Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

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 73×10(9) 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]).

• Authors: 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 Menne, B 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
• Journal: The New England journal of medicine (N Engl J Med) Vol. 368 Issue 23 Pg. 2169-81 (Jun 06 2013) ISSN: 1533-4406 [Electronic] United States
• PMID: 23738544 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Complement C5
• eculizumab

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (adverse effects, blood, pharmacokinetics, therapeutic use)
• Combined Modality Therapy
• Complement C5 (antagonists & inhibitors)
• Female
• Hemolytic-Uremic Syndrome (blood, drug therapy, genetics, therapy)
• Humans
• Kidney Diseases (drug therapy, etiology)
• Male
• Middle Aged
• Mutation
• Plasma Exchange
• Platelet Count
• Quality of Life
• Thrombotic Microangiopathies (prevention & control)
• Young Adult