Iptacopan in IgA nephropathy
The most prevalent type of glomerulonephritis globally is IgA nephropathy. Its incidence varies geographically, being higher in East Asia than other world regions. Typically seen in young or middle-aged adults, it leads to progressive loss of kidney function in most people, particularly those with elevated urinary protein excretion.
Studies have supported the involvement of the alternative complement pathway in the pathogenesis of IgA nephropathy, but therapies for the underlying immune disorder have been limited. Iptacopan is an oral, first-in-class, highly potent proximal complement inhibitor. It specifically binds to factor B and inhibits the alternative pathway. A phase 2 trial has shown that iptacopan reduces proteinuria in a dose-dependent manner in people with IgA nephropathy.
The phase 3 APPLAUSE-IgAN trial is evaluating the effects of iptacopan on proteinuria and kidney function in people with IgA nephropathy. It has recently reported the results of its prespecified interim analysis.
This international, double-blind, placebo-controlled trial enrolled participants with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimised supportive care. They were randomised in a 1:1 ratio to receive 200 mg of iptacopan twice daily or placebo for 24 months, in addition to supportive therapy.
The main trial population, which was broadly representative of people with IgA nephropathy who are at risk of disease progression, included 222 people in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included 250 participants (125 in each group) from this population (mean age, 39 years; 47.6% women and 51.2% from Asia).
At 9 months, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% lower with iptacopan than placebo (95% CI, 26.0–48.6; P<0.001). This treatment effect was consistent across subgroups defined according to sex, geographic region (including Asia) and baseline 24-hour urinary protein-to-creatinine ratio.
The reduction in proteinuria was supported by the finding that the proportion of people who had a urinary protein-to-creatinine ratio of <1 at 9 months without receiving rescue or alternative medication or undergoing kidney replacement therapy was higher in the iptacopan group (42.5%; 95% CI, 34.5–50.5) than in the placebo group (21.9%; 95% CI, 14.8–29.0) (OR, 3.12; 95% CI, 1.68–5.79).
The incidence of adverse events was similar in the two groups. Most were mild to moderate in severity, and no increase in the risk of infection was observed.
The interim analysis suggests that iptacopan may represent a targeted treatment for people with IgA nephropathy. The blinded trial will continue in order to assess the safety and efficacy of iptacopan with respect to kidney function over 2 years.
The full article can be read here.
