Iptacopan Outshines Past C3G Treatments: Carla Nester, MD, MSA, FASN

Iptacopan (Fabhalta; Novartis) was approved in March for proteinuria reduction in the setting of complement 3 (C3) glomerulopathy,1 which is a disease of damage to the kidney’s glomeruli that filter toxins from the blood.2 Data from the phase 3 APPEAR-C3G study (NCT04817618) served as the foundation for this approval, which was the third overall approval for the alternative complement pathway inhibitor.

In April, in part 1 of this interview, study coinvestigator Carla Nester, MD, MSA, FASN, gave context to the approval by explaining how the progressive C3 glomerulopathy works against the body, the potential for misdiagnosis, and the data on which the approval was based.3 Here, she delves into why this new therapeutic is effective and how it compared with past attempts to treat C3 glomerulopathy. Nester is also a pediatric and adult nephrologist at the University of Iowa Stead Family Children's Hospital.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

What is iptacopan’s mechanism of action that makes it so effective against proteinuria?

If we think about it—and actually, there were animal models that pushed us in this direction, frankly—if our understanding of C3 glomerulopathy is that it's an alternative pathway disease, so it's a hyperactive alternative pathway of complement, well, the beauty of an agent such as iptacopan is, in fact, it targets the alternative pathway.

In fact, it targets one of the major proteins involved in the enzymes of that pathway, and it actually will shut the pathway off, if you will. If your disease is motivated or driven by AP, or alternative pathway, activity, and now you can block it, for the first time we actually have a targeted approach to therapy.

The absolutely wonderful thing about a drug like iptacopan is that it targets very specifically the alternative pathway, particularly factor B, which is one of the major proteins and one of the most active enzymes in the pathway. If you block factor B, you can block the alternative pathway. If you have a disease that's complement dysregulation, particularly alternative pathway dysregulation, and you can now block the alternative pathway, this was our first opportunity to get to actually target the alternative pathway and, what we believe, frankly, is to target the underlying disease process here.

How does iptacopan compare with other treatments for C3 glomerulopathy that remain under investigation?

Let me back up even a little bit further. You may know that there have been other complement inhibitors that have been trialed in this space, other complement inhibitors that, in theory, targeted the alternative pathway. I'm specifically thinking about factor D inhibitors.

There have been a couple of those. They haven't been shown to be effective. There's also other complement inhibitors, like C5A receptor blockers, that have been attempted that also did not work. You have a randomized controlled trial that it [iptacopan] works, so reference those that are still or are finishing up or maybe in competition, if you will, with this agent.

References

1. McNulty R. FDA approves oral iptacopan for C3 glomerulopathy. AJMC®. March 21, 2025. Accessed June 25, 2025. https://www.ajmc.com/view/fda-approves-oral-iptacopan-for-c3-glomerulopathy
2. Complement 3 glomerulopathy (C3G). National Kidney Foundation. Accessed June 25, 2025. https://www.kidney.org/kidney-topics/complement-3-glomerulopathy-c3g
3. Shaw M, McNulty R, Nester C. Insights into iptacopan in C3 glomerulopathy: Carla Nester, MD, MSA, FASN. AJMC. April 9, 2025. Accessed June 25, 2025. https://www.ajmc.com/view/insights-into-iptacopan-in-c3-glomerulopathy-carla-nester-md-msa-fasn