Second-Generation C5 Inhibitors for Paroxysmal Nocturnal Hemoglobinuria.

The C5 targeting monoclonal antibody eculizumab has changed the natural history of paroxysmal nocturnal hemoglobinuria (PNH) in the last 10 years. However, some unmet clinical needs persist, including persistent anemia with some patients requiring transfusions, incomplete C5 inhibition with breakthrough hemolysis (because of pharmacokinetic or pharmacodynamic issues such as infections, as well as conditions increasing complement activity), the underlying bone marrow failure, and the significant burden on patient quality of life (intravenous route of administration and frequency of infusions). Moreover, a subclass of patients carries C5 polymorphisms resistant to eculizumab inhibition. Several second-generation C5 inhibitors are under active study to overcome unmet clinical needs with eculizumab. Current strategies encompass increasing drug half-life, developing small molecule inhibitors of C5, and exploring new routes of administration (including subcutaneous and oral agents). In this review, we summarize available data on second-generation C5 inhibitors in PNH, including novel monoclonal antibodies, a small interfering RNA, and small molecules.