There has long been suspicion of the complement system's involvement in the pathogenesis of certain glomerular diseases, such as lupus nephritis or cryoglobulinemia, where you see that the circulating levels of complement (eg, C3 and C4) are low. The immune complexes that are made in those diseases are using up those complement fragments, leading us to think that complement is a participator in the pathogenesis of those diseases.

More recently, the complement system has been implicated in the pathogenesis of glomerular diseases that do not have low levels of serum complements. Specifically, primary glomerular diseases such as IgAN and membranous nephropathy have abnormalities in the complement system that have been linked to their pathogenesis. Of course, C3G was initially included in a spectrum of membranoproliferative glomerulonephritis classes, but, as we began to better understand the pathogenesis, we also learned that C3G is predominantly driven by abnormalities in the alternative pathway of complement, resulting in C3-dominant deposits within the glomerulus of the kidney. Most commonly, this is associated with circulating autoantibodies called nephritic factors that are thought to destabilize the alternative complement pathway, allowing the constitutively active pathway to remain unchecked. This enables C3b to generate again and again, which wreaks havoc on kidney tissue and causes the glomerular injury that you see in C3G. 

A number of novel therapeutics that target the complement system are currently in clinical trials for the treatment of a spectrum of glomerular diseases, such as IgAN, C3G, and membranous nephropathy. For example, the oral factor B inhibitor iptacopan is in clinical development, and initial data that were presented at the American Society of Nephrology Kidney Week 2022 showed a significant reduction from baseline proteinuria in patients with IgAN on iptacopan compared with placebo at 3 months (31% vs 12%, respectively) and 6 months (41% vs 2%, respectively). 

Factor B is an important activator of the alternative complement pathway, so blocking it may help slow that pathway down and decrease the generation of C3. SCM23 featured several posters on iptacopan. For instance, poster 337 by Schmouder et al examined the ability of single- and multiple-dose administrations of iptacopan vs placebo to lower plasma complement fragment Bb levels in healthy volunteers. Researchers reported a rapid, dose-dependent decrease in Bb with iptacopan treatment. Whether or not that marker truly aligns with the pathophysiology in the kidney remains to be determined, but it seems to be doing what we expect it to be doing in the plasma.

One of the concerns about these complement blockers—or any novel therapy—is whether they interact with, or whether their metabolism disrupts, important enzymes that are used to metabolize other drugs. Kulmatycki and colleagues presented a poster at SCM23 looking at drug interactions with iptacopan and found that iptacopan had no meaningful interactions with P-gp or OATP transported drugs, based on coadministration with digoxin and rosuvastatin, respectively (poster 322). Further, researchers reported that both CYP2C8 and OATP inhibition—based on coadministration with clopidogrel and cyclosporine, respectively—had minimal effects on the systemic exposure of iptacopan. 

Hepatic impairment is something else that we worry about with complement inhibitors. Another abstract by Kulmatycki et al assessed the effect of hepatic impairment on iptacopan pharmacokinetics (poster 323). The study enrolled patients with mild, moderate, or severe liver impairment, and researchers found no effect of hepatic impairment on single-dose iptacopan exposure. 

Outside of the aforementioned posters, there was not a lot of coverage of complement at SCM23. It seems that complement is activated across the scope spectrum of glomerular diseases. I think that one of the most important things that will come out of these clinical trials targeting the complement system will be an improved understanding of which pathways to target to treat different glomerular diseases. We will also get a better idea of the adverse events or complications that are associated with targeting complement. That awareness is especially necessary when targeting the classical pathway, particularly with the earlier blockade of the complement system, as disrupting processes that function to clear foreign pathogens could increase the risk of infections. 

Another thing that I hope will come out of these trials is a better understanding of—or even the development of—biomarkers that we can use to help recognize which patients may benefit from complement therapeutics based on a biomarker profile that is specific to their glomerular disease. Lastly, regarding injury to the kidney, it may be that complement dysregulation contributes to the pathogenesis of more glomerular diseases than we previously recognized. We still have a lot to tease out, but this is an exciting time. Targeting different aspects of the complement system across glomerular diseases in these clinical trials may provide clues about the role of complement in the pathogenesis of each disease.