The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.
BACKGROUND
We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH).


METHODS
We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed.


RESULTS
Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.


CONCLUSIONS
Eculizumab is an effective therapy for PNH.
Hillmen
Peter
P
Leeds General Infirmary, Leeds, United Kingdom. peter.hillmen@nhs.net
Young
Neal S
NS
Schubert
Jörg
J
Brodsky
Robert A
RA
Socié
Gerard
G
Muus
Petra
P
Röth
Alexander
A
Szer
Jeffrey
J
Elebute
Modupe O
MO
Nakamura
Ryotaro
R
Browne
Paul
P
Risitano
Antonio M
AM
Hill
Anita
A
Schrezenmeier
Hubert
H
Fu
Chieh-Lin
CL
Maciejewski
Jaroslaw
J
Rollins
Scott A
SA
Mojcik
Christopher F
CF
Rother
Russell P
RP
Luzzatto
Lucio
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5 / Q000276:immunology*; D004311:Double-Blind Method; D017707:Erythrocyte Transfusion; D005221:Fatigue; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000188:drug therapy* / Q000628:therapy; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D006454:Hemoglobins; C481642:eculizumab