IgAN drug hits target in phase III study

The selective immunoglobulin (Ig)G2 antibody sibeprenlimab reduces proteinuria in individuals with IgA nephropathy (IgAN) in an interim analysis of the phase III VISIONARY study.

“Within 8 weeks of commencing treatment, sibeprenlimab recipients had a significant and clear reduction in proteinuria, which grew over time out to 52 weeks,” said Dr Vlado Perkovic from the University of New South Wales, Sydney, Australia, at ERA 2025.

By month 9, the reduction from baseline in geometric mean uPCR-24h* with sibeprenlimab was -50.2 percent vs a 2.1-percent increase with placebo, yielding a placebo-adjusted treatment effect of 51.2 percent. “The confidence intervals ranged from 42.9 to 58.2 percent, suggesting that the effect was very robust, with a p-value of <0.0001. Therefore, the primary endpoint was met in this prespecified analysis of 320 participants,” Perkovic continued.

The incidences of treatment-related treatment-emergent adverse events (TEAEs) were similar between the investigational and placebo arms (32.9 percent vs 31 percent), but the former was tied to numerically lower rates of serious TEAEs (3.9 percent vs 5.4 percent), severe TEAEs (1.3 percent vs 4.8 percent), and TEAEs leading to discontinuation (0.7 percent vs 2.4 percent) than the latter. There were no deaths. [ERA 2025, abstract 98]

The most common TEAE with sibeprenlimab was upper respiratory infection (17.8 percent), followed by injection site pain (13.2 percent) and COVID-19 (12.5 percent).

Current Txs fail to target underlying immune drivers of disease

IgAN is a leading cause of chronic kidney disease and kidney failure worldwide and is associated with a high lifetime risk of end-stage kidney disease despite supportive care, said Perkovic. “It is quite likely that we have underestimated [the importance of] this condition.”

Corticosteroids have long been used for IgAN treatment, but they have various effects on the immune system. “[Moreover, currently available therapies**] primarily act through relatively non-specific haemodynamic mechanisms and do not necessarily address the immunological basis of the condition,” he continued.

Sibeprenlimab binds to and inhibits the biological activity of the cytokine APRIL***, which is a key factor in the four-hit process of IgAN pathogenesis. [Kidney Int Rep 2022;7:993-1003; Clin J Am Soc Nephrol 2024;19:394-398; Int J Mol Sci 2024:25:10340]

The main VISIONARY cohort comprised 510 adults with biopsy-confirmed IgAN on a stable ACEi/ARB^# dose with or without SGLT2i**. They were randomized 1:1 to receive SC sibeprenlimab 400 mg or placebo Q4W (26 doses).

The prespecified interim analysis cohort comprised 152 sibeprenlimab and 168 placebo recipients. Overall, the median age was 42 years, two-thirds were male, and about 60 percent were Asian. The median uPCR-24h was about 1.2 g/g, and the mean estimated glomerular filtration rate (eGFR) was 63 mL/min/1.73 m².

A novel mechanism of action

The current findings come on the heels of the phase II ENVISION study, which demonstrated a robust uPCR reduction and eGFR stability across a range of sibeprenlimab doses at 12 months, with an acceptable safety profile, in patients with IgAN. [N Engl J Med 2024;390:20-31] “[This study showed] very promising data that needed to be tested in a phase III trial,” Perkovic noted.

In a press release, co-investigator Dr Dana Rizk from the University of Alabama at Birmingham in the US noted that the interim analysis results of VISIONARY – the largest phase III IgAN trial to date – “affirm our belief in the efficacy of sibeprenlimab … The study enrolled a diverse population reflective of the disease epidemiology.”

“The safety data … are reassuring and add to our existing knowledge about sibeprenlimab’s safety profile from prior programmes. This is very exciting news for patients and adds a therapeutic option with a novel mechanism of action, potentially targeting the immunologic pathogenesis of IgAN,” Rizk added.

The full analysis results are anticipated in 2026.