Phase II study shows promising results for targeted treatment for IgA nephropathy
Due to the immunological pathogenesis of IgA nephropathy (IgAN), patients used to be given immunosuppressive therapy; however, this was shown to have no long-term benefit over optimal supportive therapy.
Promising data from the interim analysis of a Phase II study with iptacopan now show that the targeted inhibition of a specific factor of the immune system (complement factor B) allows a specific approach to therapy for IgAN without burdening patients with the severe side effects of immunosuppression.
IgA nephropathy is a chronic kidney disease occurring in young adults and is one of the most common reasons for kidney transplantation in this age group. IgAN is the most common form of glomerulonephritis (GN), i.e., immunologically induced inflammation of the renal glomeruli. It is characterized by glomerular deposition of immune complexes containing immunoglobulin A (IgA), and by a complex inflammatory response and progressive loss of kidney function. For many decades, IgAN has therefore been treated with anti-inflammatory or strong immunosuppressive agents. However, the STOP-IgAN study and its ten-year follow-up showed that the addition of immunosuppressive therapy to optimal supportive therapy (strict blood pressure control, proteinuria treatment with RAS blockers, dietary and lifestyle measures), has no additional benefit. During the follow-up period, approximately half of all patients reached the primary combined endpoint (progressive loss of renal function >40%, dialysis requirement or mortality). However, immunosuppression increased the incidence of adverse effects, especially infections. The use of immunosuppressants in IgAN has since been increasingly questioned by experts and should only be applied to rapid-progressive courses. Long-term outcomes are generally unfavourable, so targeted therapy is still urgently needed in addition to optimization of supportive therapy.
It is now known that overactivity of the alternative complement signalling pathway of the immune system plays a role in the pathogenesis of IgAN, thereby increasing the chronic inflammation. Targeted inhibition of this signalling pathway is thus a logical therapeutic approach.
Iptacopan is an oral, highly selective inhibitor of complement factor B and the alternative complement signalling pathway, and has now been investigated in a randomized, doubleblind placebo-controlled Phase II clinical trial.
The analysis showed a statistically significant dose-response effect of iptacopan versus placebo, with a 23% decrease in proteinuria under 200 mg iptacopan versus placebo at 90 days. Renal function (eGFR) showed a trend to stabilization, and biomarkers also improved. Side effects were mild to moderate; there were no serious adverse effects.
