A number of therapies are available or are under investigation for the treatment of IgA nephropathy (IgAN), the leading cause of primary glomerular disease worldwide. Data on several of these therapies from important clinical trials in IgAN were presented at the National Kidney Foundation (NKF) 2024 Spring Clinical Meetings (SCM24).

Following these proceedings, featured expert Samir V. Parikh, MD, FASN, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis. Dr Parikh’s clinical perspectives are presented here.

There has been a shift in how we think about the treatment of IgAN. The historical approach has always been to treat patients with IgAN conservatively, largely due to a lack of effective treatment options and concerns regarding the known side effects that are associated with corticosteroids. However, we now know from the National Registry of Rare Kidney Diseases (RaDaR) database that approximately 20% of patients with low levels of proteinuria (<0.44 g/day) progressed to kidney failure within 10 years. Further, among all patients, 50% progressed to kidney failure or died after a median follow-up of nearly 6 years. Similar findings were presented at SCM24 from a study that looked at electronic medical record data from 1541 patients with IgAN to assess the incidence of chronic kidney disease stage progression and kidney failure (poster 394). The 12-month rate of kidney failure–free survival was 89.7% overall, but it was only 55% in patients who had stage 4 chronic kidney disease at diagnosis. Together, these data underscore how we need to recognize this disease and treat early with disease-modifying treatment.

When we think about novel therapies for IgAN, these therapies target the disease pathogenesis according to the four-hit hypothesis of IgAN, such as by blocking B-cell proliferation, class switching, and galactose-deficient IgA production, thereby blocking the autoimmune and inflammatory responses that result at the glomerular level and systemically.

Sparsentan is a nonimmunosuppressive dual endothelin and angiotensin II receptor antagonist (DEARA) that has US Food and Drug Administration (FDA) accelerated approval for the treatment of primary IgAN in patients who are at risk for rapid disease progression. Data from the phase 3 PROTECT trial showed a dramatic reduction in proteinuria and the better preservation of estimated glomerular filtration rate (eGFR) in patients who were treated with sparsentan compared with those who were treated with irbesartan alone. Updated data from PROTECT shared at SCM24 found a greater rate of complete remission with sparsentan vs irbesartan with better GFR preservation (poster 375).

Also presented at SCM24 was a matching-adjusted indirect comparison of eGFR slopes in the PROTECT study with the RaDaR database and the control arm of the NefIgArd trial (presentation 446). The results suggested that the use of sparsentan resulted in a slower decline in kidney function vs standard of care.

Data for sparsentan as a first-line therapy in patients from the phase 2 SPARTAN trial who were newly diagnosed with IgAN were examined at SCM24 in poster 384. These patients had not previously received an RAAS blocker. Although there were only 12 patients in this preliminary analysis, what is striking is that proteinuria was reduced by more than 80% over 48 weeks of follow-up. Sparsentan was mostly well tolerated, but 1 patient discontinued treatment due to hypotension.

A prespecified interim analysis of the phase 3 APPLAUSE-IgAN trial data was also presented at SCM24 (presentation 448). Iptacopan is a complement factor B inhibitor, and this interim analysis compared iptacopan with placebo in 250 patients with IgAN. Iptacopan reduced proteinuria by 35.8% relative to placebo, and nearly twice as many patients on iptacopan achieved a proteinuria level of less than 1 g at 9 months. Further, the proteinuria reduction started as early as week 2 in some patients, which is quite rapid. These data suggest that iptacopan is affecting glomerular inflammation. A drug like iptacopan may be relevant in the treatment of IgAN by reducing glomerular inflammation.

The small phase 1b/2a RUBY-3 study on povetacicept, which inhibits both APRIL and BAFF in patients with autoantibody-associated glomerulonephritis, was shared at SCM24 (poster 401). Blocking the action of APRIL and BAFF may help reduce the proliferation, maturation, and survival of B cells, decreasing the production of galactose-deficient IgA1. Preliminary data showed an approximate 30% reduction in proteinuria and much lower galactose-deficient IgA1 with povetacicept treatment.

There are also phase 1/2 studies looking at the anti-APRIL therapies sibeprenlimab and zigakibart. These drugs also help reduce the production of galactose-deficient IgA1. Across these studies, there were drops in proteinuria and circulating galactose-deficient IgA1 vs placebo. These promising data have led to phase 3 studies.