P812: LONG-TERM COMPLEMENT INHIBITION AND SURVIVAL OUTCOMES IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: AN INTERIM ANALYSIS OF THE RAVULIZUMAB CLINICAL TRIALS

Abstract

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, hematologic disorder characterized by uncontrolled terminal complement activation, intravascular hemolysis, thrombotic events and significant morbidity and mortality. Complement component 5 (C5) inhibitors, eculizumab and ravulizumab, are the current standard of care in patients with PNH. Eculizumab has been the mainstay of treating patients with PNH since approval by both US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2007. Ravulizumab (approved in 2018 [FDA] and 2019 [EMA]) is a new treatment for patients with PNH, offering complete complement C5 inhibition throughout the 8-week (q8w) dosing interval. The ravulizumab clinical trial program has allowed for analysis into the long-term management of patients with PNH treated with C5 inhibitors and their associated clinical outcomes. Aims: To analyze patient survival using long-term data from the ravulizumab clinical trial program. Methods: This analysis utilized pooled long-term survival data across the ravulizumab phase 1b, 2 and 3 trials (103 [NCT02598583], 201 [NCT02605993], 301 [NCT02946463] and 302 [NCT03056040]) with up to 4 years of open-label extension. Complement C5 inhibitor (eculizumab/ravulizumab) and dose received varied during the initial treatment period. During open-label extension, patients received weight-based dosing of intravenous ravulizumab q8w. Deaths reported, patient survival over time and adverse events resulting in patient death were analyzed. Instances of patients that died owing to infection or sepsis were specifically analyzed to provide insight into the events leading to death. Results: This analysis reported 1479.0 patient-years of follow-up in 475 patients with PNH treated with ravulizumab. Of the 475 patients who received ravulizumab, 12 (2.5%) died during the initial treatment period and 4-year open-label extension with an overall incidence of 0.8 per 100 patient-years. Nine of these deaths occurred within the first 3 years of treatment. The remaining three patients died during the fourth (n = 2) and fifth (n = 1) years of treatment. Of the 12 deaths reported, six were attributed to infection or sepsis (Table 1). These patients were predominantly male (83.3%), and white or Asian (50.0%, respectively), and median (range) age was 61 (43–75) years. In addition, of these six patients, two had aplastic anemia and one patient had pancytopenia. Most (83.3%) of these patients were hospitalized owing to onset of infection; however, one patient (white male; 43 years old; ravulizumab to ravulizumab) was hospitalized owing to worsening of aplastic anemia. During hospitalization, this patient was diagnosed with acute respiratory infection and died owing to sepsis. One patient (Asian male; 62 years old; ravulizumab to ravulizumab) died owing to meningococcal sepsis (strain unknown). This patient was vaccinated against meningococcal groups A, C, Y and W-135, but had not received prophylactic antibiotics. Other causes of death included cardiac disorders (n = 1), neoplasms (n = 4; acute myeloid leukemia, metastatic urothelial carcinoma of the kidney, metastatic malignant neoplasm of the lung and non-small cell lung carcinoma) and respiratory disorders (n = 1). Image:Summary/Conclusion: This analysis reports the longest period of follow-up in 475 patients with PNH treated with ravulizumab. Overall, long-term ravulizumab treatment was associated with a low incidence of death and few patients died owing to infection. This analysis supports the long-term use of ravulizumab for PNH.