I CAN: Ravulizumab Cuts Proteinuria 43% vs Placebo in IgA Nephropathy

Ravulizumab (Ultomiris), a long-acting terminal complement C5 inhibitor, reduced 24-hour urinary protein-to-creatinine ratio (UPCR) by 43.4% versus placebo at week 34 in adults with IgA nephropathy, according to a prespecified interim analysis of the phase 3 I CAN trial.¹

Richard Lafayette, MD, of Stanford University Medical Center, presented the findings during a High-Impact Clinical Trials session at ASN Kidney Week 2026 in Denver, Colorado, with simultaneous publication in the New England Journal of Medicine.^1,2

The interim data supported US Food and Drug Administration accelerated approval of ravulizumab on October 21, 2026, to reduce proteinuria in adults with primary IgA nephropathy at risk for disease progression.³ In a prior phase 2 trial, ravulizumab reduced proteinuria by 40.3% versus 10.9% with placebo at week 26.⁴ Ravulizumab blocks formation of C5a and C5b-9 regardless of the initiating complement pathway, according to the investigators.¹

How Much Did Ravulizumab Reduce Proteinuria in the I CAN Trial?

I CAN enrolled adults with biopsy-confirmed IgA nephropathy, an eGFR ≥ 30 mL/min/1.73 m², and a 24-hour UPCR of ≥ 0.75 or urinary protein excretion of ≥ 1.0 g/day despite standard therapy. Patients were randomly assigned in a 1:1 ratio to weight-based intravenous ravulizumab or placebo every 8 weeks. All participants were vaccinated against Neisseria meningitidis before treatment.¹

Of 485 patients randomized across 28 countries, 352 (n = 176 per group) were included in the interim analysis. Background therapy included a renin-angiotensin-aldosterone system inhibitor in 96.3% and an SGLT2 inhibitor in 69.3%, and median baseline eGFR was 59.0 mL/min/1.73 m². Mean age was 42.5 years, 58.0% were men, and 61.6% were enrolled in the Asia-Pacific region.¹

At week 34, geometric mean 24-hour UPCR fell by 46.6% with ravulizumab compared with 5.6% with placebo, corresponding to an adjusted between-group difference of 43.4% (99% CI, 30.1–54.2; P < .001).¹ The reduction was evident as early as week 10, when UPCR was 30.9% lower with ravulizumab than with placebo. Results were consistent across prespecified subgroups and in an intention-to-treat sensitivity analysis.¹

What Were the Hematuria, Biomarker, and Safety Findings With Ravulizumab?

A 50% or greater reduction in UPCR at week 34 occurred in 37.7% of ravulizumab-treated patients vs 12.1% receiving placebo.¹ Partial remission was achieved by 29.7% versus 16.4%, and total urinary protein excretion < 0.5 g/day by 18.7% versus 5.2%, respectively. Mean FACIT-Fatigue scores changed by 0.26 points with ravulizumab and −1.27 points with placebo.¹

Among patients with baseline hematuria, resolution occurred in 42.4% (56/132) with ravulizumab vs 11.1% (16/144) with placebo. Among those without baseline hematuria, new-onset hematuria developed in 4.8% (2/42) versus 33.3% (9/27), respectively. Urinary biomarkers also favored ravulizumab, including soluble C5b-9 (between-group difference, −95.5%), factor Ba (−54.0%), CD163 (−29.2%), and KIM-1 (−30.1%).¹

Adverse events occurred in 69.5% (166/239) of ravulizumab-treated patients vs 75.8% (185/244) of placebo recipients. Serious adverse events occurred in 4.6% vs 9.0%, and infections were reported in 38.5% vs 35.7%, respectively. No meningococcal infections or deaths occurred.¹

The authors noted the interim analysis did not report eGFR outcomes, in accordance with regulatory guidance for ongoing trials. Those data will be available at the conclusion of the 106-week treatment period, and continued approval may depend on verification of clinical benefit.^1,3 A trial of ravulizumab in children and adolescents is ongoing.¹

References

1. Barratt J, Farag YMK, Rice K, et al. Ravulizumab in IgA nephropathy: interim analysis of a phase 3 trial. N Engl J Med. Published online October 23, 2026. doi:10.1056/NEJMoa2607544

2. Lafayette RA. Ravulizumab in IgA nephropathy: interim analysis of the phase 3 I CAN trial. Presented at: ASN Kidney Week 2026, High-Impact Clinical Trials session; October 23, 2026; Denver, CO.

3. Campbell P. Ravulizumab receives FDA accelerated approval for IgA nephropathy. HCPLive. Published October 22, 2026. Accessed October 23, 2026. https://www.hcplive.com/view/ravulizumab-receives-fda-accelerated-approval-for-iga-nephropathy

4. Derman C. Study supports the efficacy, safety of ravulizumab for patients with IgA nephropathy. HCPLive. Published November 16, 2023. Accessed October 23, 2026. https://www.hcplive.com/view/study-supports-the-efficacy-safety-ravulizumab-patients-with-iga-nephropathy