Jim Kling

June 03, 2013

ISTANBUL, Turkey — Eculizumab improves renal outcomes in patients with atypical hemolytic uremic syndrome, including patients on dialysis, intermediate results of a highly-anticipated new study have shown.

"This is a rare and very severe disease. It can be caused by infections, like the Escherichia coli toxin in the case of typical hemolytic uremic syndrome, or genetic abnormalities of the complement system, as happens with atypical hemolytic uremic syndrome," Denis Fouque, MD, from the Centre Hospitalier Lyon-Sud in France, told Medscape Medical News. "It can lead to acute kidney failure."

Atypical hemolytic uremic syndrome is often managed with plasma exchange or plasma infusion, but these treatments do not improve graft function or prevent graft loss in patients with systemic thrombotic microangiopathy.

Even with treatment, 65% of patients with this genetic disorder develop permanent renal damage, end-stage renal disease, or die within a year of diagnosis.

In 60% of patients who undergo transplantation, thrombotic microangiopathy progresses in the first year, and 80% to 90% then lose the graft. Thrombotic microangiopathy progression is defined as a platelet count below 150 × 109/L, despite at least 4 plasma exchanges or infusions in the week prior to screening.

Eculizumab is a monoclonal antibody that binds to the C5 terminal complement protein, interfering with proinflammatory and prothrombotic processes.

Dr. Fouque presented data here at the European Renal Association-European Dialysis and Transplant Association 50th Congress.

In this open-label single-group phase 2 trial, the researchers analyzed outcomes in patients with thrombotic microangiopathy who had received eculizumab for 2 years. In this analysis, the 17 patients who were 12 years or older were followed for at least 26 weeks.

Median treatment duration was 124 weeks for patients on dialysis at baseline (n = 5) and 93 weeks for patients not on dialysis (n = 12). There were no statistically significant differences between the 2 groups in baseline characteristics, such as mean age, sex, race, percentage without identified complement mutation or autoantibody, previous kidney transplantation, time to clinical manifestation of atypical hemolytic uremic syndrome, and estimated glomerular filtration rate.

The efficacy of eculizumab treatment, assessed by platelet count and renal function, was similar in the 2 groups.

Table. Outcomes After 2 Years of Eculizumab Treatment

Outcome Dialysis at Baseline (n = 5) No Dialysis at Baseline (n = 12)
Event-free thrombotic microangiopathy (%) 100 83
Hematologic normalization (%) 100 83
Improvement in chronic kidney disease of ≥1 stage (%) 80 67
Proteinuria decrease of ≥1 grade (%) 100 91*
Estimated glomerular filtration rate    
  Mean ± SD, mL/min per 1.73 m2 64.1 ± 39.5 49.2 ± 22.5
  Increase ≥15 mL/min per 1.73 m2 (%) 60 58
  Mean increase ± SD, mL/min per 1.73 m2 52.6 ± 37.2 23.8 ± 16.6

SD = standard deviation.

*n = 11.

Of 5 patients on dialysis at baseline, 4 were able to discontinue dialysis. Of 12 patients not on dialysis at baseline, 1 began dialysis during the study.

The drug was safe and well tolerated in both groups, Dr. Fouque reported.

"These data are important because, to date, we haven't had any other effective treatment. It is revolutionary," said Dr. Fouque. "What is not known right now is how long the genetic disease will express and how long patients will need the treatment. It will probably be long term; some patients have been on it longer than 2 years. In addition, we don't know if we can reduce the amount of drug — that is currently under investigation."

Eculizumab was used after an outbreak of Escherichia coli caused an epidemic of typical hemolytic uremic syndrome in Germany in 2011. Of the roughly 800 people infected, approximately 300 developed hemolytic uremic syndrome. This led to an impromptu clinical trial of eculizumab, and the treatment proved effective.

The current study is very important because we have patients who will reject a new kidney, meeting attendee Christoph Wanner, MD, from the University Clinic Würzburg in Germany, told Medscape Medical News. "We have been waiting for data on this expensive drug. This study shows that it's effective in preserving renal function, which is the best we can take from it because it's an intermediate result."

Eculizumab has garnered much attention because of its cost. Expectations for it are high, "but there is so much company interest behind it that you cannot believe every result," said Dr. Wanner.

Nevertheless, the size of the clinical network involved in this study is reassuring, Dr. Wanner noted. "Because it's a very rare disease, it is very difficult to get these patients together to study."

This study was funded by Alexion, the manufacturer of eculizumab. Dr. Fouque and Dr. Wanner have disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 50th Congress: Abstract MP035. Presented May 20, 2013.

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