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Lookup NU author(s): Professor David KavanaghORCiD, Dr Edwin Wong
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: C3 glomerulopathy (C3G) is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway (AP). Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B to selectively inhibit the AP of the complement cascade. Methods: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study (across 35 sites [hospitals, medical centers, clinical practices, clinical research sites] in 18 countries [Europe, Asia, North America and South America]) evaluated the efficacy, safety, and tolerability of iptacopan compared to placebo on top of supportive care (renin-angiotensin-aldosterone system inhibitors [RAASi]) and immunosuppression in adult patients with biopsy-confirmed C3G. The study required mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae. The study comprised 6-month (M) randomized double-blinded treatment with iptacopan 200mg twice-daily vs. placebo followed by 6M open-label iptacopan treatment. The primary objective was to demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria (measured by log-transformed ratio to baseline in urine protein-creatinine ratio [UPCR] sampled from a 24h urine collection) at 6M. ClinicalTrials.gov, NCT04817618. Findings: Between July 28, 2021 and February 15, 2023, 132 participants were screened; 74 (56%) were randomized 1:1 (iptacopan [n=38]:placebo [n=36]). The study met its primary endpoint, demonstrating a statistically significant relative reduction in 24hUPCR with iptacopan at 6M (35·1%, 1-sided p=0·0014, 95% CI: 13·8%, 51·1%) vs. placebo. During 12M of treatment, the majority of treatment emergent adverse events (TEAEs) were mild to moderate in severity. There were no deaths, no treatment discontinuations due to TEAEs, and no meningococcal infections. Serious adverse events were reported in 3 (7·9%) and 1 (2·8%) participants in the iptacopan and placebo arms, respectively. Interpretation: Iptacopan demonstrated a statistically significant, clinically meaningful proteinuria reduction on top of RAASi and immunosuppression at 6M. Iptacopan was well-tolerated with a favorable safety profile in patients with C3G.
Author(s): Kavanagh D, Bomback AS, Vivarelli M, Nester CM, Remuzzi G, Zhao MH, Wong EKS, Wang Y, Krishnan I, Schuhmann I, Trapani AJ, Webb NJA, Meier M, Israni RK, Smith RJH
Publication type: Article
Publication status: Published
Journal: The Lancet
Year: 2025
Volume: 406
Issue: 10512
Online publication date: 26/09/2025
Acceptance date: 26/09/2025
Date deposited: 03/10/2025
ISSN (print): 0140-6736
ISSN (electronic): 1474-547X
Publisher: The Lancet Publishing Group
URL: https://doi.org/10.1016/S0140-6736(25)01148-1
DOI: 10.1016/S0140-6736(25)01148-1
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