Comparative Efficacy of Complement Inhibitors in Complement Inhibitor–Naïve PNH: A Systematic Review With Supportive Exploratory Network Meta‐Analysis of Randomized Trials

ABSTRACT Introduction Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, life‐threatening disease, caused by intravascular haemolysis by the complement system. In this review, we aim to compare the efficacy of the available agents across patient‐centred outcomes in complement inhibitor‐naive patients. Methods Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane CENTRAL and ClinicalTrials.gov for studies published up to 30th May 2025. A frequentist model network meta‐analyses were conducted in RStudio (v5.4.1) using a common‐effects model. Results A total of four randomized controlled trials evaluating four complement inhibitor agents (ravulizumab, crovalimab, eculizumab and pegcetacoplan) were included in this systematic review and network meta‐analysis, involving 589 complement inhibitor–naïve adults with PNH. Across outcomes, all active treatments demonstrated benefit compared with placebo or supportive care. In the exploratory network meta‐analysis of transfusion avoidance, no consistent statistically significant differences were observed between active treatments, although ravulizumab showed higher odds compared with crovalimab (OR = 2.69, 95% CI: 1.13–6.41; p = 0.0256). For change in FACIT‐Fatigue score, all active treatments improved fatigue versus placebo, with some statistically significant differences observed between agents; however, these comparisons were based on indirect evidence from a sparse network. Conclusion This study suggests that available complement inhibitors improve key outcomes versus placebo/supportive care in complement inhibitors naive PNH. However, the evidence network is sparse (four trials) and the cross‐trial differences limit reliable inference regarding relative efficacy between active agents. Comparative findings should be interpreted as hypothesis‐generating.