Evaluation restrictive use of eculizumab

Societal relevance

Atypical hemolytic uremic syndrome (aHUS) is a rare and severe disease, characterized by micro thrombi in the renal vasculature. Without therapy, the outcome is dismal with most of the patients in need of renal replacement therapy. With the introduction of the complement C5-inhibitor eculizumab, a new era was entered in the treatment of patients with aHUS. Eculizumab therapy improved mortality and morbidity significantly. However, initial guidelines recommended lifelong treatment together with prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. There is no evidence to support lifelong therapy duration and treatment is not without risks. Furthermore, one has to consider the social impact of eculizumab therapy with costs up to €500,000 per patient per year. 

Discovery

At Radboudumc we performed two pilot studies to evaluate restrictive use of eculizumab. In the first study eculizumab therapy was tapered and/or discontinued in all 20 aHUS patients, after which only 5 (20%) experienced a relapse. Moreover, with rapid reinitiating of eculizumab no chronic sequelae were detected and therapy was tapered again in these patients.
 
In the second pilot study, 17 patients with a history of aHUS and end stage renal disease received a kidney transplantation following a specific in-house drafted protocol, without the use of prophylactic eculizumab infusions. Recurrence of aHUS was only observed in 1 of these 17 patients and no chronic sequelae were detected after rapid initiation of eculizumab. With this approach a cost reduction of €20 million was achieved.

These pilot studies paved the way toward a new Dutch guideline for the treatment of aHUS. This guideline was written by the national aHUS working group led by N. van de Kar and J. Wetzels. The guideline advocates the use of a restrictive treatment protocol of eculizumab. Meanwhile the Radboudumc has set up a nationwide, prospective, observational, study (CUREiHUS study) to monitor all aHUS patients treated with this new guideline. Blood is drawn to study potential biomarkers to predict among others recurrence, and to evaluate therapeutic drug monitoring with the potential to individualize therapy. Furthermore, cost-effectiveness analysis and budget impact analysis will be conducted. 
 
Our studies and initiatives, all in close collaboration with the Dutch Kidney patient association, have helped approval of eculizumab treatment by the national healthcare institute. They decided to reimburse eculizumab for 4 years, with the restriction that all patients need to be treated according to new guideline and (when possible and after informed consent) need to be included in the CUREiHUS study so all patients will be monitored closely.