Ravulizumab Cuts Proteinuria by 43% in IgA Nephropathy

Targeting the terminal complement cascade offers a promising therapeutic pathway for progressive kidney disease. Recently, researchers reported compelling interim data evaluating ravulizumab in IgA nephropathy. In this condition, immune complexes trigger complement activation and cause persistent glomerular inflammation. Consequently, patients often experience hematuria, worsening proteinuria, and progressive loss of nephrons. Standard supportive therapy frequently fails to halt this destructive process.

Phase 3 Trial Design and Methods

The global phase 3 I CAN trial evaluated the efficacy and safety of terminal complement inhibition. Specifically, investigators enrolled adult patients with biopsy-confirmed disease and persistent proteinuria despite receiving optimized standard care. Patients had an estimated glomerular filtration rate of at least 30 ml per minute. Additionally, participants exhibited a 24-hour urinary protein-to-creatinine ratio of 0.75 or higher, or daily protein excretion of at least 1.0 g.

Researchers randomly assigned 485 participants in a 1:1 ratio to receive intravenous ravulizumab or placebo every eight weeks. Furthermore, 352 patients contributed data to this prespecified week-34 interim analysis. The primary efficacy end point evaluated percentage change in the 24-hour urinary protein-to-creatinine ratio from baseline.

Evaluating Ravulizumab in IgA Nephropathy Efficacy

The trial demonstrated striking therapeutic benefits at week 34. Specifically, patients receiving ravulizumab achieved a 46.6% geometric mean reduction in proteinuria from baseline. In contrast, patients in the placebo group achieved only a 5.6% reduction during the same period. Therefore, ravulizumab produced an adjusted 43.4% relative reduction compared with placebo.

Moreover, the treatment showed rapid onset, with marked proteinuria drops occurring as early as week 10. These robust reductions occurred consistently across diverse clinical subgroups. Thus, terminal complement inhibition effectively suppresses pathogenic glomerular injury.

Safety and Clinical Implications for Practice

Ravulizumab maintained an acceptable safety profile consistent with its established use in other complement-mediated conditions. Importantly, clinicians must administer meningococcal vaccination before treatment to prevent encapsulated bacterial infections. In routine nephrology practice, persistent proteinuria strongly predicts progression to kidney failure. Consequently, adding targeted complement inhibition to renin-angiotensin system blockade provides substantial nephroprotection. Long-term follow-up through week 106 will further clarify its impact on filtration preservation.

Frequently Asked Questions

Q1: How does ravulizumab work in patients with IgA nephropathy?

Ravulizumab specifically blocks terminal complement protein C5. As a result, it prevents the generation of proinflammatory C5a and the cytotoxic membrane attack complex.

Q2: What magnitude of proteinuria reduction did the phase 3 interim analysis report?

Patients treated with ravulizumab demonstrated a 43.4% relative reduction in proteinuria compared to placebo at week 34.

Q3: What critical safety precaution is required prior to initiating therapy?

Patients must receive vaccination against Neisseria meningitidis prior to treatment because terminal complement blockade elevates the risk of meningococcal disease.

References

1. Barratt J et al. Ravulizumab in IgA Nephropathy - Interim Analysis of a Phase 3 Trial. N Engl J Med. 2026 Oct 23. doi: 10.1056/NEJMoa2607544. PMID: 42912700.
2. Lafayette R, Tumlin J, Fenoglio R, et al. Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial. J Am Soc Nephrol. 2025;36(4):645-656.
3. Lafayette R, Barratt J, et al. Complement Inhibition in IgA Nephropathy: Emerging Targets and Clinical Evidence. Kidney Int. 2024;105(5):980-991.