Ravulizumab's IgA Nephropathy Approval Expands Large-Molecule Biologic Demand

The FDA has granted accelerated approval to Ultomiris (ravulizumab), the long-acting C5 complement inhibitor from Alexion, AstraZeneca Rare Disease.¹ It is approved to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. The decision makes ravulizumab the first C5 inhibitor approved for the disease. It is the antibody’s fifth indication, following approvals in paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

IgAN develops when abnormal immunoglobulin A proteins form immune complexes that deposit in the kidneys.¹ These deposits activate the complement system and drive inflammation that damages the glomeruli. The disease affects more than 200,000 people in the US. Roughly half of patients with elevated urinary protein or reduced kidney function are at high risk of progressing to kidney failure within 10 years of diagnosis.

What Data Supported the Approval?

The approval followed a priority review and is based on a prespecified interim analysis of the global Phase 3 I CAN trial.¹ At week 34, ravulizumab reduced 24-hour urine protein creatinine ratio by 46.6% from baseline, compared with 5.6% for placebo. That is a placebo-adjusted treatment effect of 43.4% (P < .0001). Reductions appeared as early as week 10 and were consistent across subgroups. No new safety concerns were identified.

Because the approval rests on a surrogate end point, continued marketing may depend on confirmatory evidence.¹ The trial’s second primary end point, change in estimated glomerular filtration rate at week 106, is intended to support traditional approval.

“For many people living with IgAN, persistent proteinuria remains a significant challenge despite available treatments, signaling ongoing kidney injury and heightened risk of disease progression. With this approval of Ultomiris, physicians now have a C5 inhibitor that delivers sustained terminal complement inhibition, targeting a central driver of kidney inflammation to meaningfully reduce proteinuria in patients living with this progressive disease,” said Richard Lafayette, MD, professor of medicine (nephrology), Stanford University Medical Center and external scientific committee cochair of the I CAN trial, in a press release.¹

Why Does This Matter for Development and Manufacturing?

The IgAN treatment landscape is filling quickly.1 In July, the FDA granted accelerated approval to Trutakna (atacicept-vymj), a once-weekly autoinjector. Ravulizumab sits at the opposite end of the administration spectrum. It is an intravenous biologic given every 8 weeks after a weight-based loading dose. The 2 formats carry different implications for infusion-center capacity, fill-finish presentations, and specialty distribution.

When the application was granted priority review in June, a fifth approval would require the company and its manufacturing partners to plan for incremental demand for a large-molecule biologic.¹ The I CAN design pairs a surrogate-based interim analysis with a long-term kidney function end point. That approach gives sponsors in rare kidney disease a procedural model to follow.

“As the first and only C5 inhibitor approved for the reduction of proteinuria in adults with IgAN, Ultomiris offers a new treatment option for people living with this serious disease. Many patients continue to face the risk of progression to kidney failure, underscoring the need for more targeted therapies that can slow the course of disease. This approval marks the fifth indication for Ultomiris, building on Alexion’s pioneering leadership across multiple complement-mediated rare diseases,” said Marc Dunoyer, CEO, Alexion, in the press release.¹

Why Can Proteinuria Support an Accelerated Approval?

The end point behind ravulizumab’s approval traces to a Kidney Health Initiative project launched in 2016 by the American Society of Nephrology and the FDA.² Its workgroup reviewed epidemiologic data and trial-level analyses from 13 controlled trials, concluding that proteinuria reduction is a reasonably likely surrogate for progression to kidney failure in IgA nephropathy. The authors cautioned that a biomarker that predicts risk well may not predict a drug’s effect, particularly when it sits off the causal pathway or a therapy acts through other mechanisms. For sponsors, that makes mechanism of action central to how surrogate data are interpreted.

References

1. AstraZeneca. Ultomiris received accelerated approval in the US as first and only C5 complement inhibitor to reduce proteinuria in adults with primary immunoglobulin A nephropathy. News release. October 21, 2026. Accessed October 22, 2026. View source

2. Thompson A, Carroll K, Inker LA, et al. Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol. 2019;14(3):469-481. doi:10.2215/CJN.08600718 View source