There have been a number of recent advances in the understanding of complement-mediated kidney diseases, including complement 3 glomerulopathy (C3G) and immunoglobulin A nephropathy (IgAN), leading to an expansion of the therapeutic landscape. This important topic was discussed by Andrew S. Bomback, MD, MPH, in a symposium presented at the American Society of Nephrology’s Kidney Week 2023.

Following these proceedings, featured expert Andrew S. Bomback, MD, MPH, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Bomback’s clinical perspectives on these findings are presented here.

My first presentation at Kidney Week 2023, titled “Complement-Mediated Kidney Diseases: Novel Insights and New Possibilities,” from the educational symposium titled “Regulating the Regulator: Exploring the Therapeutic Landscape for Complement-Mediated Kidney Diseases,” described how we have entered an era in which we think about diagnosing, managing, and treating glomerular diseases through a complement lens. And for nearly every glomerular lesion that we encounter, we question whether complement activation plays a role. There are 3 complement activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. So, for each glomerular disease, we start by asking: Is complement activation playing a role? If so, then which of these pathways is involved in the kidney injury that we are seeing?

There are some diseases for which we have very good evidence that a single pathway is involved. An example of that would be C3G, which locates to overactive alternative complement pathways. There are diseases, however, that have more of an overlap, where more than one pathway is involved, and IgAN is a hallmark of that. We have good evidence that both the alternative and the lectin pathways are overactive and are involved in the pathogenesis of IgAN.

In my lecture on complement-mediated kidney diseases, we went through different types of kidney diseases and tried to show how a nephrologist and a pathologist work together to try to figure out which of the complement pathways are involved. The reason this is so important is because we are trying to not only figure out the cause of a glomerular lesion and why the kidney disease has begun to display itself on a kidney biopsy but also determine the best therapy target.

We currently have dozens of complement inhibitors that are in various stages of development. It is quite likely that, in the coming years, we will have complement inhibitors at our disposal that we can consider using in real-world practice. The more that we can understand which complement pathway is involved—and, even better, where in the complement pathway the activity is dysregulated—the better we will be able to appropriately use these new complement-inhibiting therapies to get our patients into the remissions that we seek.

Regarding the more promising therapies, a nice way to think about complement therapies, in my opinion, is to break them down into complement 5 (C5)– or C3-targeting therapies, especially the therapies that are targeting the alternative pathway, because I think that this is where we are the furthest along in development. Looking at the C5-targeting therapies, we have eculizumab and ravulizumab, which are approved by the US Food and Drug Administration (FDA) for complement-mediated thrombotic microangiopathy. And we have avacopan, which is FDA approved for antineutrophil cytoplasmic autoantibody–associated vasculitis. The question is whether you can extend those therapies to non–FDA-approved diseases, and there are trials underway that are looking at that (eg, trials evaluating C5 blockade and IgAN). There are also trials that have looked at C5 blockade for C3G that have yet to be published. So, whether that strategy will translate into some of these other glomeruli diseases is a very hot topic.

Then there are the more proximal complement inhibitors that target C3, and I think that this was an area of excitement at Kidney Week 2023. We have iptacopan, for example, which is a complement factor B (CFB) inhibitor that has already shown nice data in phase 2 studies of IgAN and C3G and is now well into phase 3 studies. Additionally, RO7434656, which also targets CFB, has shown nice phase 2 data as well and is in phase 3 studies for IgAN.

An abstract for a phase 2 study of IONIS-FB-L_Rx in 13 patients with IgAN was also presented at the meeting [abstract SA-PO926]. Interim results showed a selective reduction in both plasma CFB levels and proteinuria at week 29 with 24 weeks of treatment with monthly IONIS-FB-L_Rx therapy.

We also saw nice data for pegcetacoplan in recurrent C3G at Kidney Week 2023, with really impressive signs of treatment response when we looked at serial biopsies in transplant patients [abstract SA-PO923]. Ten transplant patients with recurrent C3G were treated with pegcetacoplan, and, at 12 weeks, 4 of 10 patients had completely eliminated their C3 staining, which is a remarkable change in the disease state. Moreover, 8 of 10 patients had significant reductions in their C3 staining. It is impressive to have that kind of response so quickly that you can see on a kidney biopsy. You might not necessarily see the response this quickly by clinical lab work, but the biopsy changes are really exciting.

Ultimately, the reason we are so optimistic and hopeful about entering a new era of complement-targeting therapies is because everything that we have tried to date has been non–disease specific and, frankly, has not been effective in quieting the disease.