Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and chronic disease originated from somatic mutation of phosphatidylinositol glycan-class A (PIG-A) gene in hematopoietic stem cells (HSCs). The subsequent loss of CD55 and CD59 in PIG-A-mutated red blood cells (RBCs)leads to ineffective complement inhibition and sensitization to intravascular hemolysis (IVH).Additionally, hemoglobin released during hemolysis in PNH results in depleted nitric oxide (NO)levels at the tissue level, leading to an increased risk of thrombosis, amongst other symptoms. Patients’ continual hemolysis, renal complications and increased risk of thrombosis pose significant impact on morbidity and mortality.

The availability of C5 inhibitors (C5i) ushered in a new era of complement treatment that demonstrated effective disease control and improvements in patients’ quality of life. However, while inhibiting C5 abolishes IVH, the upstream C3 is left unchecked, leading to C3 deposition on RBCs and onset of EVH. As such, a substantial proportion of patients undergoing C5i treatment still experience fatigue, residual anemia and even require RBC transfusions. 

To this end, multiple new agents are being developed to improve patient outcomes. These include C5 inhibitor crovalimab, C3 inhibitor pegcetacoplan, and factor B inhibitor iptacopan, amongst others. Approved recently by FDA, iptacopan is a novel, first-in-class, oral complement factor B inhibitor for the treatment of PNH. Factor B is upstream of C3 and C5 in the alternative complement pathway, and thus targeting factor B has the potential of inhibiting or preventing both IVH and EVH. Phase III clinical trial data of iptacopan in both treatment-naive and C5 inhibitor-exposed patient populations have shown highly promising data in terms of anemia control, transfusion avoidance, and quality of life improvements, with a balanced tolerabilityprofile. 

This lecture will focus on the unmet medical needs surrounding PNH, highlight the impact and significance of novel agents in the treatment of PNH, and discuss relevant clinical cases.