FDA Grants Ultomiris Accelerated Approval for IgA Nephropathy. The Approval Rests on Proteinuria, Not Kidney Function.
Ravulizumab is the first C5 complement inhibitor approved for IgAN, based on a 43.4 percent placebo-adjusted drop in proteinuria at week 34. Whether it slows eGFR decline will not be known until the 106-week data.
The Food and Drug Administration has granted ravulizumab (Ultomiris) accelerated approval to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of progression, a decision based on proteinuria, not kidney function. The drug is made by Alexion, AstraZeneca Rare Disease, and AstraZeneca announced the approval on Oct. 21, after a Priority Review.
The company says Ultomiris is the first and only C5 complement inhibitor approved to reduce proteinuria in IgAN, and that this is its fifth indication. The other four are paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis and neuromyelitis optica spectrum disorder.
What did the I CAN trial show?
The approval rests on a prespecified interim analysis of I CAN, a global, randomized, double-blind, placebo-controlled Phase 3 trial in adults with IgAN at risk of progression who had been on stable standard-of-care therapy for at least three months. AstraZeneca says the trial was designed to enroll about 510 adults in 28 countries; the release does not give the number actually enrolled or the proteinuria and eGFR entry thresholds.
At week 34, 24-hour urine protein-creatinine ratio fell 46.6 percent from baseline with Ultomiris and 5.6 percent with placebo, a placebo-adjusted reduction of 43.4 percent (95% confidence interval 33.5 to 51.8 percent; P<.0001), according to the company. The separation was visible by week 10, with reductions of 36.7 percent and 8.5 percent, and was sustained through week 34.
Proteinuria is a surrogate. The approval says Ultomiris lowers it; it does not yet say Ultomiris protects kidney function.
Is the benefit on kidney function established?
No. It has not been established whether Ultomiris slows kidney function decline in IgAN, and continued approval may depend on confirmatory evidence of clinical benefit. I CAN continues to its second primary endpoint, change in estimated glomerular filtration rate (eGFR) at week 106. Pharmaphorum reported that positive eGFR results should support full approval.
Late-breaking I CAN results are scheduled for the American Society of Nephrology's Kidney Week in Denver on Oct. 23, per AstraZeneca. Nephrologists should see more there than the press release gives, including enrollment and subgroup detail.
What are the dosing and safety details?
Ultomiris is given intravenously every eight weeks, dosed by body weight, after a loading dose. In I CAN, the most common adverse events with Ultomiris were upper respiratory tract infection (11.3 percent), nasopharyngitis (9.2 percent) and infusion-related reactions (8.4 percent), compared with upper respiratory tract infection (10.2 percent), nasopharyngitis (9.0 percent) and hypertension (6.6 percent) with placebo. AstraZeneca said no new safety concerns were identified.
The approval release does not discuss labeling. The current Ultomiris prescribing information, which predates the IgAN indication, carries a boxed warning for serious meningococcal infections. It requires patients to complete or update meningococcal vaccination against serogroups A, C, W, Y and B at least two weeks before the first dose unless delaying therapy is riskier, and limits the drug to the ULTOMIRIS and SOLIRIS REMS. Those are product-wide requirements; the updated label with the IgAN indication had not been posted on DailyMed when we checked. For context on another complement-targeted product, see our report on the Zilbrysq autoinjector for generalized myasthenia gravis.
What it means for referring physicians
Primary care physicians and cardiologists will mostly see this through their nephrology colleagues. Patients with IgAN who are on standard-of-care therapy and still at risk of progression now have another option to raise with their nephrologist. Pharmaphorum noted that about half a dozen new IgAN therapies have reached the US market in the past decade, with more in the pipeline, so choice among agents will turn on long-term eGFR data, vaccination logistics and infusion access.
"Many patients continue to face the risk of progression to kidney failure," Alexion CEO Marc Dunoyer said in the release. Bonnie Schneider, director and co-founder of the IgA Nephropathy Foundation, said, "This approval reflects the importance of continued innovation to help improve outcomes for people living with IgAN."
For this week: if you co-manage IgAN patients, check meningococcal vaccination status for anyone being considered for a C5 inhibitor, and make sure patients who start one know to seek care immediately for symptoms of meningococcal infection. Watch the Kidney Week eGFR and subgroup data on Oct. 23.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
