C3G and the Pediatric VALIANT Study
Bradley Dixon, MD
Bradley Dixon, MD, a pediatric nephrologist, and Chief of Pediatric Nephrology, Children’s Hospital of Colorado, and Professor of Pediatrics, University of Colorado School of Medicine, discusses complement 3 glomerulopathy (C3G) and the pediatric VALIANT study.
Complement 3 glomerulopathy (or C3G) is a form of membranoproliferative glomerulonephritis, an inflammatory process. It occurs when the complement system, which is a key part of the body’s defenses to fight off bacterial and viral infection, is continually engaged. When this occurs, plasma complement fragments are deposited in the glomerulus, creating inflammation and disrupting glomerular function. At this point, the clinical features of C3G are apparent, including hematuria and proteinuria.
As it is a rare disorder, it is not regularly taught during medical training, and primary care physicians will not typically see several patients with C3G. Therefore, it will not often be in the forefront of clinician’s mind when confronted with symptoms associated with C3G. Primarily a disease of the young, pediatricians may easily mistake it for other conditions, such as postinfectious (or infection-related) glomerulonephritis, which typically follows a streptococcal infection. The microscopic appearance of biopsy samples from patients with C3G may even look similar to those with postinfectious glomerulonephritis.
The VALIANT trial was a phase 3, double-blind, placebo-controlled study of the efficacy and safety of pegcetacoplan in 124 adolescent and adult patients with either C3G or the related disorder primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN). The primary endpoint was to determine this complement 3 inhibitor’s effect on proteinuria.
After 26 weeks of treatment, pegcetacoplan was associated with a 68% relative reduction in the urinary protein:creatinine ratio, the indicator of proteinuria, compared with the individuals receiving placebo. The study drug was not associated with a safety profile that was significantly different from that observed in the placebo group. A longer-term extension study demonstrated that the proteinuria reduction is maintained, along with kidney function, through at least 52 weeks. “Improvement in proteinuria really does herald long-term benefit,” stated Dr. Dixon. “The longer we see preservation of GFR, the more confident we are that these drugs will be effective over the long term.”
The VALIANT data support that blocking C3 has dramatic benefits by limiting complement deposition in the glomerulus in both adolescent and adults with C3G. With earlier intervention, long-term damage to kidney function may be prevented.
Dr. Dixon commented that although pegcetacoplan was effective in patients ages 12 years or greater, there is still an urgent need for treatment of younger patients, for which no effective treatment is approved. He added that since we are all born with a fixed number of glomeruli, kidney damage in young patients means their reserve of kidney function later in life will be limited. In his experience, 50% of patients with C3G will experience a halving of their kidney function within 10 years, and will need dialysis and/or a kidney transplant.
Bradley Dixon, MD
Pediatric Nephrologist
Chief of Pediatric Nephrology, Children’s Hospital of Colorado
Professor of Pediatrics, University of Colorado School of Medicine
Nice to nice to meet you. I’m Brad Dixon. I’m a pediatric nephrologist and I practice at Children’s Hospital Colorado and I’m on faculty as a professor of pediatrics at the University of Colorado School of Medicine. I’m also the Chief of our section of pediatric nephrology here. And I have spent the better part of two decades in complement-mediated kidney diseases, C3G being one of those, atypical hemolytic uremic syndrome being another. Both in learning new therapies for these diseases, exploring new therapies to to bring them to patients with these conditions as well as studying diagnostic evaluation of these patients.
Can you briefly explain C3G and why it is so challenging to diagnose and treat in adolescence?
Absolutely. Well, one of the challenges really off right off the bat is that it’s a rare disease and so any rare disease including C3 glomerulopathy, it may not be in the forefront of a doctor’s mind as they’re evaluating a patient. It’s not something that is regularly taught in training in a pediatrician’s training or an internist’s training. Another difficulty with a making a prompt diagnosis of C3 glomerulopathy is that it can be mimicked by other conditions. One example is an entity called post-infectious glomerulonephritis or infection-related glomerulonephritis. And this is something that occurs after, typically, strep throat or strep infection. But it can have um, features in the clinic that are very similar to C3 glomerulopathy with blood in the urine, protein in the urine, high blood pressure, abnormal kidney function. But it can even be very similar to C3 glomerulopathy under the microscope on a kidney biopsy. And so it may be very difficult to distinguish C3 glomerulopathy from infection-related glomerulonephritis, for example, until several months have gone by and the condition doesn’t seem to be resolving as infection-related glomerulonephritis tends to tends to do. Maybe to back up and talk about what C3 glomerulopathy is a little bit. This is a form of glomerulonephritis, or kidney inflammation, that happens when the normal regulation of a part of the immune system, the complement system, is lost. C3 glomerulopathy is a condition of dysregulation of the alternative pathway of the complement system. And when this dysregulation happens, when these brakes are taken off of the complement system, the activation of the complement system that happens in plasma, leads to the deposition of complement fragments into the glomerulus. And that in turn creates inflammation with inflammatory cells that enter the glomerulus, disrupt the normal architecture of the glomerulus. And that ultimately leads to the hematuria, proteinuria, and all of the the clinical features of of C3 glomerulopathy.
What did the pediatric VALIANT data show about Empaveli’s impact on proteinuria and kidney function?
So, the the VALIANT study revealed really a potent reduction in urine protein and around 65-70% depending on the patient population, depending on the specific subpopulation of patients in the study. And this was a clear signal that blocking complement at the level of C3 has dramatic beneficial consequences, dramatic benefit to to this disease. By reducing the amount of complement deposition that’s happening in the glomerulus, in turn reducing the amount of inflammation that’s in the glomerulus, and improving proteinuria. And we have hypothesized for some years that proteinuria is a surrogate for reduced kidney function. So, if we can intervene early by reducing proteinuria, we can avert long-term consequences like progression of chronic kidney disease, progressive kidney dysfunction. And that ultimately was then, in subsequent follow-up data, confirmed by the VALIANT study that EGFR was preserved in patients, in adolescent patients, but also adult patients over the course of the study, which reaffirmed that intervention, improvement in proteinuria really does herald long-term benefit.
What do the 52-week VALIANT results tell us about the longer-term impact of Empaveli on kidney health?
The 52-week data specifically that proteinuria reduction is maintained in patients on pegcetacoplan on Empaveli beyond the 26-week primary analysis time point and a similar reduction in proteinuria was seen in patients switching from placebo over to active drug, over to Empaveli. So, that preservation of the effect of reduced proteinuria indicates that this is not a transient benefit, but really a long-standing benefit. The improvement or stabilization of GFR was also noted to continue beyond the 26-week endpoint. And I think that is particularly important that the longer we see, because these diseases, C3 glomerulopathy and immune complex MPGN, which was the other disease studied in the VALIANT study, um because these diseases cause a slow but relentless decline in kidney function over time, the longer we see preservation of EGFR, the more reassured and affirmed we can be that this drug is has long-term benefit for for patients with these conditions.
What treatment gaps remain for children and adolescents with C3G?
As a pediatrician, I guess my first response would be that Empaveli is only approved for ages 12 and up, and we certainly have patients with quite severe disease who are not yet 12. And so, exploring the benefit of this drug in individuals less than 12, is a current gap. We still don’t have appropriate, we don’t have effective tools to treat C3G and IC-MPGN in younger patients. I think another research gap is what characteristics of a patient, either on their clinical characteristics or biopsy characteristics, will point to the greatest benefit of Empaveli. We know in the VALIANT study in the subpopulation analysis that adolescents and adults had similar benefit of Empaveli, patients with C3G and IC-MPGN had similar benefit, patients who were had disease in their native kidneys versus kidney transplant had similar benefit. But what we really need to understand is which patients is it critical to start Empaveli at the earliest time point, as soon as the diagnosis is made. What patient would benefit the most from initiation. We’re also, I think, needing to learn because there are other complement targeted agents that are entering the marketplace or have entered the marketplace. Are there patient characteristics that might favor one of these agents versus another or even potentially combination therapy?
Can you discuss the urgency of diagnosing and beginning treatment for patients with C3G?
A mantra that we use in nephrology, not limited to or specific to C3G, but is relevant to many kidney conditions, is time is kidney. We are really, we’re born with a fixed number of glomeruli. That’s all the glomeruli we’ll have throughout life. And so, as those individual nephrons are lost, you’re really, you’re up against a ticking clock, if you will. That the the more nephrons are lost, the the fewer nephrons you’ll have throughout life. I think another point that is relevant in this is that C3 glomerulopathy tends to be a disease of the young. It’s not exclusive. It it certainly spans the age range from young children all the way to late adulthood, but it tends to be a disease of the young. And so if you’re losing nephrons early in life as a as a young adult or as an adolescent, that ultimately will mean that your nephron endowment, your reserve of kidney function is going to be much more limited or narrow for the rest of your life. And so we know that decline in GFR happens naturally as a function of aging and so if you’re losing nephrons early in life, that really portends a more rapid decline in kidney function later in life. And so intervening early to prevent any erosion of that kidney reserve I think is critical.
What do the 52-week VALIANT results tell us about the longer-term impact of Empaveli on kidney health?
Again as a pediatrician just to make a plea to the pharmaceutical industry as a whole to focus on pediatric disease in inclusion development and inclusion of younger children in trials to get these agents in the hands of pediatric nephrologists like myself to treat younger patients. That’s, I can’t underscore enough how much of a gap that really is that when we’re looking at a pediatric patient and we have limited tools to offer a family with a disease that could really, over 10 years as the journal article suggests 50% of patients that we found in this CJASN article, 50% of patients will have a having of their kidney function go on to dialysis or need a kidney transplant within 10 years. And so it really is a relentless disease even in the young and so having the tools to treat these patients earlier in their life is vital.
C3G and the Pediatric VALIANT Study
Brad Dixon, MD