A new study has further confirmed the benefits of ravulizumab over eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH), but also found that progressive C3d binding to PNH red cells and the subsequent onset of extravascular hemolysis could still occur.

The study, published in the British Journal of Haematology, suggests that the prevention of hemolysis might require proximal complement inhibitors alone or with an anti-C5 molecule.

“Ravulizumab is expected to have a positive impact on the life of PNH patients because it alleviates the burden of treatment and, possibly, it may reduce the risk of pharmacokinetic breakthrough hemolysis,” the authors wrote. “Nevertheless, these in vitro and in vivo observations confirm that C3d binding to PNH red cells is a phenomenon inherently associated with the inhibition of C5 and, likely, with the inactivation of any other component of the terminal complement pathway.”

The research team highlighted the significant benefits and safety of ravulizumab, an anti-C5 monoclonal antibody, over eculizumab in terms of more consistent control of free C5 levels and much less frequent dosing requirements (6.5 doses per year with ravulizumab vs 26 doses per year with eculizumab), which may reduce the risk of breakthrough hemolysis and improve quality of life.

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However, when comparing the effects of the 2 inhibitors on C3d binding in red blood cell samples from patients with PNH, they found that a similar proportion of PNH red cells became C3d bound regardless of which inhibitor was used. This progressive binding can eventually lead to the onset of C3-mediated extravascular hemolysis.

Furthermore, they observed that switching from eculizumab to ravulizumab did not significantly alter the percentage of C3d binding.

The authors suggest that this phenomenon is inseparable from anti-C5 therapy and might only be preventable with the use of additional complement inhibitors in conjunction with an anti-C5 inhibitor.


Sica M, Barone F, Nannelli C, et al. The long-acting anti-C5 ravulizumab results in C3 binding to PNH red cells similar to its parental molecule eculizumab. Br J Haematol. Published online January 19, 2023. doi:10.1111/bjh.18662