A 43.4% placebo-adjusted reduction in urine protein at 34 weeks was enough for the Food and Drug Administration to grant accelerated approval to Ultomiris for adults with primary IgA nephropathy at risk of progression—but it does not yet prove that the drug preserves kidney function.
The approval, announced Wednesday by manufacturer AstraZeneca and independently reported by Reuters, adds the first C5 complement inhibitor to a rapidly expanding treatment field for IgA nephropathy, or IgAN. Ultomiris, also known as ravulizumab, is given by intravenous infusion after a loading dose and then every eight weeks. The FDA used its accelerated-approval pathway, which permits approval on a marker considered reasonably likely to predict clinical benefit while a confirmatory study continues.
That distinction is central to understanding the decision. Less protein in the urine is a favorable signal and a major treatment target in IgAN, but the company’s approval announcement explicitly says it has not been established that Ultomiris slows the loss of kidney function. The ongoing Phase 3 trial is scheduled to measure that harder outcome at 106 weeks.
Why proteinuria mattered to the FDA
IgAN develops when abnormal immune deposits collect in the kidneys’ filtering units, provoking inflammation and scarring. The course varies: some people remain stable for years, while others progress to kidney failure and may need dialysis or a transplant. The National Institute of Diabetes and Digestive and Kidney Diseases explains that there is no cure; current care is intended to slow damage, manage blood pressure and reduce urine protein.
Persistent proteinuria is one of the strongest practical indicators of progression risk. The 2025 international KDIGO guideline recommends aiming for protein excretion below 0.5 grams per day and ideally below 0.3 grams, while keeping estimated glomerular filtration rate, or eGFR, stable. It also emphasizes that IgAN requires a kidney biopsy for diagnosis and that treatment rests on optimized supportive care, including blood-pressure control and renin-angiotensin-system blockade, with other therapies layered according to risk.
The FDA has repeatedly accepted proteinuria reduction as the basis for accelerated approvals in IgAN. Its surrogate-endpoint table lists changes in urine protein for this setting. In a prior IgAN decision, the agency similarly said a treatment reduced proteinuria while acknowledging that an effect on kidney-function decline had not yet been established. The pathway gives patients earlier access, but it places real weight on the completion of confirmatory evidence.
What the I CAN trial found—and has not found
The approval rests on an interim analysis of I CAN, a randomized, double-blind, placebo-controlled trial planned for about 510 adults across 28 countries. The public trial record identifies participants with biopsy-confirmed primary IgAN, substantial proteinuria and ongoing progression risk despite stable standard therapy. The main cohort required an eGFR of at least 30 milliliters per minute per 1.73 square meters and stable treatment with an ACE inhibitor or angiotensin-receptor blocker, when tolerated.
Participants were assigned equally to Ultomiris or placebo. At week 34, the Ultomiris group had a 46.6% reduction in urine protein-to-creatinine ratio from baseline, compared with 5.6% for placebo, producing the reported 43.4% treatment effect. The difference was statistically significant, and separation was visible by week 10. Those results are consistent with an earlier randomized Phase 2 study, in which ravulizumab produced a 30.1% relative reduction in 24-hour urine protein versus placebo at week 26.
Still, the Phase 3 analysis has important limits. Proteinuria is a surrogate rather than the clinical outcome patients care about most. The trial has not yet shown that patients on Ultomiris avoid dialysis, transplantation, major loss of filtration capacity or other long-term complications. The crucial co-primary endpoint is change in eGFR through week 106; those data are meant to confirm whether the early laboratory improvement translates into slower disease progression. Until that readout, the magnitude and durability of clinical benefit remain uncertain.
The interim result also applies to a defined trial population. Eligibility criteria excluded several groups, including people with a recent history of certain immunosuppressive treatments, prior kidney transplantation, active serious infection or meningococcal infection. That improves interpretability, but it means the results cannot automatically be generalized to every adult with IgAN, especially those with more advanced kidney impairment or complex immune-suppressing conditions.
A targeted mechanism with a consequential safety tradeoff
Ultomiris is a monoclonal antibody that blocks complement protein C5. The complement system is part of the body’s immune defense, but excessive activation can contribute to inflammation and tissue injury. In IgAN, the treatment is intended to interrupt a downstream inflammatory pathway rather than directly removing the abnormal IgA deposits.
Blocking C5 also carries a serious, well-characterized infection hazard. The most recent publicly available FDA label before this new indication contains a boxed warning for life-threatening meningococcal infections and requires prescribing through a restricted safety program. Vaccination is required according to current recommendations, yet vaccination does not eliminate the risk.
The Centers for Disease Control and Prevention estimates that people receiving complement inhibitors face up to a 2,000-fold greater risk of meningococcal disease than otherwise healthy people. The CDC specifically includes ravulizumab among C5 inhibitors and advises clinicians to maintain a high index of suspicion even when a patient has been vaccinated or is taking preventive antibiotics. That safety burden makes patient education, vaccine timing and rapid evaluation of symptoms integral to treatment—not administrative details.
In the 34-week I CAN analysis, no new safety signal was identified. The most commonly reported adverse events with Ultomiris were upper respiratory infection, nasopharyngitis and infusion-related reactions. However, a trial of several hundred selected participants is not designed to precisely quantify very rare, catastrophic infections. The established class risk therefore remains more informative than the absence of a new signal in the interim dataset.
Where Ultomiris may fit in a changing treatment landscape
IgAN care has moved quickly from broad supportive treatment toward multiple disease-targeted options. Some drugs act on immune-cell signaling or complement pathways, some reduce pathogenic antibody production, and others aim to protect the kidney through hemodynamic or anti-inflammatory effects. Several have entered the market through accelerated approval based on proteinuria, creating more choices but also a more complicated evidence hierarchy.
Ultomiris has practical advantages and disadvantages. Dosing every eight weeks is less frequent than many infusion regimens, but it still requires an infusion center, infection-risk procedures and ongoing specialist coordination. Cost and insurance coverage will shape access. There are no head-to-head data showing that ravulizumab is superior to other approved IgAN therapies, and the I CAN trial was not designed to establish the best sequence or combination.
The 2025 KDIGO framework favors a layered strategy: optimize supportive care for everyone, assess the risk of progressive kidney loss, and add targeted therapies where the anticipated benefit justifies the burden and risk. Ultomiris is therefore not a replacement for blood-pressure management, proteinuria monitoring or other kidney-protective treatment. Its likely role will depend on a patient’s disease activity, prior response, infection risk, infusion access and the evolving evidence for competing agents.
The 106-week result is the real test
The FDA decision makes a meaningful new option available to adults whose disease continues to threaten kidney function despite standard care. It also demonstrates the value and the limitation of accelerated approval: a strong short-term biological signal can support earlier access before the definitive clinical question has been answered.
The next decision point is the 106-week eGFR analysis. A convincing reduction in the rate of kidney-function loss would validate proteinuria as an informative early marker for this drug and strengthen its place in practice. A weak or inconsistent result would force clinicians, patients and regulators to reassess how much weight the surrogate deserved.
For now, the evidence supports a narrow conclusion. Ultomiris substantially reduced proteinuria over 34 weeks in a rigorously controlled trial of adults with biopsy-confirmed, high-risk IgAN. It has not yet demonstrated that it prevents kidney failure or slows long-term decline, and its complement-blocking mechanism carries an uncommon but potentially fatal infection risk. The approval expands choice, while leaving the most consequential measure of benefit still to come.
