The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.

Abstract

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.

• Authors: Peter Hillmen, Neal S Young, Jörg Schubert, Robert A Brodsky, Gerard Socié, Petra Muus, Alexander Röth, Jeffrey Szer, Modupe O Elebute, Ryotaro Nakamura, Paul Browne, Antonio M Risitano, Anita Hill, Hubert Schrezenmeier, Chieh-Lin Fu, Jaroslaw Maciejewski, Scott A Rollins, Christopher F Mojcik, Russell P Rother, Lucio Luzzatto
• Journal: The New England journal of medicine (N Engl J Med) Vol. 355 Issue 12 Pg. 1233-43 (Sep 21 2006) ISSN: 1533-4406 [Electronic] United States
• PMID: 16990386 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: 2006 Massachusetts Medical Society

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Complement C5
• Hemoglobins
• eculizumab

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Complement C5 (immunology)
• Double-Blind Method
• Erythrocyte Transfusion
• Fatigue
• Female
• Hemoglobins (analysis)
• Hemoglobinuria, Paroxysmal (blood, drug therapy, therapy)
• Hemolysis (drug effects)
• Humans
• Male
• Middle Aged
• Quality of Life