Supplementary Materialsblood876805-suppl1. 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for 6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Main efficacy end point was percentage switch in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, switch in Functional Assessment of Chronic Illness Therapy (FACIT)CFatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (= .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, ?8.89 to 18.99]), switch in FACIT-Fatigue score (difference, 1.47 [95% CI, ?0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, ?4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, ?10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due TAS-114 to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT03056040″,”term_id”:”NCT03056040″NCT03056040. Visual Abstract Open in a separate window Introduction The discovery that uncontrolled match system activation plays a key role in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH),1 atypical hemolytic uremic syndrome,2 and myasthenia gravis3,4 was established upon results of several trials demonstrating the efficacy and security of complement-inhibitor therapy to treat these severe and potentially life-threatening diseases.5-12 Eculizumab (Soliris; Alexion Pharmaceuticals, Inc., Boston, MA), the only approved match inhibitor for PNH,13,14 is usually associated with sustained improvements in intravascular hemolysis, anemia, thrombotic events, transfusion independence, survival, and quality of life.5-7,15,16 Although eculizumab therapy is highly effective, up to 27% of eculizumab-treated patients may experience breakthrough hemolysis,17-19 resulting in a return of PNH symptoms and increased risk of serious complications. In addition, the treatment burden associated with an every-2-week dosing regimen of an IV infusion may negatively impact quality of life.20 Ravulizumab (ALXN1210) is a new complement component 5 (C5) TAS-114 inhibitor that produces immediate, complete, and sustained inhibition of C5 with an extended, 8-week dosing interval.21,22 Ravulizumab binds to C5 with high TAS-114 affinity and prevents hemolysis by inhibiting formation of C5a and C5b.23 In ravulizumab, 4 amino acid substitutions in the complementarity-determining and Fc regions of eculizumab result in enhanced TAS-114 endosomal dissociation of C5 and recycling to the vascular compartment through the neonatal Fc receptor pathway.22 These modifications result in a terminal half-life that Rabbit Polyclonal to USP30 is approximately fourfold longer than that of eculizumab.21,22,24 Results of phase 1b/2 studies in complement-inhibitorCnaive patients with PNH demonstrate that ravulizumab provides rapid and sustained reduction in complement-mediated hemolysis at dosing intervals up to 12 weeks and overall improvement of PNH-related symptomatology and quality of life.25 In the largest phase 3 study in complement-inhibitorCnaive PNH patients conducted to date, ravulizumab was shown to be noninferior to eculizumab for all those end points, including transfusion avoidance, lactate dehydrogenase (LDH) normalization, percentage change in LDH levels, change in Functional Assessment of Chronic Illness Therapy (FACIT)CFatigue score, breakthrough hemolysis, TAS-114 and hemoglobin stabilization.26 In this phase 3 study, we assessed the noninferiority of ravulizumab vs eculizumab in patients with PNH on stable eculizumab therapy. Methods Trial oversight and study design ALXN1210-PNH-302 was a multicenter, randomized, open-label, active-controlled study conducted in 49 centers in 11 countries (registered at www.clinicaltrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT03056040″,”term_id”:”NCT03056040″NCT03056040 and EudraCT as #2016-002026-36, CHAMPION 302). This study was performed in accordance with the principles of the Declaration of Helsinki and the Council for International Businesses of Medical Sciences International Ethical Guidelines. The study consisted of a 4-week screening period followed by a 26-week randomized treatment period and an extension period during which all patients received ravulizumab for.