Sibeprenlimab Halves uPCR in IgA Nephropathy Trial
Beyond this clinical effect, a notable observation was the lack of safety concerns, especially given that, although sibeprenlimab is a selective agent, there may have been unexpected off-target effects.
'Safety's been a key consideration with these drugs,' study presenter Vlado Perkovic, MD, PhD, provost and scientia professor, University of New South Wales, Sydney, Australia, told Medscape Medical News .
Sibeprenlimab represents a new mechanism of action and 'we don't yet fully understand the profile, so we've been looking at that data very carefully,' explained Perkovic. 'In particular, the infection risk has been my biggest concern, given we know that infections are dramatically increased in people with steroid therapy for example, in IgA nephropathy.'
The results of the trial — the largest to date in the field — were presented at the 62nd European Renal Association Congress 2025 on June 6 and drew a warm applause from the audience.
An Underestimated Condition
IgA nephropathy is estimated to affect 2.5 per 100,000 people per year, although 'it's possible that that number is a significant underestimate,' said Perkovic.
Diagnosis typically occurs between 20 and 40 years of age. And, despite supportive care, the majority of patients have a high lifetime risk of end-stage kidney disease (ESKD), with up to 50% of patients progressing to ESKD within 20 years of their clinical presentation.
'It's quite likely we've underestimated just how important this condition is,' said Perkovic, but 'we're fortunate that we're in the middle of something of a golden age of developing new treatments.'
A number of therapies have been shown to reduce the risks associated with the disease, although they do not necessarily address the immunological basis of the condition.
In addition to newer treatments, 'corticosteroids have long been used for people with IgA nephropathy,' Perkovic said, 'but of course, corticosteroids also have a range of different effects across the immune system,' which can lead to adverse outcomes.
Sibeprenlimab is a selective IgG2 antibody that binds to and inhibits the biological activity of APRIL (a proliferation-inducing ligand), which is produced by mucosal epithelial and myeloid cells and binds to B cells. APRIL regulates B-cell-mediated immune responses and mediates IgG and IgA class switching in mature B cells.
It is these two actions that make APRIL a key factor in the so-called 4-Hit process in the pathogenesis of IgA nephropathy, which results in the deposition of immune complexes in the glomerulus, leading to proteinuria and loss of kidney function.
Phase 3 VISIONARY TRIAL
Following on from the successful phase 2 ENVISION trial of sibeprenlimab, the researchers undertook the phase 3 VISIONARY trial, an ongoing study involving patients with biopsy-confirmed IgA nephropathy from 240 sites in 31 countries, who were randomized to sibeprenlimab or placebo for 100 weeks and followed up for a further 12 weeks.
All patients were required to have a uPCR of ≥ 0.75 g/g or urine protein excretion of ≥ 1.0 g/day, an estimated glomerular filtration rate (eGFR) of ≥ 30 mL/min/1.73 m2, and to have been on a stable dose of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, with or without a SGLT2 inhibitor, for ≥ 3 months prior to screening.
For the current pre-specified interim analysis, Perkovic reported the efficacy and safety results in the first 320 randomized patients (152 in the sibeprenlimab group and 168 in the placebo group), focusing on the primary endpoint of 24-hour uPCR at 9 months vs baseline, with eGFR and other data expected to be presented in 2026.
The median age of the patients was 42-43 years. There were proportionally fewer females in the sibeprenlimab group (34.2%) vs the placebo group (40.5%). The majority of the patients were Asian, at 61.8% and 56.5%, respectively.
Compared with a rise in uPCR at the 9-month follow-up in the placebo group, sibeprenlimab was associated with a 50.2% reduction in uPCR, giving a highly significant placebo-adjusted treatment effect of 51.2% ( P < .0001). Importantly, the benefit of sibeprenlimab on uPCR was seen as early as 4 weeks after initiating treatment and continued to accrue throughout follow-up.
Ronald T. Gansevoort, MD, PhD, professor of medicine and a nephrologist at the Department of Nephrology, University Medical Center Groningen, Netherlands, who co-chaired the session, told Medscape Medical News that the results look 'very promising.'
'Recently, we have had several agents working in different ways that all show proteinuria lowering,' he continued, but the results from those studies show that the improvements seen in VISIONARY are 'the best proteinuria lowering' seen so far.
Gansevoort noted, however, that this remains an interim analysis, and that he is really looking forward to seeing the kidney function results, adding: 'It was a little bit of a pity that they were not allowed to show at least the 9-month interim data on kidney function, which would have been so interesting.'
Safety Results
In terms of safety, the proportion of patients experiencing a treatment-related treatment-emergent adverse event (TEAE) was marginally lower with sibeprenlimab, at 32.9% vs 31.0% with placebo. The proportion of patients having a TEAE that led to treatment discontinuation was 0.7% vs 2.4%, respectively, and there were fewer severe and serious TEAEs with the experimental drug.
'If we focus on the infection-related adverse events,' Perkovic said, 'we can see that rates were numerically slightly higher in the sibeprenlimab than the placebo group, with a pattern that was broadly consistent, but with perhaps a slight excess of COVID 19.'
He noted that this was 'the reverse of the pattern we've seen in the phase 2 trials, suggesting a chance' outcome.
'The data so far look remarkably encouraging,' he added. There's really no suggestion of an increased risk of infection,' with no opportunistic infections identified, 'and certainly no deaths.'
More data is required from the ongoing follow-up to support what has been observed so far, but if the final results do bear out both the efficacy and safety outcome, it will show that sibeprenlimab is 'a precision approach to the fundamental abnormality in IgA nephropathy: that's the really exciting part,' said Perkovic.
The study was funded by Otsuka Pharmaceutical Development and Commercialization.
Perkovic declares relationships with Amgen, AstraZeneca, Bayer, Biogen, Boehringer Ingelheim, Chinook Therapeutics, Eli Lilly & Company, Gilead Sciences, GlaxoSmithKline, Guard Therapeutics, Incyte, Janssen, Merck, Mitsubishi Tanabe Pharma, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Sanofi, Shaanxi Micot Technology, Travere Therapeutics.
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