Navigating the paroxysmal nocturnal hemoglobinuria (PNH) landscape

Area of Science:

• Hematology
• Immunology
• Pharmacology

Background:

• Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder.
• PNH is characterized by complement-mediated hemolytic anemia, bone marrow failure, and thrombosis.
• Glycosylphosphatidylinositol-anchored complement regulatory proteins are reduced or absent due to PIGA mutations.

Purpose of the Study:

• To review the long-term efficacy and safety of complement inhibitors for PNH.
• To discuss the development and application of upstream complement inhibitors for PNH.
• To highlight the management of both intravascular and extravascular hemolysis in PNH.

Main Methods:

• Review of clinical trial data and real-world evidence for complement inhibitors in PNH.
• Analysis of treatment outcomes for terminal complement inhibitors (C5 inhibitors) and upstream complement inhibitors.
• Evaluation of safety and efficacy profiles of eculizumab, ravulizumab, crovalimab, pegcetacoplan, iptacopan, and danicopan.

Main Results:

• Terminal complement inhibitors (e.g., eculizumab, ravulizumab) effectively manage intravascular hemolysis and thrombosis.
• Approximately 30% of patients on C5 inhibitors experience residual extravascular hemolysis.
• Upstream complement inhibitors (e.g., pegcetacoplan, iptacopan) show efficacy in controlling both intravascular and extravascular hemolysis, improving hemoglobin levels and reducing transfusion needs.

Conclusions:

• Terminal complement inhibitors have transformed PNH management, improving survival and quality of life.
• Upstream complement inhibitors offer new therapeutic options for patients with residual hemolysis on C5 inhibitors.
• Combination therapies and further real-world data are needed to fully understand the long-term impact and safety of novel complement inhibitors in PNH.