Highlights of 2025: IgA nephropathy – an embarrassment of therapeutic riches

Exactly 12 months ago, I reported on the results of a phase 3 randomised controlled trial assessing the effects of iptacopan on proteinuria in individuals with IgA nephropathy at risk of disease progression (see summary). Iptacopan inhibits factor B, a single-chain polypeptide in the alternative complement pathway, blocking the formation of the membrane attack complex.¹ By doing so it interrupts one of the key pathological processes that drives inflammation and kidney damage in IgA nephropathy. 

The trial was positive, with patients receiving iptacopan having notable reductions in proteinuria (38.3%) compared to the control group. At the time, I wrote that this was a big step forward in the management of IgA nephropathy, with a second agent (in addition to enteric-coated oral budesonide; Nefecon²) now available for management of the condition. And so, it has come to pass with KDIGO updating their guidelines at the end of 2025 to include recommendations about the use of Nefecon and iptacopan for patients with IgA nephropathy, suggesting early initiation of these “nephron-sparing agents” to target disease processes that limit glomerular injury and stifle disease progression.³ These guidelines are comprehensive and easy to follow, but I fear they will need a further update in the coming year, with the arrival of new classes of drug that target different pathological processes driving disease progression in IgA nephropathy.

At the recent American Society of Nephrology meeting in Houston, USA, the following clinical trials were presented in late-breaking sessions, with simultaneous publication in the New England Journal of Medicine. First, the phase 3 randomised trial of atacicept.⁴ Atacicept is a human transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI–Fc) fusion protein that inhibits two key immunoregulatory cytokines – B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) – both of which are central to the pathophysiology of IgA nephropathy. In the (prespecified) interim analysis, 203 patients were included: 106 randomised to atacicept and 97 to placebo. At week 36, the percentage reduction from baseline in the urine protein-to-creatinine ratio was 45.7% in the atacicept group and 6.8% in the placebo group – a monumental difference. 

Next up was sibeprenlimab, a humanised IgG2 monoclonal antibody that selectively binds to and inhibits APRIL (Perkovic, 2025).⁵ This randomised controlled trial also reported a prespecified interim analysis of a phase 3 trial, with a total of 320 participants included, 152 of whom were randomised to the sibeprenlimab group and 168 to the placebo group. At 9 months there was a significant reduction in urine protein-to-creatinine ratio in those receiving sibeprenlimab (−50.2%) compared with an increase with placebo (2.1%). Additionally, levels of APRIL and pathogenic galactose-deficient IgA1 at week 48 were significantly reduced from baseline in the sibeprenlimab group compared to control.

So, there you are. Two new therapies in addition to the iptacopan and Nefecon, meaning there is now an embarrassment of therapeutic riches for the treatment of IgA nephropathy compared to what you might consider a desert only a few years ago. What remains to be seen is how these therapies should/could be used together in different patients with different disease phenotypes. Surely, over the coming years, there will be studies looking at combinations of these (and drugs still under testing) novel therapies to optimally manage this condition. Equally, the role of these treatments in managing recurrence of the condition post transplantation is not known and must be the subject of future research. Whichever way you look at it, the future is certainly bright in the field of IgA nephropathy, and I look forward to seeing how this translates into meaningful impacts for patients with the condition.

References

1. Perkovic V, Barratt J, Rovin B et al; APPLAUSE-IgAN Investigators (2025) Alternative complement pathway inhibition with iptacopan in IgA nephropathy. N Engl J Med 392: 531–43 
2. Lafayette R, Kristensen J, Stone A et al; NefIgArd trial investigators (2023) Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet 402: 859–70
3. KDIGO IgAN and IgAV Work Group; Rovin BH, Barratt J, Cook HT et al (2025) KDIGO 2025 clinical practice guideline for the management of immunoglobulin A nephropathy (IgAN) and immunoglobulin A vasculitis (IgAV). Kidney Int 108(4S): S1–71
4. Lafayette R, Barbour SJ, Brenner RM et al; ORIGIN Phase 3 Trial Investigators (2025) A phase 3 trial of atacicept in patients with IgA nephropathy. N Engl J Med 6 Nov [Epub ahead of print]
5. Perkovic V, Trimarchi H, Tesar V et al; VISIONARY Trial Investigators Group (2025) Sibeprenlimab in IgA nephropathy – interim analysis of a phase 3 trial. N Engl J Med 8 Nov [Epub ahead of print]