Overview of treatment advances with complement inhibitors in patients with paroxysmal nocturnal hemoglobinuria

Abstract

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder that leads to lifelong risk for thrombosis, bone marrow failure, and complement-mediated hemolysis. Before complement inhibitor therapy, patients diagnosed with PNH had a life expectancy of 10–15 years. Terminal complement inhibitors that block C5 such as eculizumab and ravulizumab revolutionized PNH care by controlling intravascular hemolysis (IVH), leading to normal life expectancy. However, about 30% of patients receiving C5 inhibitors remain anemic, require transfusions due to ongoing C3-dependent extravascular hemolysis (EVH), and have reduced quality of life with on-going disease symptoms. The success of terminal C5 inhibitors emboldened researchers to investigate proximal complement inhibitors that have the potential to control both IVH and EVH, such as pegcetacoplan (C3/C3b inhibitor) and iptacopan (factor B inhibitor), as well as danicopan (factor D inhibitor) used as an add-on to C5 inhibitors. We reviewed the latest published evidence on treatment with proximal complement inhibitors in patients with PNH and hemoglobin (Hb) ≥10 g/dL while receiving terminal complement inhibitors. Methods: This narrative review summarizes findings from the most recent studies of proximal complement inhibitors in patients with PNH who were previously treated with C5 inhibitors and had Hb ≥10 g/dL. Endpoints of interest included Hb level, Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) scores, transfusion independence, and safety to assess residual clinical burden and associated risk. Results: Two recent studies in C5 inhibitor-experienced patients with residual anemia (Hb ≥10 g/dL) were identified: the open-label, phase 3 APPULSE-PNH trial (NCT05630001) of 52 patients (mean age 46 years) previously treated (mean duration of 3.5 years) with ravulizumab (88.5%) or eculizumab (11.5%) who received iptacopan for 24 weeks;[Kulasekararaj A, et al. European Hematology Association Congress; 12–15 June 2025; Milan, Italy] and a PEGASUS (NCT03500549) post hoc analysis of 11 patients (mean age 40 years) who had Hb ≥10 g/dL after receiving eculizumab for ≥3 months and were treated with pegcetacoplan for 16 weeks.[Panse J, et al. PLoS ONE. 2024;19(7):e0306407] Mean Hb levels increased by 2.0 g/dL (from baseline [BL] mean 11.9 g/dl) and 2.6 g/dL (from BL mean 10.2 g/dL) in each study, respectively. Mean FACIT-Fatigue score improved by 4.3 points (from 38.9 to 43.1) in APPULSE-PNH and by 14.3 points (from 28.4 to 42.7) in PEGASUS post hoc; both improvements are considered clinically significant (≥3–5 points) and reached levels that were close to healthy population norm (~43.5). All patients on iptacopan for 24 weeks and 9 of 11 patients on pegcetacoplan for 16 weeks maintained transfusion avoidance. Adverse events of interest included 3 cases of infections likely caused by encapsulated bacteria (1 bacterial pneumonia, 2 otitis media) and no breakthrough hemolysis in APPULSE-PNH; no encapsulated bacteria infections and 1 event of breakthrough hemolysis (deemed not related to pegcetacoplan) occurred in PEGASUS post hoc. No study of danicopan in patients with Hb ≥10 g/dL after C5 inhibition was identified. In the most recent analysis of the phase 3 ALPHA trial (NCT04469465), 57 patients (mean age 53 years) with PNH and residual clinically significant EVH (Hb ≤9.5 g/dL with ARC ≥120 × 109/L) while receiving ravulizumab (63%) or eculizumab (37%) for a mean of 5 years were given danicopan in addition to their current C5 inhibitor for 12 weeks.[Kulasekararaj A, et al. Blood. 2025;145(8):811] Changes in least square means were +2.8 g/dL for Hb levels (BL mean, 7.7 g/dL), and 8.1 for FACIT-Fatigue scores (BL mean, 34.0); 78.9% patients were transfusion free; no meningococcal infections were reported. Conclusions: Across clinical studies that included patients with PNH and Hb ≥10 g/dL after C5 inhibition, proximal complement inhibitors improved measures of residual anemia and quality of life to clinically significant degrees (increases of ≥2 g/dL in Hb levels and ≥3–5 points in FACIT-Fatigue scores). Transfusion requirements were greatly improved but not fully eliminated. Breakthrough hemolysis events and encapsulated bacterial infections (very few reported yet with proximal complement inhibitors) remain a risk. Overall, proximal complement inhibitors represent advances in therapy for patients with PNH.