The complement system contributes to the development of kidney inflammation and damage in IgA nephropathy (IgAN), making it a potentially ideal target for therapeutics. Researchers at Kidney Week 2024 presented data on complement-targeting treatments that are currently available or under investigation for IgAN.

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

The complement system is comprised of the classical, lectin, and alternative pathways. Dysregulation of the complement system can occur in the fluid phase or at cell surface level within the kidney. The complement system seems to play a role in the setting of immune complex–mediated injury in the kidney. If you look at a kidney biopsy from a patient with IgAN, almost invariably you are going to see some C3 deposition, and the intensity of C3 staining correlates with a poorer prognosis. With immunofluorescence and immunohistochemistry studies of kidney biopsies from patients with IgAN, we see not only C3 deposition but also the increased deposition of other alternative, lectin, and terminal pathway proteins within the glomeruli compared with healthy controls.

Iptacopan is a factor B inhibitor that has received conditional US Food and Drug Administration (FDA) accelerated approval for the treatment of IgAN on the basis of a significant reduction in proteinuria in an interim analysis of the phase 3 APPLAUSE-IgAN trial. Since factor B is one of the key drivers of the alternative pathway, blocking it could reduce inflammation within the kidney in patients with IgAN. At Kidney Week 2024, a poster by Dana V. Rizk, MD, and colleagues reported the results of an exploratory analysis from the APPLAUSE-IgAN trial looking at changes in complement biomarkers with iptacopan vs placebo (abstract FR-OR61). The analysis found that there was a reduction in the activity of the alternative pathway and a decrease in plasma Bb and urinary sC5b-9 with iptacopan at month 9 of the study.

Ravulizumab, a monoclonal antibody targeting C5, is FDA approved for several indications but remains investigational for IgAN. A poster by James A. Tumlin, MD, et al from Kidney Week 2024 presented week 50 results from the placebo-controlled phase 2 SANCTUARY clinical trial of ravulizumab with standard-of-care therapy in patients with IgAN (abstract FR-OR60). There was a 33.2% reduction in proteinuria in the ravulizumab-treated arm at week 26. At that time, patients who were in the placebo group began receiving ravulizumab. At week 50, those patients who switched from placebo to ravulizumab had a 43.1% reduction in proteinuria from baseline. There also seemed to be some benefit in the estimated glomerular filtration rate slope, but long-term studies are needed to confirm this. A phase 3 study evaluating ravulizumab for the treatment of IgAN is underway. Other drugs targeting the complement pathway are under investigation for IgAN, including the C5-targeted siRNA agent cemdisiran, the factor D inhibitor danicopan, and the C3 inhibitor pegcetacoplan.

Overall, based on the current evidence from clinical trials, it certainly appears that the complement system is playing a role in the pathogenesis of IgAN. Therefore, targeting the complement cascade seems like a good idea for IgAN based on the proteinuria reductions that we are seeing in clinical trials. The alternative and terminal complement pathways appear to be important mediators of inflammation in IgAN. Targeting these pathways has been shown to significantly reduce proteinuria better than placebo and thus may be important in helping to improve or stabilize kidney function and slow the progression of chronic kidney disease long-term. However, more data are needed, and we need to see longer-term follow-up from these original trials.