[Challenges in optimizing targeted complement inhibitor therapy for paroxysmal nocturnal hemoglobinuria in an expanding treatment landscape].

Abstract

The advent of the C5 inhibitor eculizumab marked a paradigm shift in the management of PNH, transforming it from "a rare disease with a poor prognosis" to "a manageable disease". However, emerging challenges such as primary nonresponse due to C5 gene polymorphisms and residual extravascular hemolysis have prompted the development of new therapeutic agents. Three C5 inhibitors and three proximal complement inhibitors are now available. For complement inhibitor-naïve patients with PNH, C5 inhibitors are the first-line therapy. Selection of eculizumab, ravulizumab, or crovalimab should be based on factors such as dosing frequency, route of administration, C5 gene polymorphisms, and pregnancy status. When C5 inhibitor therapy does not yield sufficient improvement in anemia or quality of life, second-line treatment with proximal complement inhibitors should be considered. Selection of pegcetacoplan, danicopan, or iptacopan should be guided by the underlying pathology of anemia, lifestyle factors, and treatment adherence. This article provides an overview of the pharmacological mechanisms, efficacy, safety, and clinical applications of each drug, along with the future outlook, based on the latest findings.