Kidney Compass: VISIONARY 2-Year eGFR Data in IgA Nephropathy

Welcome back to Kidney Compass!

Hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, welcome Dana Rizk, MD, professor of medicine in the Division of Nephrology at the University of Alabama at Birmingham. Rizk walks through the 24-month eGFR and safety findings from the phase 3 VISIONARY trial of sibeprenlimab (Voyxact) in IgA nephropathy (IgAN).

She presented the late-breaking results at GlomCon Hawaii 2026, building on the proteinuria data reported earlier this year at the European Renal Association meeting. The conversation covers trial design, the eGFR slope and change-from-baseline outcomes, subgroup consistency, safety, and where residual proteinuria fits into the picture going forward.

VISIONARY Trial Design and 2-Year eGFR Results in Sibeprenlimab-Treated IgAN

Wadhwani opens by asking Rizk to set the scene, noting VISIONARY enrolled 510 patients with biopsy-proven, high-risk IgAN, making it the largest phase 3 trial in the disease to date. Rizk describes the eligibility criteria, an eGFR > 30, a recent biopsy for patients on the lower end, and significant proteinuria of ≥ 1 g/day. Patients were randomized to sibeprenlimab 400 mg subcutaneously every 4 weeks or placebo, on top of maximum tolerated RAS inhibition.

Rizk explains sibeprenlimab targets APRIL, a cytokine driving B cells to become IgA-secreting within the four-hit model of IgAN pathogenesis, and Wadhwani calls the mechanism one of the most exciting new directions in the field.

Neuen reminds listeners the earlier phase 2 signal was compelling but short, often under a year, and asks Rizk for the full picture now the trial has matured. Rizk reports an annualized eGFR slope of 0.3 mL/min/1.73 m² per year with sibeprenlimab against a placebo decline of 4.2, a 4.5 mL/min/1.73 m² per year treatment difference. Mean eGFR change from baseline told a similar story, with a 9.2 mL/min gap between arms at 2 years. Rizk calls the result striking against the 2025 KDIGO goal of holding eGFR loss < 1 mL/min per year, a bar she once doubted was achievable within a 2-year window.

Consistent Subgroup Benefit and Reassuring Safety Data From VISIONARY

Rizk noted a trio of prespecified subgroups, defined by proteinuria level, baseline eGFR, and SGLT2 inhibitor use, all favored sibeprenlimab with no meaningful difference in effect size across strata. Neuen called the consistent benefit in SGLT2 inhibitor users reassuring for clinicians considering combination therapy for long-term kidney preservation.

On safety, Neuen names the theoretical concern hanging over any B-cell modulating agent: infection risk from suppressing immune function. Rizk reports adverse events in about 90% of both arms, with treatment-related events similar between groups and serious infections less common with sibeprenlimab than placebo. No deaths occurred, and discontinuation for adverse events stayed in the low single digits. Wadhwani follows up on immunoglobulin monitoring, and Rizk notes patients needed an IgG level > 600 at entry, with full IgA, IgG, and IgM data still to come.

Residual Proteinuria and the Road Ahead for B-Cell Therapy in IgAN

With median proteinuria still > 0.5 gram/day despite the 51% reduction, Wadhwani raised concern about residual proteinuria as a cardiovascular risk factor independent of stabilized eGFR. She compared it to how cardiologists treat persistent albuminuria. Rizk agreed proteinuria cannot distinguish ongoing immunologic activity from fixed scarring, and said mechanistic studies pairing biopsies before and after treatment should help clarify the distinction.

The conversation closes on biomarkers, with Wadhwani asking whether galactose-deficient IgA1 can separate disease activity from fibrosis on its own. Rizk says the field has been spoiled by the PLA2R antibody in membranous nephropathy and expects IgAN will need a panel of biomarkers rather than one perfect test. She points to pediatric IgAN, membranous nephropathy, lupus nephritis, and IgA vasculitis as likely next frontiers for anti-APRIL therapy.

Wadhwani adds trials still struggle to capture good hematuria data given how urine samples are collected. Rizk says post hoc analyses are planned for patients enrolled with lower baseline proteinuria, thanking the patients and investigators who carried VISIONARY through its multi-year follow-up.

Wadhwani closes by reflecting on how far the field has moved. A decade ago, clinicians reserved corticosteroids for patients with more than a gram of proteinuria after months of failed RAS inhibition, often leaving patients undertreated given the steroid burden. She contrasts this with a once-monthly injection appearing well tolerated and capable of stabilizing kidney function outright. Rizk also raises a question about whether anti-APRIL therapy has a role preventing IgAN recurrence after kidney transplant, calling it an open area for future study.

Editors’ 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.