Introduction: Eculizumab, a terminal complement C5 inhibitor, has significantly changed the treatment paradigm for paroxysmal nocturnal hemoglobinuria (PNH)—a rare hematologic disorder driven by uncontrolled intravascular hemolysis and thrombosis. Although widely used, a consolidated summary of randomized data comparing eculizumab to standard or alternative therapies has not been previously reported.

Objectives: To evaluate the clinical efficacy and safety of eculizumab compared to control therapies in adult patients with PNH using pooled data from randomized controlled trials (RCTs).

Methods: A systematic literature review was conducted in PubMed, Embase, Scopus, and Web of Science through May 2025. Six RCTs comparing eculizumab to placebo, supportive care, or other complement inhibitors were included. Primary outcomes were breakthrough hemolysis (BTH), hemoglobin and LDH normalization, and transfusion avoidance. Secondary outcomes included adverse events (AEs), serious AEs (SAEs), treatment-emergent AEs (TEAEs), discontinuation due to AEs, and mortality. A random-effects model was used to estimate pooled risk ratios (RRs) with 95% confidence intervals (CIs). A total of 1,060 patients were included (491 eculizumab; 569 control).

Results: Across trials, eculizumab did not significantly reduce breakthrough hemolysis (RR 1.17; 95% CI: 0.64–2.13), and the risk of hemoglobin normalization was comparable between groups (RR 0.95; 95% CI: 0.85–1.05). Similarly, LDH normalization (RR 0.99; 95% CI: 0.90–1.09) and transfusion avoidance (RR 0.85; 95% CI: 0.66–1.11) did not show a statistically significant advantage for eculizumab.

In terms of safety, rates of any AE (RR 0.98; 95% CI: 0.75–1.29), SAEs (RR 0.79; 95% CI: 0.53–1.17), drug withdrawal due to AEs (RR 0.96; 95% CI: 0.28–3.27), and mortality (RR 1.28; 95% CI: 0.34–4.83) were similar across groups. TEAE data showed high heterogeneity (I² = 89%), and the pooled estimate (RR 0.49; 95% CI: 0.01–18.75) was inconclusive.

Discussion:This meta-analysis of six randomized trials found no statistically significant differences in key clinical or safety endpoints between eculizumab and control therapies. While previous observational studies and registries have shown clear benefits, these RCT data suggest a more nuanced picture. Variability across trials, modest sample sizes, and evolving comparator arms (including newer complement agents) may have influenced outcomes. Nevertheless, eculizumab remains a well-tolerated option with established real-world efficacy, and these findings provide a critical benchmark for evaluating emerging treatments in PNH.

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2025
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