Complement-mediated kidney disease (CMKD) is a broad term, and we are learning more and more about the role of complement across the spectrum of kidney disease. C3G and IgAN unequivocally have contributions from complement, but you could also say that a host of other glomerular diseases, including lupus nephritis, infection-related glomerulonephritis, and membranous nephropathy, all have some contribution from complement. It is an important distinction to make because there will be some kidney diseases that will respond purely to complement-targeting therapy. 

C3G represents the most obvious type, where we think that all of its pathogenesis is from dysregulation of the alternative pathway (AP) of complement activation. More precisely, it involves the overactivation of the already constitutively active AP or the loss of inhibition of that constitutively active pathway. With IgAN, we know that there is some contribution from both the lectin pathway and the AP, so that is a disease in which it would make sense to consider targeting complement when you are thinking about treatment. Additionally, we know that the classical complement pathway is activated in lupus nephritis. In immune complex–mediated membranoproliferative glomerulonephritis, we have to assume that there is classical pathway activation, but there can also be clear evidence of these patients having AP dysfunction as well.

I think that as we appreciate the role of complement across the spectrum of kidney diseases, one of the challenges that we are going to face—if these complement pathway inhibitors become accessible—is figuring out which diseases can be treated solely with complement inhibition and which diseases will require complement inhibition as an adjunct. For example, there is a newly US Food and Drug Administration–approved complement-targeting therapy, the C5a receptor blocker avacopan, for antineutrophil cytoplasmic autoantibody–associated glomerulonephritis. Avacopan is not used as the sole therapy, but rather is used in conjunction with rituximab, cyclophosphamide, or conventional immunosuppression, and it has replaced corticosteroid use in some patients. This approach acknowledges that complement activation is clearly involved in the disease and in the inflammation that we see in the disease, but it is not the sole contributor. As we identify diseases to include in the CMKD category, we should differentiate between kidney diseases that are solely complement mediated and kidney diseases that include complement-mediated pathology in addition to other forms of immunopathogenesis. 

SCM23 did not include a lot of presentations on CMKD, despite a high unmet need for new treatment options in this area. Indeed, in poster 311, Dudzenski et al reported that 85% of surveyed US nephrologists indicated that C3G had the greatest perceived unmet need for new treatment options among kidney diseases and that this high unmet need correlated with greater challenges in management and a lower percentage of patients viewed as being “optimally managed.”  

There were some data presented at SCM23 on iptacopan, an investigational drug that inhibits the AP specifically by inhibiting factor B. In poster 337, for example, the complement fragment Bb, a biomarker of AP activity, was measured in healthy patients to determine the effect of single-dose iptacopan on the AP. Schmouder and colleagues reported a rapid, substantial, dose-dependent decrease in Bb following a single dose of iptacopan in these patients. Phase 3 studies of iptacopan are ongoing in paroxysmal nocturnal hemoglobinuria, C3G, IgAN, and atypical hemolytic uremic syndrome.