The FDA has granted priority review status for pegcetacoplan (Empaveli) to treat two rare kidney diseases that can lead to kidney failure. Up until now, there hadn’t been any drugs approved specifically for these two conditions, called C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN). It’s already in use to treat a rare blood disorder called PNH (paroxysmal nocturnal hemoglobinuria). It also treats geographic atrophy, a leading cause of blindness in people with age-related macular degeneration.
You inject pegcetacoplan under your skin twice a week. It comes in an injector you can use yourself at home in about 30 to 60 minutes.
For a long time, doctors had to treat C3G and IC-MPGN with medicines such as corticosteroids that weaken the immune system. But they didn’t have a way to target the specific part of the immune system that goes awry in these kidney conditions. That’s where pegcetacoplan comes in.
Before pegcetacoplan could be used to treat any condition, it had to go through a lengthy drug development process. This process included plenty of research in the lab and in animals before the drug was ever given to people. It also had to be studied and reviewed carefully by teams of researchers and other experts in clinical trials to make sure it’s both safe and effective.
It can take more than a decade to develop a single drug, and many never make it all the way through to the market. Some of the earliest discoveries that led to pegcetacoplan as a safe and effective medicine go back to 1996.
Step 1: Understanding the Disease
Before making a drug that specifically targets any disease, scientists have to understand the underlying causes of the condition. For C3G and IC-MPGN, they needed to know exactly what causes the kidney inflammation and damage that may lead your kidneys to fail.
Both of these conditions belong to a group of rare kidney diseases that have a common cause. The trouble starts in part of the innate immune system called the complement system. The innate immune system is the part of your immune system you’re born with. Unlike antibodies in your adaptive immune system, this part doesn’t have to “learn” from experience how to recognize and fight infections. It can do it right from the start.
The complement system includes more than 50 proteins and peptide fragments. These proteins target infectious microbes and destroy them. It also helps clear away immune complexes and dead cells you don’t need anymore. When it’s working as it should, it leaves your healthy cells alone.
When you have a disease related to overactivation in your complement system, things go awry. Your complement system attacks your own cells. When the complement system attacks and destroys healthy cells in your blood, you can get PNH. When it happens in your kidneys, you can get kidney conditions, including C3G and IC-MPGN. In both kidney diseases, complement activation causes inflammation in your kidneys as protein fragments build up and damage your kidney filters.
As those filters in your kidneys stop working the way they should, you’ll get protein and blood in your urine. Over time, the damage to your kidneys can lead to complete kidney failure. You may need dialysis or a kidney transplant.
Step 2: Identifying a Promising Target for Drug Discovery
Scientists realized early on that medicines directed at the complement system might treat many different diseases that affect different parts of the body. Because the complement system includes many proteins, they had lots of possible targets to choose from.
It turned out it was harder than it looked to find the right target. But it seemed especially promising to target a protein called C3. The reason is that C3 is a central hub of the complement system. That meant drugs targeting C3 could affect many other parts of the system. However, early attempts to find a small molecule that could target C3 didn’t work as well as had been hoped. They weren’t strong or specific enough. They also broke down too fast.
Eventually, scientists landed on a peptide called compstatin that binds to C3 directly. They realized its small size and ability to target the central hub of the complement system made it a promising candidate for further study and development. Pegcetacoplan belongs to the compstatin family of C3 blockers. It got its name because it’s PEGylated. That means it has a synthetic polymer of polyethylene glycol (PEG) attached to help keep your kidneys from filtering it out.
Step 3: Further Testing in the Lab
To put compstatins to the test, researchers studied their effects in blood circulating through PVC tubes. They knew plastic surfaces used during bypass surgeries or dialysis to circulate blood outside the body could activate the complement system. They found evidence that compastatin could reduce those inflammatory effects.
The complement system also plays a role in inflammation that can lead to rejection of organ transplants. Studies in animal models of organ transplants helped to show how targeting C3 could help. More studies showed it could also reduce inflammation caused by E. coli bacteria. The findings suggested targeting this system might help treat sepsis, along with many inflammatory conditions.
Further study and more tinkering with compstatins led to the discovery of pegcetacoplan (Empaveli). In 2006, scientists found that this version of compstatin stayed in the blood longer. It also bound C3 better than other versions. The findings had important implications for complement inhibitors as potentially useful medicines in the future.
Step 4: Clinical Trials Testing the Drug in People
Scientists first studied the potential for this drug to treat age-related macular degeneration (AMD). But those early trials didn’t work as well as had been hoped, probably because the dose wasn’t high enough. More tinkering led to the new version that promised to stay in the blood longer.
Later, pegcetacoplan was tested in people with PNH to see if it's safe and if it works as had been hoped. Researchers also had to try different doses and see if it might work better than other treatments already in use. These tests are called clinical trials. They all have three different phases. Any drug going through clinical trials must complete all three:
- Phase I: Is it safe? The first trial tested pegcetacoplan in nine adults at different doses to find out if it was safe.
- Phase II: Is it safe and effective? Later, more people tried it to see if it helped them and if it was still safe.
- Phase III: Is it safe and effective in larger numbers of people? Finally, more people of different ages try it to be even more sure it's safe and works as intended. Many drugs are also compared to other medicines to make sure they not only work, but that they also work better than other medicines already in use.
During these tests, doctors and clinical trial investigators watch closely to track any problems that come up. Clinical trials of pegcetacoplan showed it was safe and effective for PNH, leading to the drug’s approval for the blood disorder in 2021. From the first phase I trial in PNH, trial results showed it was tolerated well. There also were signs it worked for PNH in people already taking another medicine called eculizumab.
Later phase II and III trials confirmed the treatment worked for PNH better than eculizumab. The most common side effect was reactions at the injection site. While it comes with some infection risk, no one in the trial had a serious infection.
Other studies continued to see if it would work for other complement-related conditions. This included AMD and kidney diseases known as C3 glomerulopathies, including C3G and IC-MPGN. In 2023, a phase II study of pegcetacoplan took place with seven patients with various kidney diseases involving the complement system. It showed the treatment lowered protein in the urine. It was a sign it could reduce inflammation to keep your kidneys working better.
Based on positive results from a larger phase III trial, the drug was granted FDA priority review status review for this new indication, or use of the drug.
How Safe Is Pegcetacoplan?
Pegcetacoplan is safe for most people to take. It comes with a risk of infection. But the most common side effects in the phase II clinical trial of people with kidney diseases were:
Injection site reactions, including redness
Respiratory infections
Nausea
Headache
No one in the phase II study got meningitis or sepsis. There also weren’t any other serious treatment-related side effects.
Early results from a bigger, phase III study in kids aged 12 and up and adults with C3G or IC-MPGN showed pegcetacoplan lowered protein in the urine by 68% after 26 weeks. The findings also confirmed that the drug is safe and well-tolerated.
The FDA label for pegcetacoplan warns about the possibility of:
Serious infections from encapsulated bacteria
Infusion-related reactions
Interference with lab tests
Less serious side effects include:
Diarrhea
Fatigue
Pain or redness at the injection site
Stomach pain
It’s generally safe to take unless you are hypersensitive or allergic to the drug or have a serious infection. You should get vaccinated against certain bacterial infections first.
Step 5: FDA Review and Monitoring
Before a drug gets approved, it goes through detailed FDA review. Based on the promising clinical trials results, the FDA accepted pegcetacoplan for priority review as a new treatment for C3G and IC-MPGN. Priority review means the FDA aims to take action within six months, which is faster than a standard review. This designation is given to select drugs that, if approved, would lead to a significant improvement in safety and effectiveness.
Step 6: New Hope for Treating C3G and IC-MPGN
Because the drug has already been in use for other conditions, there’s a lot already known about how it works and how safe it is. More long-term study is needed to know how well the treatment will work to prevent kidney failure over many years.
Researchers will keep studying pegcetacoplan for these kidney conditions and others, along with many other diseases involving the complement system. But this new medication offers great promise for targeting the underlying causes of these diseases to lower inflammation and improve kidney function in ways that hadn’t been possible before.