C10-003 ASH 2013 abstract
Eculizumab (Ecu) Inhibits Thrombotic Microangiopathy (TMA) and Improves Renal
Function in Pediatric Patients (Pts) with Atypical Hemolytic Uremic Syndrome (aHUS)
Larry A. Greenbaum, MD, PhD1, Marc Fila, MD2, Gianluigi Ardissino, MD, PhD3, Samhar I. AlAkash, MD4, Jonathan Evans, MD5, Paul Henning, MD6, Kenneth V. Lieberman, MD7, Silvio
Maringhini, MD8, Lars Pape, MD, PhD9, Lesley Rees, MD10, Nicole C.A.J. van de Kar, MD11,
Johan Vande Walle, MD12, Masayo Ogawa, MD, FAAP13, Camille L. Bedrosian, MD13, Christoph
Licht, MD14
Emory University, Atlanta, GA, USA, 2Hôpital Robert-Debré, Paris, France, 3Fondazione IRCCS
Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy, 4Driscoll Children's Hospital, Corpus
Christi, TX, USA, 5Nottingham University Hospitals, Nottingham, UK, 6Women's and Children's
Hospital, North Adelaide, South Australia, Australia , 7Hackensack University Medical Center,
Hackensack, NJ, USA, 8G. Di Cristina Children's Hospital, Palermo, Italy, 9Hannover Medical
School, Hannover, Germany, 10Great Ormond Street Hospital for Children, NHS Trust, London,
UK, 11Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 12University
Hospital Ghent, Ghent, Belgium, 13Alexion Pharmaceuticals, Inc., Cheshire, CT, USA, 14The
Hospital for Sick Children, Toronto, Canada
Introduction: aHUS is a rare, genetic, life-threatening disease of uncontrolled and chronic
complement activation, leading to systemic TMA and severe end-organ damage. Despite
plasma exchange/plasma infusion (PE/PI), up to 65% of all pts sustain permanent renal
damage, progress to end-stage renal disease, or die within a year of diagnosis. Ecu, a terminal
complement inhibitor, is approved for the treatment of aHUS, and was shown to be safe and
effective in pediatric pts in a retrospective study. Previous studies have shown that early
intervention with Ecu leads to significant, time-dependent improvements in hematologic and
renal outcomes. Here, we report safety and efficacy results from the first prospective trial of
pediatric pts with aHUS at 26 weeks (wks).
Methods: This was an open-label, single-arm, Phase 2 trial of Ecu in pediatric pts with aHUS.
Admission criteria included platelet count < the lower limit of normal (LLN) at screening and at
baseline (BL), LDH ≥1.5 times the upper limit of normal (ULN) at the start of the current aHUS
manifestation, and elevated serum creatinine (Cr) at screening. An identified complement gene
mutation was not required. Pts with STEC-HUS (shiga toxin + E. coli) or severe ADAMTS13
deficiency (<5%) were excluded. The primary endpoint was complete TMA response at 26 wks
(normalization of platelets and LDH, and ≥25% improvement in Cr from BL on 2 consecutive
measurements ≥4 wks apart). Dosing was based on weight cohorts.
Results: 22 pts (1 month to 17 yrs) were enrolled and 19 completed 26 wks. 16 pts (73%) were
newly diagnosed, with a median of 6 days from diagnosis to the first dose of ECU. 12 pts (55%)
had no PE/PI during the current manifestation. At wk 26, 14 pts (64%) achieved the primary
endpoint of complete TMA response (Table). Platelets (Fig 1) and eGFR (Fig 2) increased
significantly from BL through the 26-wk study period. 9 of 11 pts (82%) on dialysis at BL
discontinued dialysis. 100% of the 11 pts not on dialysis at BL remained off dialysis through wk
26. Mean increase in eGFR through wk 26 was 64 mL/min/1.73m2. All 10 pts on PE/PI at BL
C10-003 ASH 2013 abstract
discontinued PE/PI. QoL significantly improved. Ecu was safe and well tolerated. 1 pt withdrew
due to an SAE (agitation). No pts had meningococcal infection or died.
Conclusions: In this, the first prospective trial of pediatric pts with aHUS, early intervention with
Ecu improved hematologic and renal parameters. 82% of pts discontinued dialysis, and no pt
initiated dialysis during the 26-wk study. Use of Ecu has been recommended as first-line
therapy in children with aHUS. This trial confirms that Ecu inhibits complement-mediated TMA,
and is safe and effective as first-line therapy at the approved dose regimen in pediatric pts with
aHUS. Treatment in this clinical trial is ongoing.
Baseline Demographics and Disease Characteristics (N=22)
Age, mean (SD), y
6.6 (6.1)
Female sex, n (%)
10 (45)
Identified complement regulatory protein mutation or auto-antibody, n (%)
10 (45)
Time from aHUS diagnosis until screening (mo), median (range)
Duration of current clinical manifestation of aHUS (mo), median (range)
Dialysis at baseline, n (%)
Prior renal transplant, n (%)
0.56 (0.03–191.3)
0.2 (0.0–4.3)
11 (50.0)
2 (9)
Platelet count <150x109/L, n (%)
22 (100)
LDH >ULN, n (%)
19 (86)
eGFR ≤60 mL/min/1.73m2,n (%)
18 (82)
Efficacy Outcomes at Wk 26
Complete TMA response*, n (%)
14 (64)
Complete hematologic response†, n (%)
18 (82)
Platelet count normalization‡ , n (%)
21 (95)
eGFR improvement from baseline ≥15 mL/min/1.73m 2, n (%)
19 (86)
eGFR increase from baseline (mL/min/1.73 m 2), mean (95% CI)
Serum creatinine ≥25% decrease from baseline, n (%)
64 (50; 79)
P<0.0001 (wk 25)
16 (73)
*Complete TMA response: normalization of platelets and LDH, and ≥25% improvement in Cr from BL on 2 consecutive
measurements ≥4 wk apart.
Complete hematologic response: platelet and LDH normalization at ≥2 consecutive measurements ≥4 wk apart.
C10-003 ASH 2013 abstract
Platelet count normalization: platelet count ≥150x109/L at ≥2 consecutive measurements ≥4 wk apart.
Figure 1: Platelet count improvement through 26 weeks.
Figure 2: eGFR improvement through 26 weeks.