Oral Iptacopan Monotherapy: A New Frontier for Paroxysmal Nocturnal Hemoglobinuria

For paroxysmal nocturnal hemoglobinuria (PNH), the current standard of care (SOC) is intravenous treatment with monoclonal antibodies (eculizumab and ravulizumab) that block complement pathways through C5 inhibition. However, roughly 40% of patients continue to have chronic extravascular hemolysis due to ongoing activation of proximal complement pathways with C3 fragments. Iptacopan, an oral agent, inhibits factor B in the alternative complement pathway proximal to C5 generation, preventing C3-mediated hemolysis.

Two industry-sponsored, multicenter, phase 3 clinical trials evaluated the efficacy and safety of oral iptacopan (200 mg twice daily for 24 weeks) in adults with PNH. In the randomized, controlled APPLY-PNH trial, 97 patients who were treated with anti-C5 therapy but continued to have chronic hemolysis (hemoglobin <10 g/dL) were assigned 2:1 to iptacopan or to continue standard of care (SOC). The single-arm APPOINT-PNH trial enrolled 40 patients with hemolysis (lactate dehydrogenase [LDH] >1.5×ULN) who had not previously received SOC. The primary endpoint for both studies was an increase in hemoglobin by ≥2 g/dL from baseline without red blood cell transfusion. For the APPLY-PNH trial, achievement of hemoglobin level of ≥12 g/dL, without red blood cell transfusion, was a coprimary endpoint.

In the APPLY-PNH trial, estimated percentages for the first primary endpoint (82% vs. 2%; P<0.001) as well as the second primary endpoint (69% vs. 2% P<0.001) showed superiority of iptacopan over anti-C5 therapy. Secondary outcomes of fatigue, LDH level, bilirubin, and reticulocyte count improved significantly in the iptacopan group compared with the SOC arm. Headache occurred more frequently with iptacopan (16% vs. 3%). Serious infections with capsulated organisms occurred in one patient in each arm, and one transient ischemic attack was reported in the intervention arm.

In the APPOINT-PNH trial, 69% of patients reached the primary endpoint.