The Therapeutic Potential of APRIL Inhibition in IgAN, with Edgar Lerma, MD
Lerma discusses the current treatment landscape for IgA nephropathy and what role APRIL inhibition may play in treating IgAN.
Credit: X.com
Despite being the most common primary glomerulonephritis worldwide, IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and end-stage kidney disease. Despite advances in understanding its pathophysiology, treatment options have historically been limited to supportive care, including renin-angiotensin system inhibitors, blood pressure control, and corticosteroids for high-risk patients.
Recently, a growing understanding of the immunopathogenesis of IgAN has led to the emergence of novel therapeutic strategies, including the inhibition of A proliferation-inducing ligand (APRIL), a key driver of IgA production. By reducing pathogenic IgA1 production at its source, APRIL inhibition has the potential to alter the course of the disease. Accordingly, several anti-APRIL drug candidates, including sibeprenlimab, atacicept, telitacicept, and zigakibart, are in clinical development for IgAN.
For more on APRIL inhibition and the current IgAN treatment landscape, the editorial team of HCPLive Nephrology spoke with Edgar Lerma, MD, a clinical associate professor of medicine in the section of nephrology at the University of Illinois at Chicago.
HCPLive Nephrology: Can you provide an overview of the current treatment landscape for IgA nephropathy and what unmet needs exist for patients?
Lerma: One of the things that's interesting [about IgAN] is that this is considered a rare kidney disease, but it is the most common primary glomerulonephritis worldwide. In fact, there's an annual global incidence of 2.5 cases per 100,000 persons.
The disease manifests in several ways. Patients can present with asymptomatic hematuria, which means blood in the urine, or proteinuria, and that is protein in the urine, or they can present with advanced stages of kidney disease.
If you think about it, any patient who is diagnosed with what is called a rare kidney disease, it's a little bit disconcerting, right? So there's uncertainty about it, and this obviously impacts the patient's physical, mental, and emotional health. A lot of patients become anxious, and this can affect their daily activities, as well as even their daily work lives.
One of the things that's important about IgA nephropathy is that when patients are diagnosed, usually they are between 20 and 40 years of age. That's a very young population, right? So if these patients are 20 to 40 years of age, if you think about them and you think they eventually progress to kidney failure or what we call end-stage kidney disease, that means requirement of dialysis or kidney transplantation, this happens in their lifetimes.
So if they get to that point of reaching kidney failure, it's really a lifestyle change. They have to adjust to this new condition in their lives and it affects not only their personal lives, but also the lives of their families and their relatives.
HCPLive Nephrology: What challenges exist for developing effective pharmacologic therapies for IgA nephropathy?
Lerma: Let me put this in perspective. For many years, for many decades, whenever we diagnosed a patient with IgA nephropathy, and by the way, the only way to diagnose a patient with IgAN is through a kidney biopsy. Whenever a patient is diagnosed with IgAN, we explain to them that this is how the disease happens, this is what to expect, and so on and so forth.
For many years, the only thing we had to offer patients was treatment and medications to manage their symptoms and maybe slow down the progression of the kidney disease.
For blood pressure control, we use certain antihypertensive agents called renin-angiotensin system blockers. And of course, along with that, it's lifestyle – dietary salt restriction, aerobic exercise on most days, weight loss if necessary, cessation of smoking, so on and so forth.
And then the only other treatment that we offer is, whenever they don't respond to the ones I mentioned earlier, the next step would be to consider immunosuppressive therapies.However, the therapies that we had available back then had significant side effects and long-term toxicity.
So when you mention novel agents, over the past few years, we have had a deluge of novel therapeutic agents for IgAN. We now have a better understanding of the pathophysiology of how it can develop, and by understanding this mechanism, several phase 2 and phase 3 clinical trials have been published and have influenced the way we manage the disease. There are now different options for treatment that target the different pathophysiologic steps that lead to eventual kidney failure.
HCPLive Nephrology: There has recently been an increased focus on targeting APRIL. Can you tell me a little bit about that?
Lerma: So when we say APRIL, it stands for A proliferation-inducing ligand. This is actually a cytokine in the tumor necrosis factor family, and APRIL is integral to the development and progression of IgAN.
When we say cytokine, it is a substance secreted by certain cells of the immune system, and these cytokines have an effect on the other cells.
APRIL actually promotes the survival and the class switch, switching up B cells to produce IgA, particularly what we call the pathogenic galactose deficient IgA1. The abbreviation is Gd-IgA1, which actually forms immune complexes in the kidneys.
So these complexes are deposited in the glomeruli, which later on triggers inflammation, and as you trigger this inflammation, it leads to kidney damage. One way of thinking about this is you think of APRIL as a toggle within the immune system. So if you think of an electrical grid, APRIL powers specific circuits, and when you activate it, you turn it on, it helps promote the production of these pathogenic Gd-IgA1 and immune complexes formation and this leads to kidney damage and injury.
If you target APRIL, you turn it off, it is like pushing the toggle, turning it off and then this reduces the production of those harmful molecules that I mentioned. If you reduce the production of those molecules, then you prevent that damage and the injury that follows.
So, targeting APRIL represents a potential therapeutic strategy that disrupts this pathogenic sequence. If you inhibit APRIL, you can decrease the production of those harmful molecules, those Gd-IgA1, and eventual immune complex formation deposition into the kidneys, which eventually leads to end-stage kidney disease and the need for dialysis or transplantation.
HCPLive Nephrology: There are some promising agents in clinical development progressing through phase 2 and phase 3 trials. Is there anything that you think holds the most therapeutic potential for improving IgAN care?
Lerma: Right now we are actually looking at the guidelines for sort of directing how these agents will be used in the future, so it's exciting for us as nephrologists because now we have so many options. Before, we only had symptom management and blood pressure control.
For more information about IgAN and the role of APRIL, there's actually a website, www.DiscoverAPRILinIgAN.com, that has a lot of new insights and news about IgAN.
Editors’ note: Lerma has relevant disclosures with Travere Therapeutics, Akebia/Otsuka, Astra Zeneca, Bayer, Glaxo Smith Kline, Otsuka, Vifor, and Bayer.
