The inhibition of the formation of vasoactive peptides, such as angiotensin II, and their signaling is part of standard therapy in the treatment of immunoglobulin A nephropathy (IgAN). However, other novel targets have garnered interest due to their potential ability to interrupt the disease process rather than treating the downstream effects of the disease. This important topic was discussed at the American Society of Nephrology’s Kidney Week 2023.

Following these presentations, featured expert Andrew S. Bomback, MD, MPH, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Bomback’s clinical perspectives are presented here.

It is a very exciting time for IgAN because we have so many different drugs that are in trials and a few that have already received US Food and Drug Administration (FDA) approval, as discussed in the presentation by Pietro A. Canetta, MD, MS, from Kidney Week 2023 titled “Emerging Therapeutic Options in IgA Nephropathy,” which was part of the educational symposium titled “IgA Nephropathy: Proteinuria, Vasoactive Peptides, and the Evolving Treatment Landscape.”

One of the unique aspects of IgAN among the glomerular diseases is that we have strong evidence for proteinuria as both a risk factor and a surrogate outcome marker. This has actually opened up a pathway for drug approval that can be completed in a relatively short amount of time in some of these trials, which is why, I think, we are seeing so many trials evaluating newer agents. It affords us the possibility that we are going to have multiple FDA-approved agents for IgAN, and it is going to be the nephrologist’s job to determine which of these agents is most appropriate for their patient in front of them. So, it is a nice situation to be in, in that we will actually have multiple therapies to choose from.

In terms of the endothelin receptor antagonists, we already have sparsentan, which has received accelerated approval from the FDA. The ongoing AFFINITY study is investigating atrasentan, and the study methodology was discussed at Kidney Week 2023 in an abstract by Lafayette et al (abstract INFO15-TH). The way I view endothelin receptor antagonists for IgAN is that they are really a way to maximize what we call conservative therapy of the disease. Traditionally, the patient with IgAN who received conservative therapy was offered an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, as discussed in other abstracts presented at the meeting (abstracts SA-PO905 and TH-PO1026).

We have been able to expand conservative therapy by adding SGLT2 inhibitors, and we now have endothelin receptor antagonists, which may be the most profound in terms of efficacy, especially when we look at proteinuria. I also sometimes add a mineralocorticoid receptor antagonist. It is nice that these drugs do not have an immunomodulatory effect in terms of potential toxicities, including infections, and they do have the ability to significantly improve proteinuria reductions on top of what we have been able to achieve with traditional renin-angiotensin-aldosterone system inhibition.

One example of the drop in proteinuria that is produced by these agents is shown by the more recent data from the PROTECT study evaluating sparsentan. As expected, this drop in proteinuria is associated with a slower rate of decline of kidney function. So, I think that we have really good evidence that endothelin receptor antagonists—if we have access to them—should be considered part of the conservative therapy for IgAN. It is a welcome addition to what we consider conservative therapy.

When we move on to immunomodulatory therapies, we know that budesonide has been FDA approved, and more data came out on this agent at Kidney Week this year (abstract SA-PO891). Budesonide has been out for a while now, and we are seeing more and more usage of it as a first-line immunosuppressant to basically take the place of traditional corticosteroids.

There are numerous drugs that are in development in well-powered phase 3 trials that we expect will one day be available for our patients if they show the same proteinuria reductions that were reported in earlier phase 2 trials. In one class, there are the B-cell–targeting therapies that are targeting the BAFF and APRIL pathways, such as atacicept and telitacicept. Although an earlier trial with rituximab in IgAN was a negative study, anti-APRIL drugs appear to modulate B cells to produce fewer galactose-deficient IgA antibodies, which form part of the immune complexes that underlie the pathogenesis of IgAN (abstract SA-PO887).

When immune complexes deposit on glomeruli, complement plays an important role in inciting the inflammatory response of IgAN, so using complement inhibitors in IgAN is another very hot area. We have multiple phase 2 trials of complement inhibitors (eg, the CFB inhibitor iptacopan) with promising data. We are waiting for the readouts of the resulting phase 3 studies, but if the data that were reported in the phase 2 trials hold true, we think that these drugs will be available for our patients.