Real-world use of oral iptacopan monotherapy in paroxysmal nocturnal hemoglobinuria

Abstract

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by chronic complement-mediated hemolysis. Treatment involves complement inhibition (CI); C5 inhibitors (C5i) offer control over intravascular hemolysis (IVH) and thrombotic risk, but do not usually normalise hemoglobin levels, in part due to extravascular hemolysis (EVH). Iptacopan, a factor B inhibitor, is administered orally, 200mg twice daily. By blocking complement proximal to C3, iptacopan controls IVH without inducing C3-mediated EVH. Iptacopan received approval from health authorities in France and the UK in 2024. Real-world experience of iptacopan has been published on 20 patients. Here, we present the largest real-world data from PNH patients treated with iptacopan across the UK and France. Methods A retrospective study was conducted in patients with PNH treated with iptacopan in the UK and France between 12/07/2021 and 22/07/2025. Iptacopan was prescribed via clinical trial, a managed access programme, or as an approved therapy. CI-naïve patients prior to iptacopan (n=5) were excluded from analysis. Patient demographics, iptacopan start date and immediately preceding therapies were collected, as were hemoglobin (Hb), absolute reticulocyte count (ARC), and lactate dehydrogenase (LDH) prior to iptacopan (baseline) and at 3, 12, and 24 months, where available. Transfusion requirements for 6 months pre- and post- iptacopan initiation were noted. Outcomes included breakthrough hemolysis (BTH; new signs/symptoms of IVH with LDH ≥1.5x the upper limit of normal (ULN)), infections requiring antibiotics, thrombotic events, treatment discontinuation, and death. Paired cholesterol levels at baseline and ≥6 months were collected, where available, as was initiation of cholesterol-lowering therapy. Results 146 patients started iptacopan (87 [59.6%] female; median age 52), with a median treatment duration of 235 days [IQR 134.8-419.3]. Therapy received immediately prior to iptacopan included C5i (n=105), pegcetacoplan (n=27), dual proximal and terminal inhibition (n=7) and clinical trial (n=7). Baseline mean Hb was 10.4g/dL; mean LDH was 1.23x the ULN. Treatment duration reached ≥3, ≥12 and ≥24 months in 118, 45 and 11 patients, respectively. By 3 months, 56.8% (67/118) had a Hb rise ≥2g/dL, and 71.2% (84/118) had an Hb ≥12g/dL; rising to 68.9% and 73.3% respectively at 12 months. In those treated for ≥3 months, transfusion independence rose from 66.1% pre-iptacopan to 93.2% in the 6 months post. Mean ARC fell from 186 x109/L to 106 x109/L, and mean LDH fell to 1.09x ULN, at 3 months. 9 BTH events occurred in 9 patients (6.2%) over a median treatment duration of 236 days; 4 associated with infection, 1 followed missed doses, and 4 had no identifiable trigger. Mean Hb drop was 2.3g/dL; only 2 patients required red cell transfusion (1 and 2 units, respectively). Mean peak LDH rise was 5.22x ULN. 3 patients received additional doses of eculizumab, and 3 patients were permanently switched to alternative CI. Infections requiring antibiotics occurred in 21 patients (14.1%), most commonly respiratory source (9/21). 8 patients required hospitalization (urinary tract infection (n=2), chest infection (n=4), cellulitis (n=1) unknown (n=1)), 3 with BTH. There were no meningococcal infections. In 26 patients with paired cholesterol data, mean change in total cholesterol of +0.31 mmol/L and LDL cholesterol of +0.40 mmol/L were observed. 12 patients were already receiving lipid-lowering therapy at initiation (data available for 112/146 patients). Of 100 patients not on lipid-lowering therapy at baseline, 2 (2%) started during follow-up. 7 patients (4.7%) discontinued iptacopan after a median of 175 days (IQR 133.5-361.8). Reasons included an increased LDH suspected to be ongoing IVH (n=4), bone marrow transplant for aplastic anemia (n=1), palpitations (n=1) and patient preference (n=1). No thrombosis was observed. One patient died from unrelated metastatic cancer. Discussion This real-world data shows that oral iptacopan induces hematologic responses in PNH, with most patients achieving meaningful Hb rises and transfusion independence by 3 months. The rate of BTH in this follow-up period was comparable to that reported in clinical trials. Modest increases in total and LDL cholesterol were seen, with the mean degree of rise consistent with trial data. No thrombotic events occurred. These findings support the effectiveness of iptacopan in the treatment of PNH.