CUREiHUS (ENG)

The acronym CUREiHUS derives from the words “Curious” and “Cure” in HUS.

Worldwide, there is a need for prospective studies to determine the optimal duration of treatment with eculizumab and evaluate prediction markers. Recently, the national, prospective study called CUREiHUS (Full project title: National observational study to monitor the new guideline concerning treatment of patients with atypical hemolytic uremic syndrome, NTR5988) has started in the Netherlands. This study will include all aHUS patients and will monitor and evaluate the restrictive treatment regimen according the new Dutch guideline. With the CUREiHUS study we hope to show that a restrictive treatment regimen is feasible. Moreover, we want to investigate the potential efficacy of this new treatment regimen from a societal perspective with the design of a cost-effectiveness analysis. Furthermore, we will look into the pharmacokinetics and dynamics of eculizumab.

Rationale

Hemolytic uremic syndrome (HUS) is a rare, but severe thrombotic microangiopathy (TMA), that is characterized by the triad hemolytic anemia, thrombocytopenia, and acute renal failure. Atypical HUS (aHUS), an orphan disease, is seen in 5-10% of all HUS cases (estimated prevalence 1-9/1.000.000 cases per year in the Netherlands), occurs at any age and has a very poor outcome: mortality in the acute phase of the disease is 2-10% and up to 50% of patients will develop end stage renal disease. Since end 2012, there is a new drug, named eculizumab, available for the treatment of aHUS. Eculizumab is a monoclonal antibody against C5 and subsequently inhibits formation of the terminal complement complex. With the use of eculizumab, the outcome perspectives have drastically improved for patients with aHUS. Currently, this treatment regimen with both doses and duration of treatment is highly debated.

The first and most important reason to debate this duration is that historically plasma therapy could be tapered and stopped in most patients. Hereby leaving only a small proportion of aHUS patients depended on chronic plasma therapy. Even though, eculizumab improves the health-related quality of life, the burden of this lifelong treatment is still tremendous. Patients have to return to the hospital every fortnight, their entire lives. Moreover, it is noteworthy that there are no studies that provide strong evidence in favor of lifelong treatment with eculizumab.

Secondly, the long term consequences of the treatment with eculizumab are unknown. The most prominent risk is the development of a severe meningococcal infection. Other adverse outcome include: the possibility of developing (neutralizing) human antihuman antibodies, or immune-mediated drug reaction. Other unknown side effects is not yet fully comprehended. Only recently a study was published about the potential hepatotoxicity of eculizumab.

Thirdly, recent studies and our own data indicate that we exceed the pharmacodynamic target with the current treatment schedules and that despite the severity of disease, we may need less drug for effective treatment in most patients. Eculizumab concentrations in serum of patients that are treated with the recommended dosing regimen can be up to fivefold as high as reported by EMA to achieve complement inhibition. An average of 261-500 µg/ml eculizumab levels are measured in eleven patients with eculizumab treatment according EMA protocol, instead of the 50-100 µg/ml which is recommended.

Finally, eculizumab is considered one of world’s most expensive drugs with costs as high as €500.00 per patient per year. In the end leading to both political and ethical discussions regarding costs of Healthcare. In the Netherlands, this led to the development of a new Dutch guideline, drafted by the National Working Group aHUS, which enables a restrictive eculizumab regimen. Patients are divided into different groups and will either receive plasma therapy or eculizumab depending on age and their risk profile. After three months therapy is accessed and in case patients are stable and shows no signs of active TMA, therapy is withdrawn.

The implementation of this guideline led to a whole new political discussion in the Netherland. Only recently, the National Health Care Institute of the Netherlands declined reimbursement of eculizumab as lifelong therapy. This decision derived mainly from the lack of clear insight in costs effectiveness as provided by the pharmaceutical company. However, with the implementation of this new guideline, which is showed to be (cost) effective and safe, eculizumab is reimbursed, solely when subscribed according the new guideline. This advise was restricted by one important term: strict monitoring of all aHUS patients and a planned evaluation after four years.

CUREiHUS study

In 2016, the nationwide prospective study, abbreviated as CUREiHUS (NTR5988), started in the Netherlands. All aHUS patients are included in a registry, independent of the pharmaceutical company as also suggested by Karpman et al., to monitor and evaluate this restrictive treatment regimen according the new Dutch guideline. In this prospective, observational, cohort study we want to monitor this new guideline concerning the treatment of patients with aHUS in the Netherlands and investigates the potential efficiency of this new treatment regime for patients with aHUS from a societal perspective. The design of the economic evaluation follows the principles of a cost-effectiveness analysis and adheres to the Dutch manual for costing research. All this input will be used in a decision analytic model with a lifelong horizon taking into account discounting. The discount rate follows the Dutch guidelines for pharmaco-economic evaluation. Clinical symptoms, biochemical parameters as well genetic data will be gathered in an online webbased database, Castor. After four years the data will be evaluated within the Dutch aHUS working group.