Sibeprenlimab Stabilizes eGFR Over 24 Months in IgA Nephropathy: VISIONARY

Sibeprenlimab (Voyxact), a selective inhibitor of A proliferation-inducing ligand (APRIL), stabilized estimated glomerular filtration rate (eGFR) over 24 months in adults with IgA nephropathy, according to final results from the phase 3 VISIONARY trial.¹

Patients receiving sibeprenlimab had an annualized eGFR slope of 0.3 mL/min/1.73 m² per year, compared with −4.2 mL/min/1.73 m² per year with placebo.¹ Dana Rizk, MD, of the University of Alabama at Birmingham Heersink School of Medicine, presented the data during the opening plenary at ASN Kidney Week 2026 in Denver, Colorado, with simultaneous publication in the New England Journal of Medicine.^1,2

Sibeprenlimab received accelerated US Food and Drug Administration approval in November 2025 based on a prespecified interim analysis of VISIONARY, in which the agent reduced 24-hour urinary protein-to-creatinine ratio (uPCR) at 9 months by 51.2% vs placebo.^3,4 Secondary endpoints, including eGFR outcomes, had not been reported. The 2025 KDIGO IgA nephropathy guideline recommends targeting both disease-specific immunologic drivers and the generic response to nephron loss, and APRIL inhibition acts directly on production of galactose-deficient IgA1.¹

How Did Sibeprenlimab Affect eGFR Slope in the VISIONARY Trial?

VISIONARY randomized 510 adults with biopsy-confirmed IgA nephropathy in a 1:1 ratio to subcutaneous sibeprenlimab 400 mg or placebo every 4 weeks through week 100.¹ Eligible patients had a 24-hour uPCR of ≥ 0.75 or urinary protein excretion of ≥ 1.0 g/day, an eGFR of ≥ 30 mL/min/1.73 m², and a stable, maximally tolerated dose of a renin-angiotensin system inhibitor for ≥ 3 months. At baseline, median eGFR was 60.0 mL/min/1.73 m², and 45.3% of patients were receiving a sodium-glucose cotransporter 2 inhibitor (SGLT2i).¹

The between-group difference in annualized eGFR slope, the key secondary end point, was 4.5 mL/min/1.73 m² per year (95% CI, 3.6–5.4; P < .001).¹ At 24 months, the least-squares mean change in eGFR from baseline was +1.3 mL/min/1.73 m² with sibeprenlimab and −7.9 mL/min/1.73 m² with placebo, a difference of 9.2 mL/min/1.73 m² (95% CI, 7.1–11.4; P < .001).¹

Prespecified sensitivity analyses, including placebo-based imputation for missing eGFR values, produced consistent results. The effect on eGFR slope was similar across prespecified subgroups, including baseline proteinuria, baseline eGFR, SGLT2i use, and prior immunosuppressive therapy. According to the investigators, the slope with sibeprenlimab approached the KDIGO target of less than 1 mL/min/1.73 m² of annual eGFR decline.¹

Did Sibeprenlimab Reduce Kidney Failure Risk, Proteinuria, and Hematuria?

A composite kidney end point of sustained 40% eGFR decline, sustained doubling of serum creatinine, sustained eGFR below 15 mL/min/1.73 m², or kidney-replacement therapy occurred in one patient (0.4%) receiving sibeprenlimab and 28 patients (11.2%) receiving placebo (hazard ratio, 0.029; 95% CI, 0.004–0.214; P < .001). A total of 5 patients in the placebo group and none in the sibeprenlimab group initiated kidney-replacement therapy.¹

In exploratory analyses, 24-hour uPCR fell 61.3% from baseline at 24 months with sibeprenlimab vs 1.3% with placebo. Urinary protein excretion below 0.5 g/day was reached by 36.7% of sibeprenlimab-treated patients vs 9.1% of placebo recipients. Among patients with dipstick hematuria at baseline, resolution occurred in 78.6% (162/206) vs 20.2% (37/183), respectively.¹

Adverse event rates were similar between groups (90.7% vs 90.0%), while serious adverse events (8.1% vs 12.7%) and serious infections (1.9% vs 4.0%) were less frequent with sibeprenlimab. Mean serum IgA, IgG, and IgM fell by 74.8%, 37.4%, and 77.4%, respectively; none of the 24 patients with postbaseline IgG < 400 mg/dL had a serious or severe infection. No deaths occurred, and discontinuation due to adverse events was less common with sibeprenlimab (1.2%) than placebo (4.0%).¹

“For patients with IgA nephropathy, preserving kidney function and preventing kidney failure are the outcomes that matter most,” Rizk said in a press release.⁵ “In the largest Phase 3 IgA nephropathy dataset reported to date, VISIONARY demonstrated sustained kidney function stabilization over two years, aligning with the KDIGO eGFR treatment goals. The trial also showed a 97.1% reduction in the risk of kidney failure events. For clinicians, the consistency and magnitude of these results provide compelling evidence that sibeprenlimab delivers a significant treatment effect. These findings suggest that selective APRIL inhibition has the potential to change the long-term trajectory of IgA nephropathy and redefine what may be possible for patients living with this progressive disease.”

How Do VISIONARY eGFR Results Compare With Other IgA Nephropathy Therapies?

The authors placed the findings alongside other phase 3 trials of immunologic therapies reporting 2-year eGFR outcomes in IgA nephropathy. Targeted-release budesonide was associated with a 5.1 mL/min/1.73 m² difference in eGFR change from baseline, and iptacopan produced a 3.0 mL/min/1.73 m² per year slope difference. In both trials, kidney function continued to decline in treated patients, albeit more slowly than with placebo, whereas eGFR remained stable with sibeprenlimab.¹

Differences in trial design, end point definitions, and populations limit direct cross-trial comparison. Efficacy and safety data beyond 24 months are not yet available, and an open-label extension is ongoing. Patients with crescents in more than 25% of glomeruli, more than 50% tubulointerstitial fibrosis, or full nephrotic syndrome were excluded, so efficacy in these groups remains unknown.¹

References:

1. Rizk DV, Barratt J, Suzuki Y, et al. Sibeprenlimab in IgA nephropathy: final phase 3 trial analysis. N Engl J Med. Published online October 22, 2026. doi:10.1056/NEJMoa2609127

2. Rizk DV. Sibeprenlimab in IgA nephropathy: final phase 3 VISIONARY results. Presented at: ASN Kidney Week 2026, Opening Plenary: ASN President’s Address, State-of-the-Art Lecture, Featured High-Impact Clinical Trials; October 22, 2026; Denver, CO.

3. Perkovic V, Trimarchi H, Tesar V, et al. Sibeprenlimab in IgA nephropathy: interim analysis of a phase 3 trial. N Engl J Med. 2026;394:635-646.

4. Voyxact (sibeprenlimab-szsi) injection, for subcutaneous use. Prescribing information. Otsuka Pharmaceutical Company; November 2025. Accessed October 21, 2026. https://www.otsuka-us.com/media/static/VOYXACT-PI.pdf

5. Otsuka. Otsuka Presents Landmark Final Phase 3 VISIONARY Results at ASN Demonstrating VOYXACT® (sibeprenlimab-szsi) Stabilized Kidney Function and Reduced Risk of Disease Progression and Kidney Failure, Redefining Treatment Paradigm in IgA Nephropathy. October 22, 2026. https://www.otsuka-us.com/Otsuka-Presents-Final-Phase-3-VISIONARY-Results