Disease Activity After Switching From Eculizumab to Ravulizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria: Real World Data From Denmark and Finland.

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disorder characterized by acquired PIGA mutations making red blood cells (RBCs) susceptible to complement‐mediated hemolysis and activating white blood cells and platelets, leading to thrombosis, organ damage, and premature mortality [ 1 ]. PNH frequently coexists with bone marrow failure syndromes such as aplastic anemia, but classical PNH presents with preserved bone marrow function. In PNH‐associated hemolysis, RBCs are lysed by membrane attack complexes (MACs) generated by uncontrolled activation of the terminal complement [ 1 ]. Untreated PNH has a poor prognosis, with a median survival of 10 years [ 2 ]. In 2007, the approval of the first C5 inhibitor revolutionized PNH treatment. Today, lifelong complement inhibition, primarily targeting C5, effectively manages the disease. Eculizumab, the first monoclonal antibody, improved overall and transfusion‐free survival [ 3 , 4 ]. Ravulizumab, a long‐acting C5 inhibitor, later emerged as non‐inferior to eculizumab in both C5 inhibitor‐naïve [ 5 ] and exposed patients [ 6 ]. Patients switching to ravulizumab reported improved quality of life (QoL) due to reduced dosing frequency [ 7 , 8 ]. Both the 301 (C5 inhibitor‐naïve) and 302 (C5‐inhibitor exposed) studies confirmed its non‐inferiority in transfusion avoidance, LDH levels and breakthrough hemolysis (BTH) episodes [ 5 , 6 ]. A recent follow‐up among the 301 and 302 study participants showed that long‐term ravulizumab treatment provides excellent disease management and survival [ 9 ].

Ravulizumab was made generally available to treat Danish patients with PNH in routine care from December 2022, and almost all patients switched during the following year. Similarly, in Finland, ravulizumab was made available in February 2020, and likewise, the majority of patients were switched within the next year. Real‐world data on clinical parameters after switching C5 inhibitor treatment to ravulizumab are lacking.

In this study, we describe parameters from individual patients with PNH who switched from eculizumab to ravulizumab treatment using real‐world data. Based on our clinical experience and the published data, we additionally hypothesized that a standard dose of ravulizumab provides equal or a better clinical outcome than high‐dose eculizumab.

Methods

Data was collected prospectively, including patients receiving eculizumab from four Danish hospitals: Odense University Hospital, Rigshospitalet, Aalborg University Hospital and Aarhus University Hospital, and one Finnish hospital—Helsinki University Hospital.

Inclusion criteria were (1) Patients diagnosed with classical PNH, or PNH in combination with aplastic anaemia (AA‐PNH), or myelodysplastic syndrome (MDS‐PNH), (2) treated in routine care for at least 6 months with eculizumab and at least 3 months with ravulizumab and, (3) no history of allogeneic hematopoietic stem cell transplantation.

Both eculizumab and ravulizumab were dosed at the discretion of treating physicians, mostly according to the approved label. Eculizumab was generally provided a 900 mg dose every two weeks; however, some patients received higher doses prior to the switch, and one patient received reduced doses on both treatments.

Ravulizumab was dosed every eighth week according to weight. Patients weighing 30–59.9 kg, 60–99.9 kg, and above 100 kg received 3000, 3300, and 3600 mg, respectively, as the labeled standard dosage. To describe the individual patient's disease activity before and after the change of treatment, routine blood test results were collected 3 months prior to switching, while patients were on eculizumab, and compared with the results during the first 3 months after switching to ravulizumab. Based on these results, the mean LDH and reticulocytes levels before and after switching were calculated. In addition, the need for blood transfusions as well as BTH episodes was monitored for 12 months both before and after switching. BTH signs monitored included hemoglobinuria, fatigue, abdominal pain, dyspnea, or hemoglobin drop <6.3 g/dL.

Patients gave consent after oral and written information on sharing their routine health data from medical files, and the study was registered at Odense University Hospital under the Personal Data Act Umbrella (#20/50561) and in the Helsinki University Hospital under the Hospital study permit (#HUS/3137/2023). Data analysis was conducted using STATA BE 18.5.

Results

A total of 14 patients from Denmark and 6 patients from Finland fulfilled the inclusion criteria, and all gave consent and were included. This group was comprised of 70% with classical PNH and 30% with combined PNH and aplastic anemia or other bone marrow failure syndromes (Table 1 ). Despite a young age at diagnosis, concurrent diagnoses, mostly cardiovascular disorders, were frequent (Table 1 ). The median time on eculizumab treatment was 4.6 years prior to the switch to ravulizumab.

Patient data are presented in Figure 1 and numerically in the supplementary table. Patients were treated with the standard intervals of 2 or 8 weeks with eculizumab, or ravulizumab respectively, with the exception of patients 8 and 14, who received eculizumab with increased frequency every 10–12 days. Increased frequency of ravulizumab every 7 weeks was attempted for patient 14 due to some persisting symptoms after 33 months of treatment, but standard dosing was resumed after 8 months because of patient preference, with no clear clinical benefit. Patient 16 with a diminishing PNH clone was well controlled on a significantly reduced dose of both eculizumab and ravulizumab (Supporting Table S1 ). After switching, patients generally remained well controlled or improved their biochemical results, transfusions, and symptoms. The need for transfusions in 4 patients and BTH in 3 patients was reduced significantly. One example is patient 8, where transfusion needs were reduced from 26 to 1 transfusion 12 months prior to ravulizumab compared to 12 months after switching. BTH episodes were also largely reduced in patients 1, 2, and 6. Patient 6 exhibited the largest reduction from 37 to 0 BTH episodes.

Most patients were well managed on either treatment—eleven experienced neither BTH nor needed transfusions during the 12 months prior to and after switching. Most patients had uniform LDH and reticulocyte levels both before and after switching to ravulizumab, as illustrated by patients 3, 4, 5, 15, 17, 18, 19, and 20. For three patients (9, 10, and 16) without additional treatment needs, numerically lower LDH levels were seen after switching.

Finally, only patient 13 had signs of better disease control during eculizumab treatment, with a small LDH level decline and an increase in transfusions after switching. Of note, patients 2 and 20, who despite elevated eculizumab dose had a high volume of transfusions and BTH, were generally well managed after switching to standard‐dose ravulizumab.

Discussion

This case series aligns with previous findings that ravulizumab provides at least comparable disease control compared with eculizumab in most patients with PNH. Notably, individuals with high transfusion needs or frequent BTH episodes experienced significant improvement after switching. In addition, among patients without clear clinical benefits, some showed numerically decreasing LDH levels after switching. The clinical benefits combined with the known QoL‐benefits of ravulizumab lead to more beneficial, tolerable, and less time‐consuming treatment for the patients [ 7 ]. Even patient 13, who experienced an increase from 0 to 2 transfusions after switching from eculizumab, netto saved trips to the hospital. While two transfusion episodes were needed, this patient saved around 22 trips in the same period by reducing the need for complement inhibitor infusions from every second to every eighth week.

Our results are consistent with the 302 study [ 6 ], where the results numerically was in favor of ravulizumab regarding both the primary endpoint and all secondary endpoints. Our real‐world data reflect routine clinical practice, supporting the notion that ravulizumab may provide enhanced disease stability in high‐risk patients. Of note, suboptimal hemoglobin response may reflect ongoing extravascular hemolysis that is not inhibited by eculizumab or ravulizumab.

The primary limitations of this case series include the small sample size and potential variability in underlying disease progression. In addition, our follow‐up period is limited to 12 months, whereas others have provided longer follow‐up data [ 9 ]. While hemoglobin levels are often reported in PNH patients, we did not include this parameter since it may fluctuate both due to hemolysis and transfusions. We did not calculate group‐based treatment efficacy estimates since the 20 included patients experienced such different developments after the switching, that treatment efficacy on a group basis would not provide informative estimates. Of the available study base, almost all patients from our institutions were included since only two patients in eculizumab treatment either remained on this treatment or were included in another study and therefore were ineligible for inclusion.

With time, PNH patients may require more transfusions if an underlying MDS or aplastic anemia progresses, leading to secondary bone marrow failure. Similarly, spontaneous remissions may occur. We measured reticulocyte levels in almost all patients and found no signs of change in the degree of bone marrow failure. However, this phenomenon should be kept in mind when interpreting the need for additional treatment before and after switching medication, since improvements may partly be attributed to changes in the underlying condition unrelated to the C5‐inhibitor treatment. Based on our case series, we conclude that ravulizumab provides the same or better disease activity management than eculizumab in PNH and that ravulizumab decreases transfusion needs and BTH episodes efficiently in individual patients with a high burden on these parameters.

Author Contributions

HF conceived and designed the study. AG designed the data entry module. All authors excluding ARF and DLH included patients and registered data. ARF and DLH performed analyses. ARF wrote the first draft of the manuscript. All authors contributed with subsequent manuscript revisions and approved the final version.

Conflicts of Interest

DLH: Advisory board (Janssen, Takeda), travel grants (EUSA Pharma, Alexion, SOBI). UMO: Consultancy (Roche), Advisory board (Alexion, SOBI, Novo Nordisk), Speaker fee (Alexion, SOBI, Novo Nordisk), research support (Novo Nordisk). A‐EL: Consultancy (Roche, SOBI, Takeda). AG: Consultancy / advisory boards (Agios, Disc Medicine, Novo Nordisk, Pharmacosmos, Vertex Pharmaceuticals), research support (Agios, Bristol Myers Squibb, Novo Nordisk, Sanofi). HF: Speaker fee (Griffols, SOBI), travel support (Johnson & Johnson), research support (Alexion, Sanofi). ARF, VN, RSB, JS: None

Supporting information

Supplementary Table : Individual level routine findings among 20 patients with Paroxysmal Nocturnal Haemoglobinuria before and after switching from eculizumab to ravulizumab treatment.

Acknowledgements

The study was supported by a research grant from Alexion.

Rønneholt‐Frederiksen A., Hansen D. L., Nummi V., et al. “Disease Activity After Switching From Eculizumab to Ravulizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria: Real World Data From Denmark and Finland.” eJHaem 6, no. 4 (2025): 6, e70132. 10.1002/jha2.70132

Funding : The study was supported by a research grant from Alexion.

Data Availability Statement

Danish and Finnish national legislations prohibits sharing of routine care data from individual patients.

References

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Associated Data

Supplementary Materials

Supplementary Table : Individual level routine findings among 20 patients with Paroxysmal Nocturnal Haemoglobinuria before and after switching from eculizumab to ravulizumab treatment.

Data Availability Statement

Danish and Finnish national legislations prohibits sharing of routine care data from individual patients.