Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombotic events, and peripheral cytopenias secondary to bone marrow failure. Eculizumab, an intravenous anti-C5 monoclonal antibody, has served as the standard of care; however, its current dosing schedules have presented therapeutic limitations. Crovalimab, a novel subcutaneous humanized anti-C5 recycling monoclonal antibody, has demonstrated potential as an alternative. Direct comparative evidence on efficacy, safety, and patient-reported outcomes of these therapies remains limited. This systematic review and meta-analysis directly compares crovalimab and eculizumab in adults with PNH in C5 inhibitor naive individuals and in those transitioning from prior C5 inhibitor therapy. Methods: Databases such as PubMed, EMBASE, Scopus, Cochrane, CENTRAL, Google Scholar, and Web of Science were queried until July 2025 for relevant randomized controlled trials (RCTs). Two independent reviewers conducted the relevant selection of studies and corresponding data extraction. A total of 250 articles published after 2022 were screened, of which 9 RCTs were deemed eligible and subsequently included alongside 16 studies identified from a previously published meta-analysis. Primary outcomes included hemolysis control (LDH ≤1.5× ULN) and transfusion avoidance. Secondary outcomes evaluated included breakthrough hemolysis, haemoglobin stabilization, treatment-emergent adverse effects (TEAEs), and serious adverse events (SAEs). Patient-reported outcomes, such as assessment of fatigue using the FACIT-Fatigue scale, as well as noting treatment preferences, were also evaluated. Crucial safety outcomes were also included in this update, which were missing in the prior meta-analysis. The effect size for efficacy outcomes was estimated using pooled means with corresponding 95% confidence intervals (95% CIs). AE rates were pooled using the Freeman-Tukey transformation and reported as proportions with 95% CI. RevMan (version 5.3) was used to calculate the hazard ratio (HR), and a p-value of less than 0.05 was considered statistically significant. Results: Across all primary endpoints, crovalimab demonstrated non-inferior efficacy to eculizumab in C5-inhibitor naive individuals and previously treated adults with PNH. Lactate dehydrogenase (LDH) reduction from baseline was significant at both time points, with a pooled mean difference of –1501.12 U/L 95% CI: –1921.63 to –1080.60 at 26 weeks and –1517.62 U/L 95% CI: –1723.28 to –1311.95 beyond 26 weeks. With a pooled mean increase of 1.78g/ dL 95% CI: 1.09 to 2.47 at 26 weeks, hemoglobin levels improved. Similarly, patient-reported fatigue, assessed by FACIT-Fatigue scores, showed clinically meaningfulimprovements with pooled changes of 7.35 95% CI: 5.15 to 9.56 and 7.34 95% CI: 6.66 to 8.02 at 26 and 26 weeks, respectively. Transfusion avoidance was achieved in 82% 95% CI:65% to 98% of patients within 26 weeks and sustained beyond 26 weeks with a Freeman-Tukey pooled proportion of 2.35 95% CI: 2.16 to 2.53. AE incidence was 1.88 95% CI: 1.65 to 2.11 at 1-56 weeks and 2.11 95% CI: 1.64 to 2.57 at 1-24 weeks. SAEs occurred in 0.82 95% CI: 0.65 to 0.98 of patients at 1–24 weeks and 2.35 95% CI: 2.16 to 2.53 at 1–56 weeks. Heterogeneity varied across the majority of outcomes, but it did not substantially change the significance or direction of the results. The consistent efficacy and safety profile of crovalimab throughout treatment settings was supported by the lack of statistically significant differences between the naive and switch categories in transfusion avoidance (p = 0.40) among other key endpoints. Conclusion: Crovalimab offers comparable efficacy and safety to eculizumab in the treatment of PNH, both in C5-inhibitor–naive patients and those transitioning from prior therapy. With no rise in SAEs, crovalimab was linked to notable improvements in hemoglobin levels, fatigue scores, hemolysis control, and transfusion avoidance. Due to its subcutaneous mode of administration and long-lasting therapeutic benefit, crovalimab offers an adequate prospective alternative for conventional intravenous C5 inhibitors. These benefits could enhance treatment convenience, adherence, and patient-reported outcomes in the therapy of PNH.
Khan et al. (Mon,) studied this question.