title: 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.affiliation: Université Paris Descartes and Assistance Publique–Hôpitaux de Paris, Hôpital Necker, INSERM Unité 845, Paris, France. christophe.legendre@nck.aphp.fr.
authors.forename: C M
authors.initials: CM
authors.lastname: Legendre
authors.forename: C
authors.initials: C
authors.lastname: Licht
authors.forename: P
authors.initials: P
authors.lastname: Muus
authors.forename: L A
authors.initials: LA
authors.lastname: Greenbaum
authors.forename: S
authors.initials: S
authors.lastname: Babu
authors.forename: C
authors.initials: C
authors.lastname: Bedrosian
authors.forename: C
authors.initials: C
authors.lastname: Bingham
authors.forename: D J
authors.initials: DJ
authors.lastname: Cohen
authors.forename: Y
authors.initials: Y
authors.lastname: Delmas
authors.forename: K
authors.initials: K
authors.lastname: Douglas
authors.forename: F
authors.initials: F
authors.lastname: Eitner
authors.forename: T
authors.initials: T
authors.lastname: Feldkamp
authors.forename: D
authors.initials: D
authors.lastname: Fouque
authors.forename: R R
authors.initials: RR
authors.lastname: Furman
authors.forename: O
authors.initials: O
authors.lastname: Gaber
authors.forename: M
authors.initials: M
authors.lastname: Herthelius
authors.forename: M
authors.initials: M
authors.lastname: Hourmant
authors.forename: D
authors.initials: D
authors.lastname: Karpman
authors.forename: Y
authors.initials: Y
authors.lastname: Lebranchu
authors.forename: C
authors.initials: C
authors.lastname: Mariat
authors.forename: J
authors.initials: J
authors.lastname: Menne
authors.forename: B
authors.initials: B
authors.lastname: Moulin
authors.forename: J
authors.initials: J
authors.lastname: Nürnberger
authors.forename: M
authors.initials: M
authors.lastname: Ogawa
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
authors.forename: T
authors.initials: T
authors.lastname: Richard
authors.forename: R
authors.initials: R
authors.lastname: Sberro-Soussan
authors.forename: B
authors.initials: B
authors.lastname: Severino
authors.forename: N S
authors.initials: NS
authors.lastname: Sheerin
authors.forename: A
authors.initials: A
authors.lastname: Trivelli
authors.forename: L B
authors.initials: LB
authors.lastname: Zimmerhackl
authors.forename: T
authors.initials: T
authors.lastname: Goodship
authors.forename: C
authors.initials: C
authors.lastname: Loirat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010951:Plasma Exchange; D010976:Platelet Count; D011788:Quality of Life; D057049:Thrombotic Microangiopathies / Q000517:prevention & control*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; C481642:eculizumab