Advancements in complement inhibition for PNH and primary complement–mediated thrombotic microangiopathy
Terminal C5 inhibitors (eculizumab, ravulizumab) remain the backbone for PNH and complement-mediated TMA/aHUS, but newer proximal inhibitors—pegcetacoplan (C3), iptacopan (factor B), and danicopan (factor D)—now address residual and extravascular hemolysis in patients who break through on C5 blockade.
Background
Paroxysmal nocturnal hemoglobinuria (PNH) and primary complement-mediated thrombotic microangiopathy (atypical hemolytic uremic syndrome, aHUS) are driven by dysregulation of the complement system, producing intravascular hemolysis, thrombosis, and other potentially lethal systemic complications. The 2007 introduction of the anti-C5 agent eculizumab transformed management of these disorders.
Key recommendations
C5 inhibition with eculizumab and ravulizumab is the established standard of care, yet a substantial proportion of PNH patients still experience clinically significant breakthrough extravascular hemolysis. For those patients, proximal-pathway agents now approved include the C3 inhibitor pegcetacoplan, the oral factor B inhibitor iptacopan, the oral factor D inhibitor danicopan, and the anti-C5 monoclonal crovalimab. For aHUS, only the terminal inhibitors eculizumab and ravulizumab are currently approved.
Clinical implications
An expanding therapeutic toolkit allows a more personalized, mechanism-based approach to complement-mediated disease, with proximal inhibitors offering better control of both intravascular and extravascular hemolysis and improved convenience through oral or subcutaneous dosing. The review emphasizes that long-term efficacy and safety data for the newer agents, and their role in aHUS, still need to be established.
Category
News
Source
Blood Advances
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