DerSarkissian, Maral

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; p<0.001 and p<0.05), 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; p<0.001 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; p<0.001). 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.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by uncontrolled terminal complement activation. Treatment with terminal complement inhibitors ravulizumab or eculizumab has led to improved clinical outcomes for patients with PNH. Evidence on real-world treatment patterns and healthcare resource utilization (HRU) in this patient population, which includes emerging data on pegcetacoplan, is limited. Objective To describe real-world drug adherence and persistence in patients with PNH receiving ravulizumab, eculizumab or pegcetacoplan, and compare HRU for patients pre- and post-ravulizumab initiation in the USA. Methods ADVANTAGE is a retrospective, longitudinal analysis using the Komodo Health Research Database, a large multi-payer US health insurance claims dataset, among patients with PNH and ≥ 1 claim for ravulizumab, eculizumab or pegcetacoplan. Patients aged ≥ 18 years at index date (defined as the date of first claim for a given complement inhibitor on/after 1 January, 2019), with ≥ 12 months enrollment prior to this date, ≥ 1 claim with an ICD-10-CM code indicating PNH prior to/at index date and no ICD-10-CM code suggesting an alternative indication, were included. Patients were followed until the end of continuous enrollment, death, or end of data availability. Adherence was assessed by proportion of days covered (PDC) and treatment duration was estimated using Kaplan-Meier analysis. The HRU analysis included patients with ≥ 12 months follow-up and compared rates of HRU per-patient per-year (PPPY) in the 12 months pre- and post-ravulizumab treatment initiation. Pre-post differences in HRU were estimated using generalized estimating equations with robust standard errors. Results The sample included 344, 342 and 97 patients with index treatments for ravulizumab, eculizumab or pegcetacoplan, respectively. Age and sex distribution of patients were similar among patients treated with ravulizumab (mean age: 44 years; 57% female), eculizumab (mean age: 44 years; 60% female), or pegcetacoplan (mean age: 45 years; 62% female). More patients in the ravulizumab cohort were complement inhibitor-naive (31%) compared with eculizumab (20%) or pegcetacoplan (24%). Mean (standard deviation [SD]) duration of follow-up was 25.3 (15.9), 33.5 (18.9) and 13 (8.0) months, and mean (SD) proportion of days covered (PDC) was 0.98 (0.05), 0.90 (0.14) and 0.77 (0.30) for the ravulizumab, eculizumab and pegcetacoplan cohorts, respectively. The percentage of patients with PDC ≥ 0.8 (a widely used threshold for treatment adherence) was 98.5% for ravulizumab, and 84.5% and 78.4% for eculizumab and pegcetacoplan, respectively. The median (interquartile range [IQR]) duration on ravulizumab treatment was 48.4 (11.5, not reached [NR]) months, compared with 7.6 (3.4, 23.3) for eculizumab and 14.6 (0.2, NR) for pegcetacoplan. Among patients with ≥ 12 months on ravulizumab treatment (n = 183), a 24.8% reduction in all-cause HRU was observed during the first 12 months of treatment compared with the prior 12 months. Statistically significant reductions were observed in mean (SD) all-cause hospitalizations (0.2 [0.6] PPPY during follow-up; % difference -44.6%, p = 0.014), outpatient visits (24.3 [17.8] PPPY; % difference -19.1%, p < 0.001) and emergency room visits (0.5 [1.3] PPPY; % difference -39.8%, p = 0.008). Similar results were observed for PNH-related HRU, including a 32.1% reduction in the overall number of visits (p < 0.001). Notably, a statistically significant reduction in PNH-related hospitalizations (0.2 [0.5] PPPY; % difference -37.8%, p = 0.044) and outpatient visits (14.3 [10.7] PPPY; % difference -22.4%, p < 0.001) was observed. Ravulizumab initiation was also associated with fewer PNH-related emergency room visits (0.2 [0.7] PPPY; % difference -32.7%, p = 0.170) and blood transfusions (0.8 [2.9] PPPY; % difference -30.7%, p = 0.277); however, these changes were not statistically significant. Conclusions In this retrospective analysis, patients demonstrated higher adherence and persistence to ravulizumab treatment compared to other complement inhibitors. HRU decreased following ravulizumab initiation, indicating an alleviated burden of disease in these patients after treatment initiation. These real-world data provide further evidence of the benefit of ravulizumab in patients with PNH.