Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. Academic Article uri icon

Overview

MeSH

  • Adolescent
  • Adult
  • Aged
  • Combined Modality Therapy
  • Female
  • Humans
  • Kidney Diseases
  • Male
  • Middle Aged
  • Mutation
  • Plasma Exchange
  • Platelet Count
  • Quality of Life
  • Young Adult

MeSH Major

  • Antibodies, Monoclonal, Humanized
  • Complement C5
  • Hemolytic-Uremic Syndrome
  • Thrombotic Microangiopathies

abstract

  • 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. 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). 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. 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]).

publication date

  • June 6, 2013

has subject area

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Combined Modality Therapy
  • Complement C5
  • Female
  • Hemolytic-Uremic Syndrome
  • Humans
  • Kidney Diseases
  • Male
  • Middle Aged
  • Mutation
  • Plasma Exchange
  • Platelet Count
  • Quality of Life
  • Thrombotic Microangiopathies
  • Young Adult

Research

keywords

  • Clinical Trial, Phase II
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1056/NEJMoa1208981

PubMed ID

  • 23738544

Additional Document Info

start page

  • 2169

end page

  • 2181

volume

  • 368

number

  • 23