Authors' Reply: Complement Inhibition Therapy in IgA Nephropathy: Total or Selective Inhibition?

We thank Zhu et al.1 for their commentary on our JASN article2 “Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial” and the questions for discussion. The phase 2 randomized, double-blind, placebo-controlled SANCTUARY trial evaluated the complement C5 inhibitor, ravulizumab, in 66 adults with IgA nephropathy.2 Change from baseline to week 26 in 24-hour urine protein was −41.9% with ravulizumab and −16.8% with placebo (30.1% treatment effect). Our results with ravulizumab, as well as those from the phases 2 and 3 trials of the factor B, alternative pathway inhibitor, iptacopan, suggest that inhibition of the complement system results in a clinically meaningful reduction in proteinuria and, pending data from phase 3 trials, may result in the preservation of kidney function. As the authors note, both the alternative and lectin pathways are involved in IgA nephropathy. The activation of either leads to terminal pathway activation and generation of C5a (potent anaphylatoxin) and C5b-9 (membrane attack complex). Terminal pathway activation leads to mesangial cell apoptosis, podocyte injury, and damage to the glomerular basement membrane. Beyond glomerular damage, urinary membrane attack complex levels have been shown to correlate with interstitial fibrosis,3 and studies in mouse models provide evidence of C5a and C5b-9 involvement in the development of tubulointerstitial fibrosis.4,5 Regarding the contribution of the lectin pathway to complement-mediated damage in IgA nephropathy, lectin pathway activation has been detected in approximately 38% of patients in one cohort study.6 More data from phase 3 studies, or even head-to-head studies, would be needed to compare the effectiveness of targeting different complement pathways in IgA nephropathy. The authors state that blocking the terminal pathway may lead to greater risk of meningococcal infection than alternative pathway inhibition. However, inhibition of the terminal pathway preserves proximal pathway–mediated opsonization of other pathogens and clearance of immune complexes. In SANCTUARY, there were no reported meningococcal infections in patients treated with ravulizumab, and treatment was well tolerated.2 The safety profile was consistent with the >37,000 patient-years of experience with ravulizumab across several indications, including in combination with immunosuppressants. The cumulative rate of Neisseria meningitidis infection in patients treated with ravulizumab has remained stable at <0.2 cases/100 patient-years,7 and there is an established and effective risk mitigation program. The risk of meningococcal infection and requirement for vaccination is common to complement inhibitors as a class. A phase 3 randomized, double-blind, placebo-controlled trial of ravulizumab (NCT06291376; European Union Clinical Trials 2023-507851-31-00) is enrolling patients globally. The trial will provide confirmatory evidence on the safety and efficacy of ravulizumab in IgA nephropathy.