Professor Vlado Perkovic

The cytokine A proliferation-inducing ligand (APRIL)-inhibiting monoclonal antibody sibeprenlimab is associated with a significant reduction in proteinuria in patients with IgA nephropathy.

An interim analysis of the phase 3 VISIONARY trial, presented at the American Society of Nephrology’s Kidney Week meeting, found sibeprenlimab halved the 24-hour urinary protein-to-creatinine ratio (UPCR) in treated participants compared with participants randomised to placebo.

The analysis, concurrently published in the NEJM [link here], comprised the first 320 patients in the trial with biopsy-confirmed IgA nephropathy recruited from 31 counties including Australia.

Almost all participants (98%) were on an ACE inhibitor, ARB or both, and about 40% were on an SGLT2 inhibitor.

Participants, with a median age of 43 years, a mean UPCR of 1.33, and a mean eGFR of 63 ml/min/1.73m², received subcutaneous sibeprenlimab 400 mg or placebo every 4 weeks to week 100.

The analysis found a 50.2% reduction in the 24-hour UPCFR from baseline among patients assigned to receive sibeprenlimab compared with a 2.1% increase in patients assigned to receive placebo at week 40.

At 12 months (week 52), the 24-hour UPCR was 56.6% lower in patients receiving sibeprenlimab compared with 5.1% lower in patients receiving placebo.

“With regard to spot assessment of urinary protein-to-creatinine ratio levels according to visit, the mixed model for repeated measures showed that separation between the groups occurred rapidly, with a substantial difference observed at 8 weeks and sustained through 12 months,” the study said.

“Results of efficacy assessments for change in 24-hour urinary albumin-to-creatinine ratio were consistent with the proteinuria findings.”

The study also found the effects of sibeprenlimab on 24-hour UPCR were consistent across prespecified subgroups based sex, ethnic group, region, race, age, screening 24-hour UPCR (≤2 vs. >2), eGFR (30 to 44 ml per minute per 1.73 m² vs. ≥45 ml per minute per 1.73 m²), and background use of SGLT2 inhibitors.

Total IgA and IgM levels were reduced by about 70% with sibeprenlimab, whereas IgG levels were reduced by 35%.

The incidence of adverse events were similar in the two groups (74.1% with sibeprenlimab versus 82.1% with placebo) and were mainly upper respiratory tract infections and nasopharyngitis.

The investigators, led by Professor Vlado Perkovic from the University of NSW, said the 51.2% relative reduction in proteinuria appeared to be at least as large as those reported with currently approved therapies, including budesonide, sparsentan, atrasentan, and iptacopan.

“We speculate that the present results suggest that sibeprenlimab may protect kidney function,” they said.

The VISIONARY trial was sponsored by Otsuka Pharmaceutical Development and Commercialisation.

Starting off with IgA Nephropathy at Plenary Session!
▶️ 1. The impact of new tools by @VladoPerkovic – first #ASN2025 publication @Kidney_Int! 🔥
▶️ 2. Just published @NEJM – Dr. Richard Lafayette on the ORIGIN 3 trial: Atacicept led to remarkable results! 🤯
#GlomerularDisease pic.twitter.com/J4hCC4T0L1

— International Society of Glomerular Disease (@ISGDtweets) November 6, 2025

Meanwhile, an interim analysis of the phase 3 ORIGIN trial featured in the Opening Plenary at Kidney Week, found the recombinant fusion protein atacicept resulted in a significantly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy.

Delegates heard that treatment with atacicpet, which targets cytokines B-cell activating factor (BAFF) as well as APRIL, resulted in a 45.7% reduction in the UPCR from baseline compared to a 6.8% reduction in the placebo group.

The analysis comprised 203 patients, with a mean age of 40 years, baseline UPCR of 1.7 and eGFR of 65 ml/min/1.73m². Almost all participants (99%) were on a RAS inhibitor and about 53% on an SGLT2 inhibitor. They were randomised to either once-weekly atacicept 150 mg or matching placebo.

“Proteinuria appeared to decrease as early as week 12, with apparent sustained improvement through week 36 in the atacicept group,” the study said.

“Serum levels of IgG, IgA, and IgM decreased as expected after treatment with atacicept, which is consistent with its mechanism of action owing to B-cell modulation.”

Adverse events, reported in 59.3% of the atacicept group and 50.0% of the placebo group, were mostly mild or moderate and included injection site reactions in 19.2% of the atacicept group.

Serious adverse events occurred in only one patient in the atacicept group and was evaluated as unrelated to the trial drug. Meanwhile, 11 patients in the placebo group reported SAEs.

The study, also published in the NEJM [link here], said the finding suggests dual BAFF and APRIL inhibition with atacicept may modify the disease course in IgA nephropathy.

“The ongoing trial is designed to assess the long-term benefits of atacicept as a targeted, disease-modifying therapy that stabilises kidney function,” it said.

The ORIGIN trial was sponsored by Vera Therapeutics.

A Chinese phase 3 trial of telitacicept in patients with IgA nephropathy was also presented at the ASN Annual Meeting.