Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).
