What drives our alumni?
What drives our course participants and alumni? These entrepreneurial biomedical professionals from academia and industry all work to improve human health. What is their motivation to do what they do? What is their vision for the future of their field?
We’ll start the series off with Juul van den Reek, MD PhD, epidemiologist in training in the dermatology department of Radboud University Medical Center in the Netherlands. Juul’s work focusses on biologic treatment of plaque psoriasis. She recently completed the PJ Futurelab blended course Clinical Development and is finalizing her clinical trial proposal for submission in the “PJFL Best Clinical Trial Challenge” and a chance to win a €500.000 ZonMw grant. In this interview, she shares her thought on the urgent questions in the field and highlights the importance of pragmatic trials in drug development.
From clinically relevant data to personalized medicine. At the moment, a lot of expensive drugs [biologics] are available and new drugs are introduced to market that claim better performance. However, we know that these agents often have different results in practice than in early phase clinical trials. We think that it is very important to better connect RCTs with real-world evidence. The existing biologicals for psoriasis are TNF-alpha or interleukin IL-17 or IL-23/IL12-23 inhibitors, but the real-world evidence with these agents is lacking. We would like to give clinicians the information they need to make the judgement how to treat and which patients to treat with which agent. For example, co-morbidities, other medication, recent malignancies, and pregnancy, these are all indications to exclude patients from RCTs. But these are the patients that we are treating in real life, especially in tertiary centers.
Although biologics are reimbursed by most health insurance companies in the Netherlands, biologics are relatively expensive. They are indicated for moderate to severe psoriasis and strict requirements exist for reimbursement e.g. failure with other treatments and intolerance for light therapy.
Another urgent matter, which is of course difficult to solve, is personalized medicine. We are searching within other fields, such as genetics and immunology, to find predictors that will help us use the available agents as efficiently as possible. Right now, many treatments are by trial and error: we treat with agent A and if it doesn’t work, we try agent B. This is very inconvenient for the patient because we have to wait a few months before we can switch to another agent. In the meantime, the patient continues to suffer from active psoriasis. It is also very costly because we have to find the correct starting dose each time, we do all the lab and then after 3 months we have to conclude that it isn’t working.
Biomarkers in the broadest sense. We are looking for biomarkers in the broadest sense which also includes clinical biomarkers. For example, we know that women generally don’t respond very well to certain agents. Being a woman can of course not directly be considered a biomarker but it can have a large impact on the results. In addition, we are looking at pharmacogenetic markers, e.g. if certain SNPs [single-nucleotide polymorphisms] or genes can predict effecacy, and immunological markers such as cytokines and if we can predict responses based on immune phenotyping.
Recently published studies in the Britisch Journal of Dermatology showed correlations between pharmacogenetic markers and response to biologic treatment.
*Variations in CD48 SNP predicts response to etanercept use (van den Reek, Coenen, Arias et al, BJD 2017;176(5):1288-96)*
*HLA-Cw6 is a promising predictor for ustekinumab response (van Vugt, van den Reek, Coenen en Jong, BJD 2018;178(17):86-94)*
These are all prospective studies. In 2005, the RadboudUMC set up a prospective registry to collect real-world safety and efficacy data from patients who are taking biologics. The clinical data comes from 16 dermatological centers in the Netherlands, including UMC Utrecht, Maastricht and several peripheral center. In addition, we collect blood and DNA samples from these patients and the aim is to couple the registry data with the blood and DNA data.
Looking beyond your own little niche. The RadboudUMC is a great environment to work. Part of the mission statement of RadboudUMC is to work along the full spectrum of medicinal research: from molecule to human. Within RadboudUMC we are part of an overarching theme inflammatory diseases together with, amongst others, gastroenterology and rheumatology. We have shared meetings and research proposals with these groups. It is a useful collaboration because we each have our specific experience with these agents and learn from each other. It also allows you to share your research with a wider audience. It is important to look beyond your own research towards what could be possible in the future, an important lesson that is stimulated by RadboudUMC and is also embodied in the course from Futurelab. For my work, this is what I mean when I say we should look beyond the selected patient groups.
Juul during the Clinical Development on-campus course in June 2018
Need for more pragmatic trials. We need to have more pragmatic studies included in clinical trials so that trial data is more comparable to real-world practice. Look beyond a selected patient group and adhere to less stringent in- and exclusion criteria to assess agents in patients like those who come to the dermatologist’s office. This will give us, clinicians, much more information about how to deal with failures. It would be beneficial for manufacturing companies to investigate this while the drug is still in development, for example adding a randomised pragmatic phase 3 trial.
Recently we had, for instance, high expectations of a new drug which was really successful in early clinical trials. In clinical practice, the experiences were different because the drug was initially prescribed to patients that failed many other biologics before. Our analyses showed that patients who were treated with more than 2 agents did not respond well to it, while patients who had not used other biologics did respond well (the early clinical trial patients). Such data are very important in practice to assign the drug to the right population.
These analyses were recently published in Acta Dermato-Venereologica: van den Reek, van Vugt, van Doorn et al, Acta Derm Venereol 2018;98(7):648-654.
Winning the US National Psoriasis foundation fellowship 2017. It was a great honor to win that fellowship. It helped me to shape the research plan for the immunological and genetic predictor studies. It was also great to visit the National Psoriasis foundation symposium to present my research. I hope it may lead to more collaborations with research groups in the US.
Next step in psoriasis predictors. We now want to take the next step to find predictors for the treatment of psoriasis. Winning this grant would be a big contribution towards finding a patient-friendly way to expand this research. Psoriasis is a skin disease and it is possible to measure cytokine levels with a skin patch, meaning that we would no longer need invasive tests. This ultimately saves the society a lot of money and spares the patient significant discomfort. Especially for children and elderly this would be a big improvement. These patches already exist and they are produced by several manufacturers. But, we must validate this way of measuring by comparing with blood and biopsies. There are still many unknowns. After doing the Futurelab course, I completely rewrote my protocol. I realized that we needed to take a step back and put more effort in understanding what the patches can actually measure, how we can validate these results, and if the patches are able to accurately detect responses to treatment.
This grant refers to a €500.000 grant from ZonMw. Juul is finalizing the clinical trial proposal that she started during the PJ Futurelab Clinical Development course and will submit her proposal in the “Best Clinical Trial Proposal” Challenge for a chance to win the competitive grant.
*The winner of the “Best Clinical Trial Proposal” Challenge 2018 has since been announced. Read more*
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