is an immune-mediated disease, and its pathogenesis has been summarized by the four-hit hypothesis: overproduction of galactose-deficient IgA1 (Gd-IgA1) triggers the formation of autoantibodies against it, which in turn form circulating immune complexes. Those complexes ultimately deposit in the kidneys, driving inflammation and, over time, fibrosis.

“Targeting B cells and this immune backbone to the disease is of course important, makes sense, and that was the premise for the anti-APRIL therapy design,” Rizk said.

Sibeprenlimab (marketed as VOYXACT) received accelerated approval from the U.S. Food and Drug Administration (FDA) in November 2025 for reduction of proteinuria in adults with IgAN at risk of disease progression, based on VISIONARY's primary endpoint results. The trial's key secondary endpoint, annualized eGFR slope over 24 months, offers a longer-term view of whether that upstream mechanism translates into preserved kidney function.

ditors’ Note: Disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for Rizk include Novartis Pharmaceuticals, Otsuka Pharmaceutical Inc., Vera Therapeutics, Biogen, Travere Therapeutics, and others.

References

1. Perkovic V, Trimarchi H, Tesar V, et al. Sibeprenlimab in IgA nephropathy: interim analysis of a phase 3 trial. N Engl J Med. 2026;394(7):635-646. doi:10.1056/NEJMoa2512133

2. Otsuka. Otsuka unveils unprecedented phase 3 VISIONARY two-year eGFR results demonstrating VOYXACT (sibeprenlimab-szsi) stabilizes kidney function decline to baseline physiologic rate, fundamentally altering disease progression in IgA nephropathy (IgAN). News release. August 3, 2026. https://www.otsuka-us.com/news/otsuka-unveils-unprecedented-phase-3-visionary-two-year-egfr-results-demonstrating-voyxactr

3. Rizk DV, Perkovic V, Trimarchi H, et al. Two-year eGFR and safety results from the VISIONARY phase 3 trial of sibeprenlimab in IgA nephropathy. Presented at: GlomCon Hawaii; August 3-7, 2026; Maui, HI.