APPEAR-C3G: Iptacopan Shows Proteinuria Reduction, eGFR Benefits in C3G

Data from the phase 3 APPEAR-C3G trial of iptacopan (Fabhalta) in patients with biopsy-confirmed C3 glomerulopathy (C3G) are providing further support for the oral alternative complement pathway inhibitor’s use in the ultra-rare, progressive kidney disease following its March 2025 US Food and Drug Administration approval for this indication.1

Findings were published in The Lancet and showed a statistically significant and clinically meaningful proteinuria reduction at 6 months, along with stabilization of estimated glomerular filtration rate (eGFR) and reduction in C3 deposits, following treatment with iptacopan, which showed a rapid onset of action and sustained efficacy through 12 months.1

“Current guideline recommendations for C3 glomerulopathy rely on supportive treatments—eg, blockade of the renin–angiotensin–aldosterone system with angiotensin-converting enzyme inhibitors or AT1-receptor blockers, with or without mycophenolic mofetil or corticosteroids,” David Kavanagh, MBChB, PhD, professor of complement therapeutics at the National Renal Complement Therapeutics Centre, and colleagues wrote.1 “However, evidence related to these supportive treatments is limited to small, retrospective observational studies and such treatments often come with considerable side-effects. Therefore, a concerted effort is required to develop a novel, targeted therapy for C3 glomerulopathy, to address the high unmet medical need for patients with this condition.”

Iptacopan’s initial FDA approval came in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria and was followed by an August 2024 accelerated approval for proteinuria reduction in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression. The agent later received approval for the treatment of C3G on March 20, 2025, based on data from APPEAR-C3G, making it the first FDA-approved agent for the ultra-rare kidney disease.2

A multicenter, randomized, double-blind, placebo-controlled, phase 3 study, APPEAR-C3G assessed the efficacy and safety of iptacopan versus placebo, both in addition to supportive care and immunosuppression. It enrolled adult participants 18–60 years of age with biopsy-confirmed C3 glomerulopathy from 35 hospitals or medical centers in 18 countries. For inclusion, patients were required to have reduced serum C3 concentration <77 mg/dL, defined as <0.85 × lower limit of the central laboratory normal range, at screening, urine protein–creatinine ratio (UPCR) of ≥ 1.0 g/g at day –75 and day –15 before randomization, eGFR of ≥ 30 mL/min per 1.73 m2 at screening and day –15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae.1

All eligible participants were randomly assigned in a 1:1 ratio via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both. In the iptacopan group, participants took 200 mg iptacopan orally twice daily for 6 months followed by open-label iptacopan at 200 mg twice daily for an additional 6 months. In the placebo group, participants took placebo orally twice daily for 6 months followed by open-label iptacopan 200 mg twice daily orally for an additional 6 months.1

The primary endpoint was relative reduction in proteinuria measured by log-transformed ratio to baseline in UPCR sampled from a 24-h urine collection at 6 months.1

Between July 2021, and February 2023, 132 participants were screened, of whom 74 (64% male; 69% White) were randomized to receive either iptacopan (n = 38) or placebo (n = 36). Investigators noted one participant in the placebo group discontinued treatment during the open-label period.1

Results showed the 24-h UPCR percentage change relative to baseline at 6 months was –30.2% (95% CI, –42.8 to –14.8) in the iptacopan group and 7.6% (95% CI, –11.9 to 31.3) in the placebo group. In the iptacopan group, the geometric mean of 24-h UPCR was 3.33 g/g (95% CI, 2.79 to 3.97) at baseline and 2.17 g/g (95% CI, 1.62 to 2.91) at 6 months, whereas in the placebo group, this was 2.58 g/g (95% CI, 2.18 to 3.05) at baseline and 2.80 g/g (95% CI, 2.37 to 3.30) at 6 months.1

Investigators noted the primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 35.1% (95% CI, 13.8 to 51.1; P = .0014).1

Regarding safety, 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, with most being mild or moderate severity. Of note, there were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.1

Serious adverse events were reported in 3 (8%) participants in the iptacopan group and 1 (3%) participant in the placebo group.1

“The positive results presented here provide evidence that iptacopan targets the underlying cause of C3 glomerulopathy and has the potential to alter the course of this progressive disease and improve patient outcomes,” investigators concluded.1

References

1. Kavanagh D, Bomback AS, Vivarelli M, et al. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study. The Lancet. doi:10.1016/S0140-6736(25)01148-1

2. Campbell P. FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy. HCPLive. March 20, 2025. Accessed October 15, 2025. https://www.hcplive.com/view/fda-approves-oral-iptacopan-fabhalta-as-first-c3-glomerulopathy-therapy