<p>At the recent <strong>Kidney Week 2025</strong>, researchers shared positive data from 2 phase 3 clinical trials of novel B-cell–targeting agents for IgA nephropathy (IgAN). Both trials resulted in accompanying publications in <em>The</em> <em>New England Journal of Medicine</em>.</p> <p><br></p> <p><em>Following these presentations, featured expert Pietro A. Canetta, MD, MS, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Canetta on these findings are presented here.</em></p>

IgAN was a major focus at this year’s meeting, continuing the theme from previous Kidney Weeks. We now have agents to target B-cell activation, along with the supportive studies of these agents in IgAN, and the trials show rather dramatic improvements in markers of disease compared with historical outcomes.

<br>

In the 4-hit conceptualization of IgAN pathogenesis, the first hit involves galactose-deficient IgA1 (Gd-IgA1) production. In healthy individuals, this type of IgA1 is primarily found at mucosal surfaces, with lower levels in the bloodstream, but, in patients with IgAN, circulating levels are increased. Moreover, Gd-IgA1 accounts for nearly all the IgA that is detected in glomerular deposits in patients with IgAN. It appears that Gd-IgA1 production occurs in the mucosal lymphatic tissue, especially in the gut-associated lymphatic tissue.

<br>

However, a key unanswered question remains: Why do certain individuals produce Gd-IgA1 and progress to develop IgAN while other similar individuals (eg, family members) do not? It really comes down to a complex interaction of genetics, environment, and stochastic differences in autoimmunity or immunity—and part of that is related to the gut microbiome and how it may or may not stimulate the production of Gd-IgA1 and perhaps even stimulate its trafficking into the bloodstream.

<br>

Targeted budesonide, which is designed to spare patients from some of the side effects of systemic glucocorticoids, does appear to affect this mucosal pathway by having its local anti-inflammatory effects at the surface of the gut, resulting in decreased Gd-IgA1 production. Data recently reported from the TESTING study of systemic glucocorticoids vs placebo in IgAN also showed a decrease in IgA and Gd-IgA1 production that was comparable in magnitude to that observed with targeted budesonide. I think that this is a nice proof of principle, and it brings us back to a physiological rationale for a mechanism involving at least 1 of the 4 hits, and possibly more.

<br>

A different set of drugs targets cytokines that activate B cells, and these cytokines can bypass the need for T-cell help and can activate B cells in a T-cell–independent manner. Multiple lines of evidence suggest that this pathway is important in the differentiation and activation of B cells and their commitment to a lineage that produces IgA and Gd-IgA1. For example, genome-wide association studies identified APRIL, specifically, as an important associated gene in IgAN.

<br>

Ali G. Gharavi, MD, reviewed these and other findings in his presentation titled “Emerging Insights in the Diagnosis and Care of Patients With IgAN” during the “Expanding Therapeutic Horizons in IgAN” symposium at Kidney Week 2025. I view these genomic data as crucial in giving biological credence to the strategy of targeting either APRIL alone or APRIL and BAFF together. Atacicept can bind to both APRIL and BAFF, while sibeprenlimab targets just APRIL. Both agents were discussed at Kidney Week 2025, and there are now approximately a half dozen BAFF/APRIL inhibitors in development. Following the meeting, sibeprenlimab became the first such agent to be approved for the treatment of IgAN. The US Food and Drug Administration (FDA) granted an accelerated approval in November 2025.

<br>

Richard A. Lafayette, MD, shared positive 9-month data from the phase 3 trial of atacicept during the opening plenary session at the meeting. And Vlado Perkovic, MBBS, PhD, presented positive phase 3 data for sibeprenlimab the following day (abstract SA-OR086). The top-line stories were the dramatic decrease in Gd-IgA1 and the substantial reduction in proteinuria when compared with placebo in each of these studies.

<br>

This was a real “stop-and-admire-the-sunset” moment—one that I am not sure I could have even imagined 10 years ago. We had 2 phase 3 studies in 1 rare renal disease, both presenting positive data, both with accompanying publications in The New England Journal of Medicine. In the field of nephrology, where, for years, we have said that we are behind our colleagues in developing specific treatments, this is a wild success. It was a win for patient advocacy groups, and it reflects a remarkable alignment between pharmaceutical companies, regulatory bodies, and academia.

<br>

Now, with several independently successful agents for IgAN that have not been compared head-to-head, the work that lies ahead will be to determine how and when to use these therapies, but these are good problems to have. With B-cell–targeted therapy, one might reason that, if you stop the first hit, everything downstream becomes irrelevant. I do think that stopping hit 1 is a nice way to approach treatment, but I also think that there is still plenty of room for a discussion of other therapeutic approaches and mechanisms of action. The truth is that we find patients with IgAN at different stages of their disease, and, although BAFF and APRIL inhibitors have shown impressive proteinuria reductions, there is no expectation of having 100% response rates in IgAN—for any therapy. Therefore, complementary mechanisms and combination strategies will remain relevant.