Complement Inhibition Therapy in IgA Nephropathy: Total or Selective Inhibition?

Recently, an interesting and encouraging study titled “Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial” was published in JASN.1 Regarding the article, we would like to have some discussion. The intensity of glomerular staining for C5b-9 correlates with the extent of mesangial expansion and hypercellularity, glomerulosclerosis, interstitial inflammation, interstitial fibrosis, and tubular atrophy in patients with IgA nephropathy.2 The urinary sC5b-9 has been reported as a marker of the terminal pathway activation associated with glomerular inflammation, and the urinary sC5b-9 levels were markedly elevated, likely reflecting the activation of the complement system in IgA nephropathy.3 In a clinical trial of ravulizumab for IgA nephropathy, if the soluble C5b-9 in blood and urine was dynamically observed, the data may be better analyzed. In the pathogenesis of IgA, the complement activation plays an important role, and the alternative pathway and lectin pathway are involved. The urinary levels of mannan-binding lectin and C4d have been shown to increase linearly with the proportion of glomerular crescents, which are prognostic of more rapid disease progression and poorer outcomes in IgA nephropathy.4 The lectin pathway activation is associated with more severe disease progression. Several possible targets in the lectin pathway might be inhibited, including pattern-recognition molecules such as mannan-binding lectin and collectin-11, complement components such as C2 or C4, or mannan-binding lectin serine peptidase 2.5 Narsoplimab is a mAb against mannan-binding lectin serine peptidase 2, a key component of the lectin pathway, while the phase 3 Omeros Corporationthe's Phase 3 trial evaluating narsoplimab for the treatment of immunoglobulin A nephropathy trial of narsoplimab did not achieve the primary end point of reduction in proteinuria at 36 weeks versus placebo.6 The iptacopan specifically binds to factor B and inhibits the alternative pathway. In a phase 3 trial of iptacopan for IgA nephropathy, the results showed that the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% at month 9, lower with iptacopan than with placebo.7 In the phase 2 trial of ravulizumab for IgA nephropathy, which showed that a statistically significant reduction in proteinuria was observed with ravulizumab versus placebo: −41.9% at 26 weeks, the results presented in this study show that ravulizumab seems to be more effective in the treatment of IgA nephropathy than iptacopan. Is the causative role of the lectin pathway in IgA nephropathy overestimated, or is it due to differences in the complement activation pathway involved in the IgA nephropathy population enrolled in clinical trials? Does the target of the intervention lectin pathway need to be adjusted? If the complement activation pathways in IgA nephropathy patients can be distinguished, is it helpful to better analyze the data? If the lectin pathway is of limited significance, then complement inhibitors targeting the complement alternative pathway may have an advantage, theoretically with a lower risk of infection than C5 monoclonal antibodies, because the alternative pathway of complement inhibitors cannot completely block the production of membrane attack complex. If we can confirm the relative contribution of different complement activation pathways to the disease activity of IgA nephropathy patients, it may help select more precise complement suppression therapy.