The era of traditional immunosuppressive treatment for IgA nephropathy (IgAN) is giving way to an era of targeted therapies. Researchers at Kidney Week 2024 presented data on new therapeutic targets for IgAN.

Following these presentations, featured expert Sayna Norouzi, Conference Reporter Associate Editor-in-Chief Rick Davis. Dr Norouzi’s clinical perspectives on these findings are presented here.

During Kidney Week 2024, there were multiple sessions about new clinical trial data for IgAN medications, including a session on complement inhibitors with Felix Poppelaars, MD, PhD, and Dana V. Rizk, MD, that I moderated. The complement system, particularly the alternative pathway, is implicated in IgAN, and therapies targeting the complement system are being evaluated to see if they can help stop the process of fibrosis and kidney damage seen over time in patients with IgAN. The CFB inhibitor iptacopan received accelerated US Food and Drug Administration (FDA) approval in August 2024 for patients with IgAN who are at risk for rapid disease progression based on having a proteinuria level of greater than or equal to 1.5 g/d. The accelerated approval for iptacopan was based on the reduction in proteinuria level observed in the APPLAUSE-IgAN trial, which is ongoing.

In terms of therapies with other mechanisms of action, delayed-release budesonide is also FDA approved for patients with IgAN, based on the results from the NefIgArd trial. An analysis of the NefIgArd study presented by Roisin Clare Thomas, PhD, at Kidney Week 2024 measured the amount of serum galactose-deficient IgA1 (Gd-IgA1) in patients receiving delayed-release budesonide or placebo (abstract FR-PO894). The results showed that there was a slight reduction in serum Gd-IgA1 in patients receiving delayed-release budesonide at 3 months but no reductions at any other point. From a pathophysiologist’s standpoint, if patients are producing less Gd-IgA1, this means that this drug may be interfering with the disease at hit 1, and fewer autoantibodies are produced. As a result, there could be fewer immune complexes that would deposit in the kidneys, and, hopefully, there would be less fibrosis over time.

Another newer FDA-approved medication for IgAN is the DEARA sparsentan. The pivotal trial of sparsentan is the PROTECT trial, which is being done in patients with biopsy-proven IgAN and compares sparsentan with the ARB irbesartan, both of which were uptitrated during the trial as tolerated by patients. Patients in PROTECT who received sparsentan had significantly reduced proteinuria when compared with the patients who received irbesartan.

Moving on to therapies that are still in development, the top results from an interim analysis of the ongoing phase 3 VISIONARY trial were recently reported. This trial is evaluating the anti-APRIL monoclonal antibody sibeprenlimab vs placebo in patients with IgAN. Patients receiving sibeprenlimab had a significant reduction in proteinuria vs placebo. These results make me hopeful as a physician that our patients will have more treatment options in the future.

We have other trials, such as the phase 3 ALIGN trial, which is evaluating the endothelin A receptor antagonist atrasentan for IgAN and was discussed at Kidney Week 2024 (abstract FR-OR62). The trial is being conducted in 20 countries, with a total of 404 patients with biopsy-proven IgAN meeting the inclusion criteria; 340 patients were enrolled into the main stratum, and 64 patients were enrolled into the exploratory SGLT2 inhibitor stratum. Patients were randomized to receive atrasentan 0.75 mg/day or placebo. The ALIGN data showed that, after 36 weeks of treatment with atrasentan 0.75 mg/day, the first 270 patients in the main stratum had a significant reduction in the urinary protein-to-creatinine ratio with a geometric mean between-group difference of 36.1 percentage points for atrasentan compared with placebo. It is interesting that, among 29 patients in the exploratory SGLT2 inhibitor stratum who completed 36 weeks of the trial, the geometric mean percentage reduction in the urinary protein to creatinine ratio was 39.6% in the atrasentan group compared with 3.4% in the placebo group.

Ultimately, it is not just about having the options for IgAN treatment right now—it is also about the ongoing trials as well. Having a better understanding of how the disease works and having more trials continually coming out are positive changes in the field. A couple of years ago, it was disappointing to diagnose someone with IgAN but not be able to offer them different options for treatment. Not only do we have several treatment options available now but we are also likely going to have even more options in the future, and that is really exciting.