Atypical HUS in the Netherlands



Combining research with deep experience in atypical HUS clinical care, the Dutch team at Radboudumc hosted a November 9-10 2018 aHUS Patient Symposium.  This event held in Nijmegen NL, in affiliation with Nierpatiënten Vereniging Nederland (NVN) and patient organization aHUS NL, was attended by advocates from several nations and groups to include the aHUS Alliance.
Fresh from their presentations titled Suboptimal Dosing of Initial Eculizumab Therapy in aHUS?  and  The Dutch Initiative to improve therapy and economize healthcare in atypical  HUS at ASN 2018 Kidney Week in San Diego (USA), the Radboudumc team has recently published an article, Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use, which references data from the CUREiHUS national study (NTR5988).  The Dutch team kindly agreed to answer questions posed by the aHUS Alliance, which are shared below.  Special thanks to Dr. Nicole van de Kar, Dr. Jack Wetzels, Dr. Caroline Duineveld,  and Dr. Kioa L. Wijnsma for their valued assistance with this article.

Questions?  Please Contact:  

OR   the aHUS Alliance:

What do you see as key issues currently facing aHUS patients and their physicians?  In NL versus other nations?
With the introduction of eculizumab, aHUS became a curable disease. This had of course major impact on the lives of patients with aHUS. In contrast, the debate regarding the optimal treatment scheme is mainly lead by professionals and politicians. Especially with such a rare disease, the patient organizations play an important role to unit all the patients and give them one voice to speak up against these same professionals and politicians. In the Netherlands, we have a close and steady collaboration with the national patient organization which helped us immensely with the drafting and implementation of the CUREiHUS study. Without the help of patients and the patient organizations, our study would not have stand ground. In our opinion, all nations should seek such contact with the patient organization, to collaborate and investigate key issues which patients are facing.
The Radboud team has both clinical and research interests.  Help us understand the many facets of your work.
The Radboudumc is an university medical hospital and expertise center for patients with thrombotic microangiopathy (TMA), among others aHUS, in the Netherlands. To provide optimal care, we believe in the strength of a multi-disciplinary team. Our team comprises among others clinicians, both pediatric nephrologists as nephrologists, pharmacist with special interest in eculizumab, the national reference laboratory for complement mediated disease and eculizumab treatment, close collaboration with health evidence department to investigate cost-effectiveness, and as stated previously all in close collaboration with the patient organization. In frequent meeting we share our experiences and have mutual benefit from each other field of expertise. For example in the CUREiHUS study, all facets (clinic, diagnostics, research, pharmacology, health technology assessment) are united, with dedicated physicians such as Dr. Nicole van de Kar (chair of the national working group aHUS) and Professor Jack Wetzels.
What is the CUREiHUS study, and why is it important to aHUS patients and those physicians who treat them?
The CUREiHUS study is the acronym of the study entitled: “National and observational study to monitor the new guideline concerning treatment of patients with atypical hemolytic uremic syndrome”. In 2016 a new Dutch guideline was implemented, drafted by the national working group aHUS. Within this guideline a new and restrictive regimen with eculizumab is described. In short, patients receive eculizumab for three months after which therapy is evaluated. When a patient is stable and in remission eculizumab therapy can be tapered or withdrawn.
The implementation of this guideline led to a whole new political discussion in the Netherland. In 2016, 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 advice was restricted by one important term: strict monitoring of all aHUS patients and a planned evaluation after four years.
All aHUS patients treated according this new guideline will be included in the CUREiHUS study, which is set up independently  of the pharmaceutical company as also suggested by Karpman et al. In this prospective, observational, cohort study we want to monitor this new guideline concerning the treatment of patients with aHUS in the Netherlands and investigate the potential efficiency of this new treatment regimen for patients with aHUS, also from a societal perspective. After four years the data will be evaluated within the Dutch aHUS working group.
We’ve heard the term ‘precision medicine’ and the idea about giving the right drug to the right patient for the right period of time. How can a patient’s length of treatment safely be determined?
In all fields of medicine, objectives for personalized medicine increases. Especially in children, dosing of drugs per weight is daily practice. Current dosage schedules of eculizumab result in large inter-individual drug concentrations. Moreover, every patient is different and reacts differently to a drug, hence no surprise individualized therapy is needed to optimize treatment per patient. One way of achieving this is via so called therapeutic drug monitoring (TDM). For TDM, the drug concentration in blood will be determined together with the elimination rate of the drug, and therapy can be adjusted accordingly. With this we can secure administration of appropriate dosage with a certain defined interval and we can prevent overtreatment for the individual patient. For example, one patient can have steady drug levels above the set target for 21 days of even 28 days, instead of the 14 days which is used now for all patients. This results in an increased interval between the eculizumab administrations up to 4 weeks.
Besides tapering (spacing the interval) of eculizumab therapy, eculizumab can also be withdrawn. As described in our review just published in Pediatric Nephrology we think there are different strategies to withdrawn eculizumab treatment in patients with aHUS. Depending age, pathogenic mutation, transplant history and other patient characteristics different strategies are possible to adjust eculizumab therapy. Most importantly is close monitoring of these patients for signs of recurrence and clear instructions for the patients and caregivers when to contact the physician. Overall, 171 patients are described in literature in which eculizumab therapy was discontinued after a median of 6 months. Looking at these data, withdrawal of eculizumab therapy in patients with aHUS seems safe and effective. Yet, studies like the CUREiHUS study have to provide additional information if withdrawal after 3 months is equal to withdrawal after 6 months (like the STOPECU trial for example).
How will the CUREiHUS study fit into a broader view that includes past research (such as Ardissino 2014 in Italy) and current studies (such as the STOPECU clinical trial in France)?
Especially in patients with aHUS, personalized therapy could be of great added value to maximize effect and minimize patient burden. To our knowledge, only 2 prospective studies (CUREiHUS study and STOPECU) are registered to determine if a restrictive eculizumab regimen is safe and effective. To investigate this, it is crucial to develop a clear protocol describing when to start eculizumab, and how to taper and discontinue therapy. Hereby all patients will be treated with the same protocol. The CUREiHUS study fulfill these criteria, and hereby could provide us which new insights in start and stop criteria for eculizumab treatment in patients with aHUS. Furthermore, a clear cost-effectiveness analysis like in the CUREiHUS study, taking into account health care consumption during treatment and after withdrawal together with quality of life, is essential for reimbursement policies in various countries.
CUREiHUS explores issues surrounding eculizumab therapy for aHUS patients, but in what ways might the study’s findings have potential to impact future use of new aHUS therapeutic drugs?
The CUREiHUS study comprises a national database, in which a large amount of data is collected of all aHUS patients in the Netherlands. Furthermore, blood is drawn al the patients to investigate potential biomarkers in the future to predict for example disease recurrence. Concluding, the CUREiHUS study provides us already with a large amount of detailed information regarding aHUS patients. Our independent registry could be adapted in case new therapeutic drugs enter the market.
Furthermore, with the introduction of the CUREiHUS study and the national working group aHUS, a new trend has developed in the Netherlands. Our initiative serves as an example of how to deal with (expensive) orphan drugs, in which clear start and stop criteria need to be formulated, together with the introduction of a registry and group of experts leading this initiative.
Without the help and knowledge of Andrei Sarlea, Dr. Elena Volokhina, Prof.Dr. Bert van den Heuvel, Dr. Rob ter Heine, Dr. Yvet Kroeze, Drs. Nienke Sonneveld and Dr. Eddy Adang the CUREiHUS study would not be possible.

The aHUS Alliance is deeply appreciative of the efforts of the Radboudumc team, and their willingness to answer questions of global interest to stakeholders interested in the rare disease atypical HUS.

The Radboudumc team is recognized for their excellence by the aHUS Alliance as a center of study for aHUS and TMA, learn more about this aspect of their work by clicking HERE.
9 & 10 November 2018 –  aHUS Alliance attends the aHUS Patient Symposium.  Gain key insight with the our article, written in real time as events unfolded:  aHUS Conference “THE DUTCH APPROACH”

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