Dana Rizk, MD, is a professor of medicine in the division of nephrology at the University of Alabama at Birmingham.

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.

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

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.

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.

include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for

include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for

include Novartis Pharmaceuticals, Otsuka Pharmaceutical Inc., Vera Therapeutics, Biogen, Travere Therapeutics, and others.

Perkovic V, Trimarchi H, Tesar V, et al. Sibeprenlimab in IgA nephropathy: interim analysis of a phase 3 trial. 

. 2026;394(7):635-646. doi:10.1056/NEJMoa2512133

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

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.

Videos

VISIONARY enrolled 510 high-risk IgAN patients globally. Learn how the trial's design and anti-APRIL mechanism were built to target disease at its root.


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 

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.

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

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. 

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for 

 include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for 

 include Novartis Pharmaceuticals, Otsuka Pharmaceutical Inc., Vera Therapeutics, Biogen, Travere Therapeutics, and others.

Podcasts

Dana Rizk, MD, joins hosts Brendon Neuen and Shikha Wadhwani to unpack 2-year VISIONARY data showing sibeprenlimab stabilizes eGFR in IgAN.

Dana Rizk, MD

Articles