Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome

C. M. Legendre, C. Licht, P. Muus, L. A. Greenbaum, S. Babu, C. Bedrosian C Bingham, D. J. Cohen, Y. Delmas, K. Douglas, F. Eitner, T. Feldkamp, D. Fouque, R. R. Furman, O. Gaber, M. Herthelius, M. Hourmant, D. Karpman, Y. Lebranchu, C. Mariat, J. MenneB. Moulin, J. Nürnberger, M. Ogawa, G. Remuzzi, T. Richard, R. Sberro-Soussan, B. Severino, N. S. Sheerin, A. Trivelli, L. B. Zimmerhackl, T. Goodship, C. Loirat

Research output: Contribution to journalArticle

794 Scopus citations

Abstract

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x109 per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08- 002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Original languageEnglish (US)
Pages (from-to)2169-2181
Number of pages13
JournalNew England Journal of Medicine
Volume368
Issue number23
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Medicine(all)

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