Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study

Background C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway.We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.Methods APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression).Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries.Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <085 lower limit of the central laboratory normal range]) at screening, urine proteincreatinine ratio (UPCR) of 10 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 173 m or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae.All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no).During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily.The primary endpoint was relative reduction in proteinuria (measured by logtransformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months.The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis.This trial was registered with ClinicalTrials.gov(NCT04817618) and the adult cohort has been completed.Findings Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36).One participant in the placebo group discontinued treatment during the open-label period.The 24-h UPCR percentage change relative to baseline at 6 months was -302% (95% CI -428 to -148) in the iptacopan group and 76% (-119 to 313) in the placebo group.In the iptacopan group, the geometric mean of 24-h UPCR was 333 g/g (95% CI 279 to 397) at baseline and 217 g/g (162 to 291) at 6 months; in the placebo group, this was 258 g/g (218 to 305) at baseline and 280 g/g (237 to 330) at 6 months.The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 351% (138 to 511; p=00014).30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity.There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group.Interpretation Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months.Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy.