Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Previously Treated with Eculizumab: A Matching-Adjusted Indirect Comparison

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population). METHODS Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin 1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively). RESULTS Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195