IgA nephropathy is the quintessential disease for novel drug therapies, or at least it felt like it at ASN 2026 in Denver. IgA nephropathy is the most common glomerular disease worldwide and, despite supportive care, can lead to kidney failure in 40% of adults younger than 50 in their lifetime. Although there has been an exciting reduction in proteinuria and modest renoprotection with hemodynamic supportive care utilizing renin-angiotensin-aldosterone inhibitors, endothelin antagonists, and sodium-glucose-cotransporter-2 inhibitors, it was clear from the STOP-IgAN trial that immunosuppression is necessary to provide renal survival benefit.
Final phase 3 data from the VISIONARY trial of sibeprenlimab, a cytokine A proliferation-inducing ligand (APRIL) inhibitor, revealed a positive secondary endpoint of a stabilized eGFR slope over 24 months compared to placebo (0.3 vs -4.2 ml/min/year), with a between-group difference of 4.5ml/min/year and the least-squares mean treatment difference for change in eGFR from baseline to 24 months was 9.2ml/min. The adverse events were similar. This study built on the initial phase 3 data, with a primary endpoint at nine months after randomization of a reduction in proteinuria of 50.2% compared to an increase with placebo of 2.1%.
The phase 3 results of TELIGAN, a 2-year trial of Telitacicept, a B-cell activating factor (BAFF) and APRIL inhibitor, met its primary endpoint of eGFR slope over 104 weeks. Telitacicept had a 2-year annualized eGFR slope of -0.6ml/min/year vs -5.7ml/min/year for placebo, with a between-group difference of 5.1ml/min. eGFR decline of >30% from baseline occurred in only 2.5% of patients in the Telitacicept group vs 16.4% in the placebo group, a hazard ratio of 0.11. There was a 60.7% placebo-adjusted UPCR decrease in the Telitacicept group. Adverse events were similar between the groups.
The ORIGIN 3 trial of Atacicept, a BAFF and APRIL inhibitor, was similarly impressive at 2-year follow-up with a near-zero eGFR slope (-0.6ml/min/year) compared to -5.6ml/min/year in placebo, a 5ml/min/year difference.
Ravulizumab, a C5 inhibitor, was tested in the 34-week phase 3 I CAN trial, yielding a 43.4% reduction in adjusted geometric mean 24h UPCR compared to placebo.
This is in addition to Iptacopan, a factor D complement inhibitor, which showed in a 24-month trial an annualized eGFR slope of -3.1ml/min/year compared to -6.12ml/min/year with placebo.
Nephrologists now have plenty of non-steroidal immunosuppressant options (along with standard-of-care hemodynamic modulators) to slow the progression of IgA nephropathy. Excitement aside, we may now have more questions to answer, such as how they function in real-world use, whether BAFF/APRIL inhibitors can be safely combined with complement blockade, how long these medications can be continued, and whether these medications provide the same benefit in recurrent or de novo IgA nephropathy after kidney transplant.
Indeed, it is an exciting time to be a nephrologist! One can now hope that this rapid pace of drug development will extend to more common kidney diseases such as polycystic kidney disease and other glomerular diseases like focal segmental glomerulosclerosis.
Dr. Bregman has no conflicts of interest to report.
