Molecular pharmacology in complement‐mediated hemolytic disorders

Abstract In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement‐targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement‐mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long‐acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti‐C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first‐line. However, recently FDA and EMA approved the anti‐C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti‐C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.