Currently, there are no US Food and Drug Administration (FDA)–approved treatments for patients with C3G. We have had 2 agents recently approved for IgAN (ie, budesonide and sparsentan, which are both antiproteinuric approaches), but there is still room for targeted therapeutics in IgAN as well. Clinical trials can be important in situations in which we know that our currently available options are limited, and there is a strong rationale for investigating agents that appear to offer a more targeted approach. Classically, we have strongly encouraged patients to consider clinical trials, and we would even help patients navigate the system, showing them how ClinicalTrials.gov can be used to learn about the different investigational approaches that might be of interest. 

In C3G, it is my impression that we are more likely to have success with protocols investigating the proximal blockade of the complement alternative pathway (eg, inhibiting factor B, factor D, or C3 for instance) rather than inhibiting the terminal pathway or C5 (downstream). For IgAN, we are also excited about proximal blockade but are perhaps a bit more open to downstream blockade. And it is possible that C5a may be more active in the pathogenesis of IgAN. There is just so much more that we need to know about this disease.

Proteinuria is generally the primary end point for clinical trials in both C3G and IgAN. While a final assessment remains to be seen, it appears that, at least up to this point, the FDA will accept proteinuria as a surrogate of risk for end-stage renal disease in both diseases. We have decent data indicating that proteinuria is a good biomarker in IgAN, but the data are more limited in C3G. In both diseases, we would like to develop additional markers of disease progression, but, ultimately, the most important outcome or end point is preventing progression to end-stage disease. However, we would have to follow these patients for 10 to 20 years, or even longer, to report on that end point. 

Phase 2 trials evaluating the C3 inhibitor pegcetacoplan and the factor B inhibitor iptacopan have reported improvements in serum C3 and proteinuria among patients with C3G. Also, in a phase 2 trial, the factor D inhibitor danicopan was effective in some patients but not in others. Further, a phase 2 trial is ongoing for the MASP2 inhibitor narsoplimab in IgAN. There are currently no trials investigating the C5 inhibitor eculizumab in C3G or IgAN. The bottom line is that the agents that we have tried thus far have had varying degrees of success, and we are hopeful that more effective strategies will emerge from ongoing trials.