AstraZeneca's Ultomiris Cuts IgAN Proteinuria 43%, but the Kidney Proof Is Still Pending
AstraZeneca's Ultomiris won accelerated FDA approval to reduce proteinuria in IgA nephropathy, becoming the first C5 inhibitor in the space. But unlike Novartis's fully approved Fabhalta, it has not yet shown it preserves kidney function.
The US Food and Drug Administration has approved AstraZeneca and Alexion's Ultomiris (ravulizumab-cwvz) under the accelerated pathway to reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of disease progression. In a prespecified interim analysis of the Phase III I CAN trial, Ultomiris produced a 43.4% placebo-adjusted reduction in proteinuria at 34 weeks (p<0.0001). AstraZeneca calls it the first and only C5 complement inhibitor cleared for that use, and Alexion chief executive Marc Dunoyer said the decision is Ultomiris's fifth US indication after Priority Review.
The proteinuria signal was large and came on early. Ultomiris reduced 24-hour urine protein-creatinine ratio from baseline by 46.6% (95% CI 39.0%-53.2%) at week 34, versus 5.6% (95% CI -4.9% to 15.0%) for placebo. The drop was observed as early as week 10 (36.7% versus 8.5% on placebo) and held through the 34-week interim look. For a disease in which leaking protein is the practical marker of activity, that is a clean surrogate win. It is also, for now, the entire clinical case.
Two drugs, two points on the same cascade
IgA nephropathy is a chronic immune-complex kidney disease. IgAN affects more than 200,000 people in the United States, and AstraZeneca notes that about half of patients with elevated urine protein or reduced kidney function are at high risk of progressing to end-stage kidney disease within 10 years of diagnosis. Complement, the innate immune cascade that damages kidney cells and fuels inflammation, is one of the pathways thought to drive that injury. The new IgAN contest is about where, exactly, to interrupt it.
Ultomiris is a terminal complement, or C5, inhibitor. It is given intravenously every eight weeks in adults on a weight-based schedule after a loading dose. Blocking C5 shuts down the terminal step of the cascade regardless of which upstream arm lit the fuse. Novartis's Fabhalta (iptacopan) works further up, as an oral Factor B inhibitor aimed at the alternative complement pathway. Same disease, same general idea of cooling complement, different lock and different key. That mechanistic split now comes with a second split that matters more to regulators and to patients: what each drug has actually proven.
AstraZeneca's own language is unusually direct. "It has not been established whether Ultomiris slows kidney function decline in patients with IgAN." Accelerated approval rests on proteinuria, a surrogate the FDA has accepted in this setting, and continued approval may be contingent on verification in the ongoing I CAN trial. That confirmatory readout is change from baseline in estimated glomerular filtration rate at week 106. I CAN (ALXN1210-IgAN-320) is a global Phase III randomized, double-blind, placebo-controlled study designed to enroll about 510 participants from 28 countries (ClinicalTrials.gov NCT06291376). Until that eGFR analysis lands, Ultomiris is a proteinuria drug with a kidney-function question still open.
Safety at the interim look lined up with the known Ultomiris profile. The most common adverse events versus placebo were upper respiratory tract infection (11.3% versus 10.2%) and nasopharyngitis (9.2% versus 9.0%). Infusion-related reactions appeared in 8.4% of Ultomiris patients and not on placebo. Hypertension was reported in 6.6% of the placebo arm only.
The proof Novartis already has
Novartis is already past that gate. Fabhalta received FDA traditional, full approval on 17 July 2026 to slow kidney function decline in adults with IgAN at risk of progression, after an initial accelerated approval in August 2024 for proteinuria reduction. In the Phase III APPLAUSE-IgAN study, Fabhalta slowed eGFR decline by 48% versus placebo over two years, with an annualized mean change from baseline of -3.0 mL/min/1.73 m2/yr against -5.7 for placebo. That is the hard kidney-function endpoint Ultomiris has not yet shown. It is also the difference between an accelerated label and a traditional one.
The commercial weight behind Ultomiris is not small. The franchise generated $4,718 million in global revenue in full-year 2025, up 19% at constant exchange rates. A fifth US indication extends an intravenous product that already sits in rare complement diseases into a much larger glomerular-disease population. Dosing every eight weeks is a different proposition from an oral capsule, which will matter in a clinic that now has more than one complement option and will have to weigh infusion logistics against a pill that already carries an eGFR claim.
None of that settles the medical question. Proteinuria fell fast and far on Ultomiris. Fabhalta has already shown that blocking a different node of complement can preserve filtration rate over two years. The race in IgAN complement is no longer only about who got there first. It is about whether a C5 antibody that cuts protein in the urine can, at week 106, prove the thing the FDA has not yet established: that it slows the kidney's decline.
