Pam Harrison

June 11, 2015

LONDON, United Kingdom — For patients with atypical hemolytic uremic syndrome (HUS), the improvement in estimated glomerular filtration rate (eGFR) is significantly better when eculizumab (Soliris, Alexion Pharmaceuticals) is initiated within 7 days of symptom onset than when it is initiated later, a pooled analysis of prospective clinical trials indicates.

In addition, more patients achieve normal renal function with earlier treatment.

"We know that time is against us in this disease, so we really should use the drug very early," said Yahsou Delmas, MD, from the University of Bordeaux in France.

"The drug should be started as soon as atypical HUS is diagnosed," she told Medscape Medical News. "When thrombotic microangiopathy is identified, physicians can quickly rule out any differential diagnosis."

Dr Delmas and her colleagues evaluated pooled data from four open-label prospective clinical trials of eculizumab in patients with atypical HUS.

She presented the results here at the European Renal Association–European Dialysis and Transplant Association 52nd Congress.

Eculizumab was initiated within 7 days of symptom onset for 21 of the 97 patients analyzed, and was initiated more than 7 days after symptom onset for the other 76 patients.

Median time from symptom onset to the initiation of treatment was 5 days in the early group and 32 days in the late group.

At treatment outset, median eGFR was lower in the early group than in the late group, although not significantly so (11 vs 16 mL/min per 1.73 m²).

At 1 month, the increase in eGFR in the early group was more than twice that in the late group. This difference in increase was sustained at 18 months (58 vs 26 mL/min per 1.73 m²).

We know that time is against us in this disease, so we really should use the drug very early.

At 12 months, the proportion of patients who achieved normal renal function — eGFR above 90 mL/min per 1.73 m² — was significantly higher in the early group than in the late group (43% vs 11%).

However, for mean time to platelet normalization, the difference between the early group and late group was not significant (14 vs 28 days).

It is likely that "stopping the injury of endothelial cells early with terminal complement blockade enables recovery of the glomerular endothelium and limits hypoxia-induced scarring and the vicious circle that leads to chronic kidney disease," Dr Delmas explained.

In standard clinical practice, it is possible to exclude differential diagnoses within 7 days. Thrombotic thrombocytopenic purpura can be excluded by establishing normal ADAMTS13 activity, and Shiga-like toxin-producing Escherichia coli HUS can be excluded with a negative bacterial assay or polymerase chain reaction.

"These data emphasize the importance of rapid diagnosis and initiation of eculizumab for the best recovery of renal function," said Dr Delmas.

Eculizumab is officially approved for the life-long treatment of atypical HUS. However, because of the cost of the drug, physicians are trying to identify a select group of patients in whom the drug can be discontinued.

To treat an adult with the currently approved maintenance regimen of eculizumab 1200 mg every 14 days, it costs about €15,000 per month (approximately US$17,000).

Dr Delmas said that she thinks eculizumab can be discontinued in patients who achieve normal renal function, have no evidence of proteinuria, and have normal hematologic parameters after the initial course of treatment.

You do not have to wait for complement mutation analysis to start eculizumab.

This study is important because it confirms results from a previous study of eculizumab in patients who experienced a recurrence of atypical HUS after transplantation (Nat Rev Nephrol. 2012;8:643-657), said Giuseppe Remuzzi, MD, from the IRCCS Istituto di Ricerche Farmacologiche Mario Negri in Bergamo, Italy.

"It also confirms what experts on atypical HUS have been telling the renal community in the past few years," Dr Remuzzi told Medscape Medical News. "Namely, you do not have to wait for complement mutation analysis to start eculizumab."

The exclusion of thrombotic thrombocytopenic purpura and Shiga-like toxin-producing E coli HUS "is enough to start eculizumab once a diagnosis of thrombotic microangiopathy is supported by laboratory findings," Dr Remuzzi stated.

The study was funded by Alexion, the manufacturer of eculizumab. Dr Delmas has received travel grants and honoraria from Alexion. Dr Remuzzi has disclosed no relevant financial relationships.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress: Abstract SaO008. Presented May 30, 2015.


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