IgA nephropathy's two-year test: on sibeprenlimab and atacicept, kidney function barely declined, and ravulizumab won accelerated approval

🎧 Listen: Weekly · Oct 26, from 01:56.

The background

IgA nephropathy often affects young adults, and despite good supportive care many progress to kidney failure over the following decades. For years the drug pipeline was nearly empty, because a kidney drug had to show that it prevented hard outcomes: kidney failure, a large and sustained fall in kidney function, or death. In a slowly progressive disease, that takes thousands of patients and many years.

What changed is that the FDA agreed that a large reduction in proteinuria is reasonably likely to predict clinical benefit, but only for accelerated approval. Full approval still needs kidney function (eGFR) data. Accelerated approval also carries a legal obligation to complete confirmatory trials, and the Food and Drug Omnibus Reform Act of December 2022 strengthened the FDA's hand: conditions can be set at approval, progress reports are required every six months, and withdrawal can be expedited.

The two-year results (phase 3, final analyses, kidney function)

• Sibeprenlimab (VISIONARY; an anti-APRIL antibody, 400 mg subcutaneously every 4 weeks), which received accelerated approval in November 2025 on its 9-month proteinuria result. In 510 patients, the eGFR slope over 24 months was +0.3 mL/min/1.73 m² per year on sibeprenlimab and −4.2 on placebo (difference 4.5; 95% CI, 3.6 to 5.4). A composite kidney end point (sustained doubling of creatinine, a sustained 40% fall in eGFR, eGFR below 15, or kidney failure treatment) occurred in 1 patient (0.4%) vs 28 (11.2%). Serious adverse events: 8.1% vs 12.7%; serious infections 1.9% vs 4.0%; no deaths. The authors note that the slope approached the 2025 KDIGO guideline's target of an annual eGFR decline below 1 mL/min/1.73 m², similar to the decline with normal aging.
• Atacicept (ORIGIN 3; blocks both BAFF and APRIL, 150 mg subcutaneously every week), which received accelerated approval in July 2026. In 428 treated patients, the eGFR slope through week 104 was −0.60 per year on atacicept and −5.60 on placebo (difference 5.00; 95% CI, 3.55 to 6.45). Composite kidney-disease progression (a sustained 30% eGFR decline, eGFR below 15, long-term dialysis, transplantation or death) occurred in 5.1% vs 17.8% (hazard ratio 0.24; 95% CI, 0.12 to 0.48); no patient on atacicept progressed to dialysis, transplantation or death. Serious adverse events: 7.0% vs 15.4%. The authors point out that landmark CKD trials, with renin–angiotensin blockade and SGLT2 inhibitors, have generally reported reductions of about 16% to 55% in composite kidney outcomes.

A new approval (phase 3, interim analysis, proteinuria)

On October 22, 2026, the FDA granted ravulizumab (Ultomiris), a C5 complement inhibitor given intravenously every 8 weeks, accelerated approval to reduce proteinuria in adults with primary IgA nephropathy at risk of progression. In the prespecified interim analysis of the I CAN trial, published in NEJM the next day, 24-hour urine protein-to-creatinine ratio at week 34 was 43.4% lower than with placebo among 352 patients (99% CI, 30.1 to 54.2). Serious adverse events occurred in 4.6% vs 9.0%, with no meningococcal infections; patients had to be vaccinated against meningococcus before treatment. The company states that it has not been established whether ravulizumab slows the decline in kidney function; that answer depends on the trial's eGFR end point at week 106.

Why it matters

This is the confirmatory step the accelerated pathway was built for, and for these two drugs the proteinuria stand-in turned into preserved kidney function over two years. It isn't the first time: Tarpeyo (Nefecon), Filspari and, in July 2026, Fabhalta (iptacopan) also moved from accelerated to full approval on two-year eGFR data, though Filspari's result was a near miss.

Stand-ins have misled us before. Dual blockade of the renin–angiotensin system lowered albuminuria without better outcomes (ONTARGET, ALTITUDE, VA NEPHRON-D), and two of those trials stopped early. Bardoxolone raised the eGFR, but heart failure increased (BEACON). Higher hemoglobin targets with ESAs improved the hemoglobin, but not the patients (CHOIR, CREATE, TREAT). Our take: a surrogate earns trust disease by disease and drug by drug, and in IgA nephropathy it has now held several times.

Also this week: povetacicept (BAFF and APRIL) reported a phase 3 interim on proteinuria in NEJM, with an FDA decision date of November 30, 2026; a long-term open-label extension of iptacopan was published in Kidney International; atacicept's PIONEER study (a conference abstract, open-label, no control group) tested it in patients the phase 3 trials excluded; and sefaxersen, an antisense factor B inhibitor, reported a phase 3 interim at Kidney Week whose results so far appear only in the presentation and a company release, so we're waiting for the paper. That makes four targets in one disease (APRIL, BAFF plus APRIL, C5 and factor B), and none have been compared head to head.

Caveats

Two years is short in a disease that unfolds over decades, and hard kidney events were few. Ravulizumab's and povetacicept's results so far rest on proteinuria alone. No trial has compared these drugs with each other, so they can't be ranked. Our take: in practice the choice will also depend on cost and access.

Funding and ties: VISIONARY was funded by Otsuka, ORIGIN 3 and PIONEER by Vera Therapeutics, I CAN by Alexion, AstraZeneca Rare Disease, RAINIER by Vertex, and the iptacopan extension by Novartis. Several authors report relationships with multiple companies developing IgA nephropathy drugs; full disclosures are in the papers.

The source: 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 Read the original

Also discussed:

• Barratt J, et al. Atacicept in IgA Nephropathy — Phase 3 Trial Final Efficacy Analysis. N Engl J Med. Published online October 22, 2026. doi:10.1056/NEJMoa2610103 Link
• Barratt J, et al. Ravulizumab in IgA Nephropathy — Interim Analysis of a Phase 3 Trial. N Engl J Med. Published online October 23, 2026. doi:10.1056/NEJMoa2607544 Link
• Barratt J, et al. Interim Analysis of a Phase 3 Trial of Povetacicept in IgA Nephropathy. N Engl J Med. Published online October 23, 2026. doi:10.1056/NEJMoa2608682 Link
• Healio, October 22, 2026: FDA approves Ultomiris for proteinuria reduction in adults with primary IgA nephropathy Link

🎧 Listen: Weekly · Oct 26, from 01:56.

Physician-led, AI-assisted. Dr. Wael Hussein chooses every item NephSpace covers and reviews and edits every story before it is published. The first draft was written in our own words with AI (Claude, by Anthropic) from the full text of the four NEJM papers, the FDA approval as reported by Healio and the Kidney Week abstracts and checked against our reading notes; Dr. Hussein then reviewed and edited it. For education and information only, not medical advice. Please talk to your own physician or care team about your health. Clinicians: read the original before changing practice. See our disclaimer and disclosures. Spotted an error? Tell us.