By Bradley P. Dixon, MD, as told to Kendall Morgan
Bradley P. Dixon, MD, is a pediatric nephrologist at Children’s Hospital Colorado in Aurora. The information here represents his knowledge and experience as a medical professional. As a research support consultant for Apellis Pharmaceuticals, he was involved in clinical trials testing the clinical safety and efficacy of pegcetacoplan (Empaveli) for complement-mediated kidney diseases.
C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) are two rare kidney diseases. They’re both driven by activity of the complement system, which is a critical part of your innate immune system. This is your body’s first defense against invaders like viruses and germs. When the complement system overreacts, it can lead to diseases in various parts of your body, including the kidneys.
Clinical trials have suggested that a medication called pegcetacoplan (Empaveli) might work to treat adults and kids aged 12 and up with C3G or IC-MPGN. This drug was first approved to treat adults with a complement-mediated blood disorder called paroxysmal nocturnal hemoglobinuria (PNH) in 2021. In April 2025, the FDA granted priority review status to these new uses for the drug, based on early data from a phase III study.
To explore how the medication works and who might benefit from it, we spoke with Bradley P. Dixon, MD, a pediatric nephrologist at Children’s Hospital Colorado in Aurora, CO.
Who may benefit from the new indication for this treatment?
The target population for this drug, specifically as it relates to kidney conditions, is people with one of two rare complement-mediated kidney diseases. One is called C3 glomerulopathy (C3G), and the other is primary immune complex membranoproliferative glomerulonephritis (IC-MPGN).
If you take a step back, both conditions involve the complement system. This is part of our innate immune system. We're protected from birth onward by these different parts of the innate immune system, and the complement system is part of that. It’s a series of proteins that are very good at recognizing danger patterns on infectious threats. But they’re also not especially good at telling your body’s cells (“self”) from foreign substances (“non-self”).
These danger patterns can be mimicked on self surfaces, and so the complement system may be turned on by mistake (overactivate), even if you’re otherwise healthy. That in some cases can lead to inflammation of the kidney filters, called glomeruli. These glomeruli can become a site where fragments of these complement proteins get deposited. That leads to inflammation and damage to the glomeruli, causing them to leak blood and protein into the urine. If that process goes on long enough, it can lead to kidney failure.
When you have C3G or IC-MPGN, overactivation happens because control of the complement system fails. This is either because there are autoantibodies that disrupt the normal brakes on the complement system or there’s a genetic abnormality.
Targeting the complement system with pegcetacoplan makes sense for these conditions. Clinical trials have shown they may be a safe treatment option.
What’s different about this drug?
Up until relatively recently, we haven't had good medications that target the complement system directly. Historically, these kidney diseases have been treated with untargeted therapies that have had varying degrees of success. Pegcetacoplan directly targets a central hub of the complement system. As a result, we expect it to be much more effective than anything we've used before.
Can you explain more about how this drug works differently?
The oldest treatments used in these kidney conditions were medications that broadly tamped down the immune system. They had no direct action on the complement system. They helped about two-thirds of people we treated, and about a third saw no results.
Another treatment that we tried for these diseases is an antibody called eculizumab. Eculizumab is a complement-targeted medication. But it targets the complement system at a different protein than the one that’s most active in these diseases. In other words, it’s slightly off-target. Studies showed it reversed the disease or improved it in about half of people and had no noticeable benefit in the other half.
Pegcetacoplan targets specifically a complement protein called C3, which is where the dysregulation and overactivation happens. That’s why this drug has shown so much promise in these diseases.
How did researchers draw the link between this medicine originally approved for PNH and these kidney conditions?
Pegcetacoplan is FDA-approved for a blood disorder called PNH, or paroxysmal nocturnal hemoglobinuria. PNH is a complement-driven blood disorder. Partly because it’s an area of unmet need, exploring the potential of pegcetacoplan for treating complement-driven kidney conditions was an obvious place to go.
How effective is this treatment?
There’s no way to know how well any individual will respond or how fast it will work. Pegcetacoplan isn’t approved for C3G or IC-MPGN yet. But I can share a couple of highlights from the phase II clinical trial, which tested its safety and effectiveness in a small number of participants over 48 weeks.
One of the key markers of kidney disease that we follow is how heavily you’re spilling protein in the urine (proteinuria). That’s a sign of the damage to the filters, or glomeruli. Less protein leakage is a strong signal that we're reversing the inflammation that's taking place. So perhaps the most promising result from that study is that there was a dramatic reduction in protein in the urine. It was particularly dramatic in those who took the medication as directed.
A year is a relatively short period of time to see a decline of kidney function. The natural history of these diseases is that, over about 10 to 15 years, 50% of people will completely lose kidney function and will need dialysis or a kidney transplant. It was encouraging that over that 48-week period of the trial, the small number of people in the study did not have a decline we could see in their kidney function. Can we project this data from that one year to 10 years and say it’s going to prevent people from losing kidney function? We hope so.
How do you take pegcetacoplan?
In the trial, pegcetacoplan was given as a daily infusion for 24 weeks. After that, you take it as an injection under the skin twice a week.
What are the side effects? How do you manage them?
The main side effect that we're worried about with this treatment is the risk of infection. The complement system protects us against infection, and especially certain kinds of bacteria that cause things like pneumonia and meningitis. When you disable the complement system, you increase the risk of those infections.
Before starting this medication, we require vaccination against those bacteria to provide an added layer of protection. Sometimes we'll even place patients on preventative antibiotics. There’s always the possibility of redness, swelling, or hardening of the skin at the site of the injection. Those are more minor side effects, but the infection risk is really the main thing to watch for.
Will people need any regular tests while on this treatment?
Some of these details aren’t worked out yet, and this is a good question to ask your doctor. I think mainly you’d need to have a heightened level of awareness about the possibility of infection. People often get instructions to see a doctor right away if they’re sick with a fever or other symptoms because it could be a sign of a severe infection.
Are there people who shouldn’t take this treatment or who may not benefit from taking it?
We don’t expect pegcetacoplan to help you if you’ve already progressed to kidney failure and are on dialysis. These conditions can recur (come back) after kidney transplant because they’re caused by circulating proteins. We do expect this medication will provide benefit after a kidney transplant if there's a recurrence.
Should people already be asking their doctors about whether this treatment might be an option for them?
Yes, 100%. Even if your doctor can't get access to the medication right now, they should get familiar with it and how to give it. They should know what the potential side effects and risks are because there's such an unmet need. People could really start to get help the day this medication is approved, and so doctors should already be asking themselves which of their patients would be helped by this medication.
Will insurance cover it?
Insurance coverage varies, but I’d expect because there is this unmet need that insurance companies will cover it. It’s possible they may not accept it as a first-line treatment right away, but I'm sure insurance coverage of this medication will come soon, either as a backup treatment or, hopefully, as a first-line treatment.