FDA Grants Accelerated Approval to Ravulizumab for Proteinuria Reduction in IgA Nephropathy

The FDA granted accelerated approval to ravulizumab-cwvz (Ultomiris; Alexion, AstraZeneca Rare Disease) to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of disease progression, according to an AstraZeneca announcement. Ravulizumab is the first and only C5 inhibitor approved for this use, and IgAN is its fifth approved indication.¹

Because the approval is based on proteinuria reduction, it has not yet been shown that ravulizumab slows the decline of kidney function in IgAN. Continued approval may depend on confirming clinical benefit in the ongoing I CAN trial.¹

Complement Activation Drives Kidney Injury

IgAN starts with the production of abnormal IgA proteins. These form immune complexes that settle in the kidneys and activate the complement system. The resulting terminal complement–driven inflammation damages glomerular cells and can progress to chronic kidney disease and end-stage kidney disease.

More than 200,000 individuals in the US have IgAN. About half of those with elevated proteinuria or reduced kidney function face a high risk of kidney failure within 10 years of diagnosis.¹

Ravulizumab is a long-acting monoclonal antibody that blocks the C5 protein in the terminal complement cascade. In adults, it is given intravenously every 8 weeks after a loading dose, with dosing based on body weight.¹

I CAN Trial Design

I CAN (NCT06291376) is a global, randomized, double-blind, placebo-controlled phase 3 trial that aims to enroll approximately 510 adults across 28 countries. Participants had been on stable standard-of-care IgAN therapy for at least 3 months before screening. They were randomly assigned 1:1 to receive ravulizumab or a placebo for 106 weeks.²

The trial has 2 primary end points:

• change in proteinuria at week 34, measured by 24-hour urine protein-to-creatinine ratio (UPCR)
• change in estimated glomerular filtration rate (eGFR) at week 106

The week 106 eGFR data are intended to support traditional approval.^1,2

Interim Efficacy and Safety Results

In the prespecified interim analysis at week 34, ravulizumab reduced 24-hour UPCR from baseline by 46.6% (95% CI, 39.0%-53.2%), compared with 5.6% (95% CI, –4.9% to 15.0%) for placebo. This was a placebo-adjusted treatment effect of 43.4% (95% CI, 33.5%-51.8%; P < .0001). The benefit appeared early, with a 36.7% reduction by week 10 vs 8.5% with placebo, and it held through week 34. Results were consistent across subgroups.¹

The safety findings matched ravulizumab’s established profile, and no new safety signals emerged. With ravulizumab, the most common adverse events were:

• Upper respiratory tract infection (11.3%)
• Nasopharyngitis (9.2%)
• Infusion-related reactions (8.4%)

In the placebo group, the most common were upper respiratory tract infection, nasopharyngitis, and hypertension.¹

Richard Lafayette, MD, professor of medicine (nephrology) at Stanford University Medical Center and external scientific committee co-chair of I CAN, explained that many individuals with IgAN still have persistent proteinuria despite current treatments, which signals ongoing kidney injury. He said ravulizumab gives physicians a way to target a central driver of that inflammation.¹

Place in Therapy

The 2025 Kidney Disease: Improving Global Outcomes (KDIGO) guideline considers individuals with IgAN and proteinuria of at least 0.5 g/day to be at risk of progressive kidney function loss. For these individuals, it recommends starting or escalating therapy. The guideline sets a proteinuria target below 0.5 g/day, ideally below 0.3 g/day. It also recommends starting immunosuppressive and anti-proteinuric treatment at the same time rather than one after the other.³

Ravulizumab enters a growing field of IgAN therapies. Its expected competitors are budesonide delayed-release capsules (Tarpeyo; Calliditas Therapeutics), iptacopan (Fabhalta; Novartis), and sparsentan (Filspari; Travere Therapeutics).⁴

Safety Considerations for Pharmacists

Ravulizumab carries a boxed warning for serious meningococcal infections. Notably, the boxed warning information below comes from the most recent publicly available prescribing information, which was last revised in February 2024 and predates the IgAN approval. An updated label reflecting the new indication had not been made publicly available at the time of publication.⁵

According to that label, patients should complete or update meningococcal vaccination at least 2 weeks before their first dose. The exception is when the risks of delaying treatment outweigh the risk of serious infection. Because of the infection risk, ravulizumab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program, the Ultomiris and Soliris REMS, and prescribers must enroll in it.⁴

Pharmacists can play a key role in confirming patients’ meningococcal vaccination status before initiation. In counseling, they can explain two key points:

• Vaccination does not prevent every meningococcal infection.
• Infection risk can continue for several months after the last dose.

For both reasons, patients need to recognize infection symptoms promptly.⁴

Looking Ahead

Late-breaking I CAN results are scheduled for presentation at the American Society of Nephrology’s Kidney Week on October 23, 2026. The final eGFR data at week 106 will show whether ravulizumab slows kidney function decline. Regulatory submissions based on the interim results are also under review in Japan and other countries.¹

REFERENCES

1. 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. AstraZeneca. October 21, 2026. Accessed October 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/ultomiris-approved-in-us-in-igan.html

2. Study of Ravulizumab in Immunoglobulin A Nephropathy (IgAN) (I CAN). ClinicalTrials.gov identifier: NCT06291376. Updated October 2, 2026. Accessed October 22, 2026. https://clinicaltrials.gov/study/NCT06291376

3. Kidney Disease: Improving Global Outcomes (KDIGO) IgAN and IgAV Work Group. KDIGO 2025 clinical practice guideline for the management of immunoglobulin A nephropathy (IgAN) and immunoglobulin A vasculitis (IgAV). Kidney Int. 2025;108(4S):S1-S71. doi:10.1016/j.kint.2025.04.004

4. FDA accepts AstraZeneca’s filing for expanded use of Ultomiris. Nasdaq. 2026. Accessed October 22, 2026. https://www.nasdaq.com/articles/fda-accepts-astrazenecas-filing-expanded-use-ultomiris

5. Ultomiris. Prescribing information. Alexion Pharmaceuticals; revised February 2024. Accessed October 22, 2026. https://alexion.com/documents/ultomiris_uspi.pdf