Iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria.

Introduction: Standard-of-care first-line treatments for paroxysmal nocturnal hemoglobinuria (PNH) include the anti-C5 therapies eculizumab and ravulizumab. However, persistent anemia, likely due to extravascular hemolysis, and reduced quality of life (QoL) due to frequent infusions remain concerns. Iptacopan is a first-in-class oral proximal complement inhibitor that targets factor B in the alternative pathway (upstream of C5), limiting intravascular and extravascular hemolysis.

Areas covered: In patients previously treated with anti-C5 therapies or naive to complement inhibitors, iptacopan 200 mg twice daily resulted in clinically meaningful results in the pivotal phase 3 APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) trials. Treatment with iptacopan was safe, and no treatment-related adverse events led to discontinuation.

Expert opinion: APPLY-PNH and APPOINT-PNH reported clinically meaningful improvements in hemoglobin, bilirubin, and lactate dehydrogenase levels; transfusion avoidance; reticulocyte count; and fatigue. Iptacopan's safety profile was comparable to other complement inhibitors. Oral iptacopan therapy allows patients to avoid infusions, limit clinical visits, decrease medical costs, improve anemia that persists with other complement inhibitors, and improve QoL. Long-term follow-up will further assess infections, thrombosis, and breakthrough hemolysis. Before treatment, physicians need to discuss current therapeutic options with patients for shared decision-making. Guidelines are being created to assist healthcare professionals in this advancing field.