Insights Into Iptacopan in C3 Glomerulopathy: Carla Nester, MD, MSA, FASN

Iptacopan (Fabhalta; Novartis) was approved by the FDA on March 20 for proteinuria reduction in complement 3 glomerulopathy (C3G), becoming the first and only therapeutic approved for this indication, based on results seen in the phase 3 APPEAR-C3G trial (NCT04817618).1 It is also approved in the US to treat paroxysmal nocturnal hemoglobinuria and to reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression.2

Discussing the results with The American Journal of Managed Care® (AJMC®), study coinvestigator Carla Nester, MD, MSA, FASN, explained the difficulty inherent in diagnosing this ultrarare kidney disease and why proteinuria reduction is such an important clinical marker for these patients. Nester, who has been in practice for 18 years, is a pediatric and adult nephrologist at the University of Iowa Stead Family Children's Hospital, where she specializes in compliment-mediated glomerular diseases.

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

Transcript

How does C3 glomerulopathy affect the body, and why is this progressive kidney disease so rare?

We don't know exactly why it is so rare because we frankly don't know why some people actually develop the drivers of disease—but it is an ultrarare disease. It is a problem with the alternative pathway of complement. It starts with either a genetic abnormality—that's the minority of patients—or autoimmunity to the alternative pathway. Again, 3 to 5 persons per 1 million, if you will, of people, so very, very rare. But it is, again, an alternative pathway disease, and we don't know exactly why people develop the drivers of this.

It is a classic glomerular disease, first of all, because a vast majority of the patients will have hematuria or blood in the urine, proteinuria, very frequently are swelling or have what we call edema, very frequently have high blood pressure. These are the classic glomerular disease signs. But they also, because of the hyperactivity, if you will, of the complement system, they're all often very inflamed. I know that's kind of a specialized term, but really what patients feel is fatigue. They have significant fatigue. Maybe their concentration is difficult, etc.

They have a number of individualized symptoms that are very hard sometimes for us to actually get a handle on—but we know that they exist because they are frequently very inflamed.

Considering this is a rare disease, is there potential for misdiagnosis?

In children particularly it can be difficult because on kidney biopsy, both C3G and an entity we call postinfectious glomerulonephritis can look exactly the same. The real trick is that in children, postinfectious glomerulonephritis is believed to be a fairly transient disease, so generally these patients are much better by 8 weeks and definitely better by 12 weeks. If your patient has that biopsy appearance—and again, it's only in about 30% of postinfectious patients that will have that same biopsy—if it's better at 8 weeks or 12 weeks, it's not C3G. If they, though, have chronic glomerulonephritis throughout that 8-week period into the 12-week and, of course, going on and on, that's when we know it's C3 glomerulopathy, for instance, because it is now a chronic glomerulonephritis.

Can you discuss the primary and secondary efficacy and safety outcomes that supported the FDA approval of iptacopan for C3G?

First of all, I will just give you a general overview of the study. It was a 6-month, randomized, placebo-controlled study. Roughly one-half of the patients actually were exposed to placebo, the other half were exposed to the iptacopan. These were adult patients, so these were greater than 18 years old, and it was for native kidney disease. That's the background information about the study.

The primary end point was actually proteinuria reduction; just in terms of general clinical approach to this, thinking about proteinuria reduction was the major end point, it was the primary end point. In fact, it is the end point that won them approval, if you will, from the regulatory agency. That's the critical one, frankly. Then there were other things, though, that were quite important for a clinician. First of all, stabilization of the GFR [glomerular filtration rate], incredibly important in this disease, because I didn't share with you earlier that what is known about this disease is that about 50% of them will go to end stage at 10 years. That means yearly they're losing GFR points, yearly. What the sponsor for this agent showed is that in that 6 months, they basically stopped losing—that's my interpretation, if you will—they basically stopped losing GFR points during that 6-month period, and that is incredible. That's not been heard of, if you will.

And then you mentioned safety end points, which, of course, are incredibly important. There was a time when we started testing complement inhibitors. We weren't sure how safe they were going to be in the humans, and we worried about it a little bit. That was years ago, frankly. But with that 6-month study, we discovered that it appeared to be quite safe to block the complement system and improve. I think we were quite satisfied with the safety profile of these agents.

Now, of course, we need real-world data. We need more data. But I, as a clinician, I'm completely comfortable with what they obtained at the end of that 6 months.

References

1. McNulty R. FDA approves oral iptacopan for C3 glomerulopathy. AJMC. March 21, 2025. Accessed April 8, 2025. https://www.ajmc.com/view/fda-approves-oral-iptacopan-for-c3-glomerulopathy

2. Fabhalta. Prescribing information. Novartis; 2025. Accessed April 8, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/fabhalta.pdf