Carla M. Nester, MD, MSA, FASN

VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN, With Carla Nester, MD

New findings show pegcetacoplan maintained a 70% reduction in proteinuria over 52 weeks in adolescents with

 and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), with many patients achieving remission (≤0.5 g/g) or normalization (≤0.2 g/g).

Data from a 26-week open-label extension of the phase 3 VALIANT trial, presented at the 

American Society of Nephrology (ASN) Kidney Week 2025

 by Carla Nester, MD, a professor of pediatrics-nephrology at the University of Iowa, highlighted sustained proteinuria reductions and stable estimated glomerular filtration rate (eGFR) in the pegcetacoplan-treated patient population.

“For the first time ever, we can offer targeted therapy specifically for adolescents. It’s a major step forward for clinicians and patients,” said Nester in an interview with 

Natural history studies of disease progression in C3G and IC-MPGN connected proteinuria <0.88 or 1 g/g or proteinuria reduction ≥50% with improved patient outcomes, including stabilization of the eGFR slope and a significantly lower lifetime risk of kidney failure.

Pegcetacoplan is a PEGylated cyclic peptide aimed to selectively bind to C3 and C3b, inhibiting C3 activation and the formation of the alternative pathway C3 convertase. The US 

 in July 2025. The FDA’s decision was based on the 26-week results from the phase 3 VALIANT trial, the largest clinical trial conducted in this patient population, and the first to include adolescent and adult patients with native and post-transplant kidneys.

The 52-week extension of VALIANT included pegcetacoplan-to-pegcetacoplan (n = 59) and placebo-to-pegcetacoplan (n = 55) groups. The primary endpoint was proteinuria change from baseline.

Patients receiving pegcetacoplan demonstrated sustained proteinuria reduction through 52 weeks, with a mean change of –67.2% at week 26 (95% confidence interval [CI], -74.9 to –57.2) and -67.2% at week 52 (95% CI, -75.8 to -55.4).

At week 26, 20 pegcetacoplan-treated patients (31.8%) achieved complete remission (≤0.5 g/g) and 11 (17.5%) reached normalization (≤0.2 g/g). These responses were maintained through week 52. By week 52, 34 patients (54.0%) had achieved a ≥50% reduction in proteinuria compared to 4.9% receiving placebo. Similar proportions of placebo-to-pegcetacoplan patients achieved remission and normalization during the open-label period, and 25 patients (41.0%) reached a ≥50% reduction.

“Many of these patients already have chronic kidney disease, so some degree of fixed proteinuria is expected. Getting them down to 0.5 g/g is remarkable, and it’s not something we’ve routinely been able to achieve in this population. Of course, the best outcome is getting patients into the normal range,” said Nester. “More than 70% of patients had a complete loss of C3 deposition on biopsy, and 17.5% achieved normalization of urine protein. That combination is a home run for this group of patients and is a tremendously satisfying outcome for clinicians treating glomerular disease.”

At 52 weeks, pegcetacoplan-treated patients saw stabilized eGFR in both adolescents and adults, signaling the therapy’s potential to change disease trajectory.

Editors’ note: Nester reports relevant disclosures with Apellis, Biocryst, Kira, Novartis, Silence Therapeutics, and Biocryst.

Nester CM, Fakhouri F, Gale DP, et al. Pegcetacoplan for 52 Weeks Results in Sustained Proteinuria Reduction to Remission (≤0.5 g/g) and Normalization (≤0.2 g/g): Phase 3 VALIANT Trial. 

Journal of the American Society of Nephrology

Kavanagh D, Ariceta G, Vivarelli M, et al. Current and Emerging Therapies for C3 Glomerulopathy and Primary (Idiopathic) Immune Complex Membranoproliferative Glomerulonephritis. 

. Published online November 5, 2025. doi:https://doi.org/10.1016/j.ekir.2025.10.020

‌Brooks A. FDA Approves Pegcetacoplan (Empaveli) for C3 Glomerulopathy, IC-MPGN. Hcplive.com. Published July 28, 2025. https://www.hcplive.com/view/fda-approves-pegcetacoplan-empaveli-for-c3-glomerulopathy-ic-mpgn

Videos

ASN 2025 VALIANT data on pegcetacoplan show proteinuria reduction, including remission or reduction, in adolescents with C3G and IC-MPGN.


VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN, With Carla Nester, MD 

Entering A New Era of C3G Care with Pegcetacoplan, with Carla Nester, MD

Pegcetacoplan’s FDA approval marks a major milestone in the treatment of 

C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN)

, particularly in populations with high unmet need, including transplant recipients and pediatric patients.

, Carla Nester, MD, the Jean E. Robillard Chair in Pediatric Nephrology and the director of the Pediatric Glomerular Disease Clinic at the University of Iowa, emphasizes how transformational it is to now have 2 approved complement inhibitors—pegcetacoplan, a C3 inhibitor, and iptacopan, a factor B inhibitor—targeting the core enzymes of the alternative pathway.

As a study investigator on the VALIANT trial supporting pegcetacoplan’s approval, Nester points to the 68% reduction in proteinuria and lack of encapsulated bacterial infections, a common concern with complement inhibitors, seen in the trial.

“The fact that we could achieve such a substantial primary endpoint in this study is, from a clinician standpoint, a pretty amazing finding and obviously very satisfying for the approval of this drug,” Nester said, describing its association with long-term kidney function decline.

In comparing the 2 currently-available therapies, Nester says a number of patient/provider preferences may influence treatment decisions, including the fact that one therapy is oral while the other is subcutaneous, their different dosing regimens, and perceptions about the phase 2 data for each drug.

Looking ahead, Nester emphasizes the importance of continued monitoring of long-term kidney outcomes and real-world safety beyond the current 52-week data: “Not to be complacent about the fact that we now have a treating agent, but I can get excited about what's next, and the first thing for me is going to be whether this equates to better renal outcomes over time.”

Additionally, she cites access as a major concern, including getting patients diagnosed earlier, getting them to the right specialists, and ensuring coverage for high-cost therapies. With updated guidelines and expanded awareness, Nester says she hopes these will eventually help move the field toward alternative pathway blockade as a new standard of care.

Apellis Pharmaceuticals. FDA Approves Apellis’ EMPAVELI® (pegcetacoplan) as the First C3G and Primary IC-MPGN Treatment for Patients 12 and Older | Apellis Pharmaceuticals, Inc. Apellis Pharmaceuticals, Inc. Published July 28, 2025. Accessed August 6, 2025. 

https://investors.apellis.com/news-releases/news-release-details/fda-approves-apellis-empavelir-pegcetacoplan-first-c3g-and

Nester CM, Bomback AS, Ariceta G, et al. VALIANT: A Randomized, Multicenter, Double-Blind, Placebo (PBO)-Controlled, Phase 3 Trial of Pegcetacoplan for Patients with Native or Post-transplant Recurrent Glomerulopathy (C3G) or Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN). 

US Food and Drug Administration. Fabhalta approved for complement 3 glomerulopathy. U.S. Food and Drug Administration. Published March 20, 2025. Accessed August 6, 2025. 

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce

Nester describes the evolving C3G therapeutic landscape, the value of now having pegcetacoplan to offer patients, and trial data supporting its approval.

I've said this many times, we're in the golden age of studies in glomerular disease. And we are making great strides in an ultra-rare disease like C3G. I know our center's certainly recruiting and there's a global network of GN centers now recruiting to these studies, which we'll hopefully deliver, but we are spoiled for choice Jerry, and we have lots of studies. I will you just first run us through your approach to managing patients in 2023 and the kind of opportunities that might be available with all the clinical trials that are happening at the moment?

I was hoping you'd come back to IgA nephropathy, because we've lacked a good biomarker. People have said, level of galactose deficient IgA or antibodies to galactose deficient IgA. But so far, we have not had a good biomarker. And the best correlation we've had is with proteinuria. Now, the good news is that the FDA realizes that some of these patients will only slowly progress. They're using the surrogate marker, which has been mentioned, a proteinuria reduction. The bad news is they're using a surrogate marker. We don't necessarily know what's going to happen to the GFR in all these cases. We've recently had 2 drugs approved in terms of treating patients with IgA nephropathy, first of all, without the final publication of the manuscript initially, and then without the final data in terms of what's happening to the GFR. And certainly, in terms of we've got the shorter terms data, not the longer term data that we might need. I'm not against the fact that the FDA is approving these, it's just making it more challenging in terms of following these patients without a good biomarker in terms of this. My view in terms of treating the patient is that given anybody with risk factors, I would put them on maximal supportive care. Now, if you look at KDIGO guidelines, they say that high risk is over 0.75 to one grams of proteinuria that persists for more than X amount of time. That which is 3 months is what they're talking about there. But in some of the studies, the stop trial that was done in Germany, they said you had to be on it 6 months. Before you had standard of care. The other thing is, none of the studies yet have included SGLT2 inhibitors, which are rapidly becoming standard of care. We already have data in IgA nephropathy that it makes a significant difference in terms of time and proteinuria and course of the patient too, in terms of GFR. Given that the standard of care has changed, we've upped the level blockade of the renal angiotensin system, strong consideration to SGLT2 inhibition, then the role of steroids, which we've certainly confused a lot of nephrologists by starting out by saying they worked because we had 3 or 4 trials, small, but they seem to work, then we all of a sudden have a big trial that looks like it's done very well, but it had unique features that made it a little different from some of the others. But the stop trial that said they didn't work long term, then we get to the testing trial that doesn't work at first, but then does work after they do it at a lower dose. Everybody has been changing what they're doing, and we're going back and forth. I feel sorry for a patient if they heard this, that the steroids you tried 3 years ago that we stopped, well now we're going to try them again. And whether those steroids or a non-absorbable steroid that works predominantly on the gut should be used, is just not clear. What we're left at least in IgA now in terms of standard of care. For anybody who's high risk, and I think high risk is probably going to be more than 0.5 grams not 0.75. It's very clear that there is data from Vega and other studies that show that, so at lower levels of proteinase should get standard of care. And then if they're not at the point that keeps them at high risk, and that's going to be different for different people, we should be doing something. And whether it's steroids, straightforward, old-fashioned steroids at a lower dose for still about a 6 month course, or whether you want to say, look a non-absorbable one because this person has high risk factors for steroids, they're they also have diabetes and where they don't want cosmetic changes that person might benefit from a non-absorbable steroid, which we don't have good proof that they're entirely non-absorbable but again, there's going to be individualization of therapy at the current time until we get more clear data or until we get a good biomarker. They are looking at new CD markers, CD8 I think it is, but they're looking at new markers trying to say that this is going to make a difference. And in some diseases it looks better than others in terms of lupus. Some people feel using urinary biomarkers is making a difference already now. But still for IgA we're left with getting what we wished for, we wished for the FDA to finally approve something, and now they're approving it faster than we know the data. And we can't make decisions based on it.

: It is a real challenge. You're right. I go to my therapeutic cupboard for my IgA patients and it's empty, and we're going to move from zero. We've had nothing for 50 years. Two new drugs in the last 18 months. Three phase 3 studies are likely to be reporting over the next 12 to 18 months. We are going to need to educate our nephrologists, our colleagues, how to use these with the right patients. What are the safety concerns? How might we potentially combine them?

Gerald B. Appel, MD, discusses the changing treatment landscape of IgAN.

Clinical trial data on IgAN for therapies

Anuja, you touched on something interesting in your context of post-transplant recurrent disease. Is transplant patients have a lot of immunosuppression on board. And it doesn't seem to impact greatly on recurrence of IgA, but also C3G in your, is that your experience?

And that shows a limitation really of conventional approaches.

Would you, in terms of your transplant practice, where would you see complement, therapies fitting in, in the context of patients already on often triple immunosuppression?

Following up on what Dr Nester mentioned, we are always worried about infections in these patients because as you said, as we know, these patients are on baseline immunosuppression to begin with. A few different things to keep in mind when we are using complement inhibition in transplant population or even in native kidneys, is that, as we've talked about, complement is part of innate immunity we are born with it, but as a person grows, your maturing adaptive immunity also starts playing a role in preventing infection. That's an important protective factor. The other thing depends on what inhibition you're using and which level that is. If you're using a C3 inhibitor, which is more central to the complement activation versus if you're using a more terminal inhibitor, you would worry that if you have a patient on a more C3 inhibitor, will that person be at a risk of broader infections. I would say that even though these drugs inhibit the complement system, they don't completely abolish the ac- abolish. There is even that little residual complement that you have is protective. And in our transplant population, my experience is that we've had a pretty good success with using these drugs, particularly patients that I take care of with atypical hemolytic UIC syndrome, where we use anti C5. And a very important factor is the vaccination. These patients are vaccinated, and the vaccination does bring down the risk of these infections, at least stand forward from what the literature shows. In addition, we keep our patients with prophylactic antibiotics. If you don't have enough time to vaccinate them and you must start the therapy, you could start them on antibiotics. And we keep our patients on antibiotics lifelong. There is a lot we can work with in using the inhibitors even in a more immunosuppressed population like the kidney transplant.

Anuja Java, MD, discusses the role of complement inhibitors in transplant patients with C3G.

Carla M. Nester, MD, MSA, FASN

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