Biotechnological products for the treatment of complement system disorders including paroxysmal nocturnal hemoglobinuria: currently available and in development

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutations in phosphatidylinositol glycan, class A gene (PIG-A) in hematopoietic stem cells which manifests as haemolytic anemia, bone marrow failure, thromboses, impaired renal function, and other severe clinical symptoms. The management of PNH is a clinical challenge requiring a comprehensive approach. Over the past decade, target therapy with eculizumab, an antibody inhibitor of terminal complement activation, has played a key role in the treatment of PNH. Eculizumab is the first humanized anti-C5 monoclonal antibody that was proven effective in inhibiting the complement system and was approved as a standard treatment for PNH in many countries. Elizaria, the first biosimilar version of eculizumab, whose similarity to the original drug in terms of efficacy and safety was demonstrated in clinical trials, has been widely used in Russia since 2019. New complement inhibitors classified by their mechanism of action into inhibitors targeting complement component C5 (the terminal pathway) and those targeting early phases of complement activation cascade (the proximal pathway) are currently in development. These new drugs include monoclonal antibodies, small molecules, small peptide inhibitors, small interfering RNA, and recombinant proteins based on endogenous regulators of complement activation.