Clinical Trial Leads to Approval of Pegcetacoplan for Two Rare Kidney Diseases

One in a million.  

Those are the odds of having C3 glomerulopathy (C3G) or immune complex membranoproliferative glomerulonephritis (IC-MPGN). For decades, there has been no targeted treatment for these rare and severe kidney diseases. Bradley Dixon, MD, wanted to change that. And he did.  

Dr. Dixon, a pediatric nephrologist, is a co-author on the recently published VALIANT study in the New England Journal of Medicine. The data and research validated through this study paved the way for the Food and Drug Administration’s (FDA) approval of pegcetacoplan as a treatment for individuals 12 and older.  

C3G and IC-MPGN are complement-mediated kidney diseases. The complement system is a part of the immune system. It’s made up of about 50 different proteins, and together, they act as an army ready to attack. Unlike other parts of the immune system, the complement system doesn’t need to be trained by a vaccine or a past exposure to a pathogen to protect against invaders. 

While it’s versatile and necessary, it’s not good at distinguishing our own bodies from invading pathogens. In most people, regulators built into the system stop the proteins from attacking the body. But for people with C3G and IC-MPGN, the complement system is not properly controlled, leading to inflammation in the glomeruli, which can cause scarring and eventually lead to end-stage renal disease.  

“It’s a slowly but relentlessly progressive kidney disease,” Dr. Dixon says. “It would just smolder and burn and eventually cause the loss of the kidney.” 

Research into pegcetacoplan 

Prior to pegcetacoplan, doctors used non-targeted immunosuppressive treatments. These treatments only worked for approximately 33% of patients. About half of the patients who didn’t respond to treatment developed kidney failure within 10 to 15 years. 

The initial pegcetacoplan trial for C3G and IC-MPGN began in 2018. The phase two open label study evaluated eight patients in the U.S., five of whom were seen by Dr. Dixon in Colorado. Building on the success of this study, the much larger, global phase three randomized placebo-controlled VALIANT study began in 2022. In the beginning, 63 of the patients received the active drug, and 61 received the placebo.  Each patient received twice weekly subcutaneous infusions. 

Dr. Dixon and his colleagues from around the world measured key endpoints including proteinuria, kidney function, waste products in the blood and more. 

“If there’s evidence of unregulated complement activation happening in the blood, the drug is working to turn off that overactivation,” Dr. Dixon says. 

For the first six months, those who received the drug had a 68.1% relative reduction in proteinuria. Those who received the placebo had a 2.9% increase over the same period. 

Patients who received the active drug stayed on the medicine for an additional six months. At the same time, those on the placebo were able to switch. 

Potential long-term impacts of pegcetacoplan  

While the earliest results of the VALIANT study published recently only focused on the first six months, Dr. Dixon and his fellow researchers have found stabilization of kidney function and sustained reduction in proteinuria at the one-year mark. Those who switched from the placebo over to pegcetacoplan at six months also saw improvement in their disease at the one-year mark. 

Dr. Dixon says the goal is to preserve kidney function, potentially rescue a transplant, and if initiated early enough, serve as a preventative strategy. Still, there’s a lot to learn — and he’s looking forward to what the future holds.  

“We don’t know yet if they need to be on this drug lifelong or if there’s a period of time in which you’re on it and the disease burns out or becomes less severe,” Dr. Dixon says. “It’s an exciting time to be in this field. We have some really exciting opportunities.”