Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and premature mortality. The complement C5 inhibitor (C5i) ravulizumab provides immediate, complete, and sustained inhibition of terminal complement activity through an 8-weekly weight-based dosing interval, resulting in control of IVH, reduced morbidity (thrombosis rate) and mortality (improved survival). Pivotal trials of ravulizumab have shown durable efficacy and safety (Kulasekararaj et al. Ann Hematol 2025). While real-world evidence supporting its use is accumulating, further data are needed to more comprehensively characterize its effectiveness and safety in routine clinical practice.Aims To evaluate the real-world effectiveness and safety of ravulizumab among US patients with PNH over 1 year, based on physician chart review data. Methods Medical chart data from 127 US patients with PNH who started ravulizumab between June 1, 2021 and May 31, 2023 were randomly selected and abstracted by 50 hematologists/oncologists from academic (n=25) or community (n=25) settings. Included patients were aged ≥18 years on the date of ravulizumab initiation (index), had ≥12 months of medical data pre- and post-index, and continued ravulizumab for ≥12 months, unless the patient died. Complement inhibitor (Ci)-experienced patients had previous eculizumab or pegcetacoplan use pre-index; Ci-naive patients had no previous use of any Ci pre-index. Outcomes included changes in lactate dehydrogenase (LDH), hemoglobin (Hb), and absolute reticulocyte count (ARC) up to 12 months post-index. Breakthrough IVH (BT-IVH) events (defined as LDH ≥2 × upper limit of normal ULN; 246 U/L and ≥1 of the following: anemia, dyspnea, hemoglobinuria, or fatigue) were assessed from index to earliest of death, loss to follow-up, ravulizumab discontinuation, or chart abstraction. Event rate was calculated per 10 person-years (PY).Results The sample included 69 Ci-naive (mean standard deviation; SD age: 51.4 14.1 years; 59.4% male) and 58 Ci-experienced patients (mean SD age: 45.0 14.7 years; 51.7% male; previous eculizumab: n=52; previous pegcetacoplan: n=6). In both respective cohorts, ravulizumab was associated with significant reductions in mean (SD) LDH level at month 12 (−348 424 U/L and −20 75 U/L; p0.001 and p0.05), with improvements observed from 1-month post-index. Similarly, mean (SD) Hb levels significantly increased over 12 months (2.2 1.8 g/dL and 1.3 1.5 g/dL, respectively; p0.001 for both), with improvements seen as early as 1-month post-index. Significant reductions in mean (SD) ARC were observed 1-month post-index and were maintained for up to 12 months in Ci-naive patients (−45 52 × 103/μL; p0.001). This effect was not observed in Ci-experienced patients (−7 85 × 103/μL; p=0.536). Over a median follow-up of 1.8 years (Ci-naive) and 1.6 years (Ci-experienced), 4 BT-IVH events occurred in 4 Ci-naive patients (5.8%; event rate: 0.30 per 10 PY), and 7 events occurred in 5 Ci-experienced patients (8.6%; event rate: 0.69 per 10 PY). All events were resolved without transfusion, dose modification, or discontinuation of ravulizumab, and no events resulted in thrombosis. Summary/Conclusion These real-world data from US adults with PNH showed that ravulizumab was associated with early and sustained significant and clinically meaningful improvements in hematological markers for PNH, in both Ci-naive patients and those with prior eculizumab or pegcetacoplan use. Ravulizumab treatment was associated with a low incidence of BT-IVH events, and all events were resolved without the need for transfusion, dose adjustment, or treatment discontinuation. Importantly, no thrombotic events occurred during these events. Despite the known differences in data collection between clinical trial and real-world populations, these findings align with an analysis of long-term clinical trial data from Kulasekararaj et al. (2025), which reported BT-IVH in 14.8% of C5i-naive (event rate: 1.0 per 10 PY) and 7.8% of eculizumab-experienced patients (event rate: 0.33 per 10 PY) with PNH over a follow-up period of up to 6 years (median: 3.9 and 2.7 years, respectively). Overall, this analysis supports the use of ravulizumab, with only 6–7 infusions per year, as an effective treatment for patients with PNH in the real-world setting.
Dingli et al. (Mon,) studied this question.