Reaction - Real Life Use of Ravulizumab in Italian Patients with Paroxysmal Nocturnal Hemoglobinuria a Multicenter Observational Retrospective and Prospective Cohort Study, Final Results

Title: REACTION - Real Life Use of Ravulizumab in Italian PatiEnts with PAroxysmal NoCturnal Hemoglobinuria a MulTicenter ObservatIONal Retrospective and Prospective Cohort Study, Final Results Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by uncontrolled terminal complement activation leading to hemolytic anemia, thrombosis, organ damage and premature mortality. In 2021, ravulizumab was approved in Italy as a treatment for PNH, but real-world evidence is currently lacking. The REACTION study (NCT05274633), a multi-center observational cohort study in Italy, aims to assess the effectiveness and tolerability in Italian patients with PNH who have switched to ravulizumab after at least 26 weeks of treatment with eculizumab. Methods: The REACTION study is an Italian multi-center, observational study composed of retrospective and prospective periods on the same PNH patients. The study is designed to collect effectiveness data of ravulizumab in patients already treated with eculizumab for at least 26 weeks and who switched to ravulizumab treatment. All patients eligible to start the new drug as per clinical practice were enrolled in participating sites, with the exception of subjects with a history of hematopoietic stem cell transplantation , pregnant or breastfeeding. Patients had to sign informed and privacy consent to be enrolled in the study. Efficacy and safety data were collected at the following timepoints: -52 weeks, -26 weeks, baseline, 18 weeks, 34 weeks and 52 weeks. Baseline was defined as the day of ravulizumab induction dose. The primary endpoint was to describe the percentage change in lactate dehydrogenase (LDH) from baseline to the end of observation period during ravulizumab treatment at 52 weeks. Here we present the final analysis on primary endpoints, breakthrough hemolysis (BTH) event rate and transfusion needs, over a follow-up period of 52 weeks of ravulizumab treatment. Results: The full analysis set comprised 80 patients, with a median age of 51.5 years at baseline, of whom 39 (48.8%) were male, enrolled in 28 centers across Italy. The median time since PNH diagnosis was 9.0 years (IQR: 4.3 - 16.7), most patients had no comorbidities (53 [66.3%]) or PNH symptoms (55 [68.8%]) at baseline. Median duration of eculizumab treatment was 6.1 (2.9 - 10.7) years, median dosage was 900.0 mg and median administration frequency was 14.0 days. Median duration of ravulizumab treatment was 50.0 weeks, median induction dose was 2700.0 mg, median maintenance dose was 3300.0 mg and median administration frequency was 56.0 days. The primary endpoint showed that the median percentage change in LDH from baseline to the end of the observation period was -2.7%. The median Hgb levels at baseline was 10.8 g/dL and at the end of the observation period was 11.2 g/dL. The observed rate of BTH events per 100 patients-year decreased from 6.3 during the eculizumab period to 2.6 during the ravulizumab period. During the eculizumab treatment period, 2 patients experienced a total of 5 BTH events, of which 4 were unrelated to any medical events. During the ravulizumab treatment, 2 patients experienced 2 BTH events, which were related to gastroenteritis and COVID-19 infections. For transfusion requirements, among the 80 patients, during eculizumab period 20 patients (25.0%) needed 108 packed red blood cells units, while in the ravulizumab period 16 patients (20.0%) needed 67 packed red blood cells units The RWE analysis did not reveal any new pharmacovigilance signals. No cases of meningococcal infections were reported. Two deaths occurred, due to senescence and to a concomitant newly diagnosed sarcoma, respectively. Both deaths were not related to ravulizumab. Conclusions: This is the first presentation of the REACTION study's final results, that confirm the effectiveness and tolerability of switching patients with PNH from eculizumab to ravulizumab, as emerged from the phase III clinical trials. Ravulizumab effectively maintained control of intravascular hemolysis, as indicated by LDH levels, and sustained stable hemoglobin levels throughout the prospective period. The transfusion need and the total number of BTH events decreased during ravulizumab compared to the eculizumab period. Furthermore, during ravulizumab, both recorded BTH events were related to medical conditions.