Innovative drugs need innovative methodology!

In drug development it is important to try to answer as many questions as possible in as few drug studies as possible. If you expose humans –or other animals for that matter- to new and potentially harmful compounds, then not getting everything you can out of it, seems a waste. After a new drug has successfully passed the stage of animal studies, a “first in human” study is planned in which  -traditionally- pharmacokinetics of the new drug and potential side effects of the compound are determined. In this phase, however, it is likely that humans will be exposed to a broader range of drug doses than ever thereafter. An ideal opportunity to also try to determine the intended pharmacological effects of the new compound. To do that you need the correct methodology and this is often unavailable.

Luckily, more and more pharmaceutical and biotechnology companies are seeing the added value of this approach. CHDR’s self-funded research is focused on the development of new biomarkers and methodology to show pharmacological effects of new drugs in the earliest stages of clinical drug development. There is a new trend: co-funding of this type of research by a pharmaceutical company with a particular interest in the new method rather than just the new medicine.

Multiple Sclerosis is caused by inflammation that leads to demyelination -loss of the myelin sheath around neurons- in the brain and spinal cord. Existing therapies target inflammation and thus lead to inhibition of demyelination. However, new MS drugs are being developed, that target enhancement of the formation of new myelin and hence improvement of the function of demyelinated neurons. These targets are completely new and methods to quantify the effects of these innovative drugs therefore don’t yet exist. In collaboration with a biotechnology company, we developed and validated a method that uses labeling with deuterated water to estimate the speed at which new myelin is formed in the central nervous system. Healthy subjects drank 120 mL of “heavy water” per day for a period of 10 weeks and we performed repeated lumbar punctures to obtain cerebrospinal fluid over a period of almost half a year. We then extracted myelin breakdown products from the CSF and measured the rate of weight increase of the molecules, which was caused by incorporation of deuterium instead of hydrogen in newly formed molecules. These measurements, in combination with mathematical modeling, allowed us to estimate the rate of myelin formation.

Being able to quantify the rate of myelin formation will be essential in the process of developing a drug that is expected to positively influence remyelination. This may ultimately lead to a new treatment for patients with MS, which is much needed. But the method by which metabolic processes that occur within the confined space of the brain can be quantified using something as innocuous as water, may in turn contribute to the rational drug development of many other future CNS drugs.

Geert Jan Groeneveld

The end of the multicenter phase II trial starts in Leiden

Clinical 03A- MQ

When performing clinical trials with novel compounds in patients there is always one major challenge. How can we enroll all 50 patients within a couple of months? Whenever CHDR gets this question we have a solid answer. Collaboration.

In 2014 we performed a proof-of-concept phase 2 trial in moderate to severe psoriasis patients. Not an easy population to recruit, especially not in summer when psoriasis tends to be better. Performing such a trial in normal circumstances involves one coordinating CRO and 15-20 hospitals. The enrollment of the 44 patients would take 7-8 months and an estimated 25 dermatologists would be co-investigators assessing the diseased skin of 1-2 patients each. Many of the centers will not recruit a single patient but require full initiation.

We chose a different path. Before start of the trial we approached all dermatologists of Western Netherlands. Although not the biggest country, we reached more than 180 dermatologists of which many were enthusiastic to help identifying potential patients in order to carry out high-quality research. At the same time we reached patients directly using an advertising campaign. And something extraordinary happened. Together with our dermatology partners we were able to enroll a total of 46 patients in 6 months. All assessments were performed by two dermatologists from the Erasmus MC at CHDR. With only two assessors we derived very consistent data, without large variability due to inter-observer variance. The logistics, execution and study handling was much less complicated since all was done at one site. And, most importantly, the patient experienced a professional and fully dedicated research atmosphere instead of a very busy outward patient clinic with long waiting times and bad coffee.

In dermatology this is a record-breaking performance in terms of speed. For the dermatological community in the Netherlands this first proof-of-concept study within the Dutch Trial Network Dermatology means a very important success on the road to more collaborative projects. After this kick off there are many projects evolving.

Obviously, this approach is also taken for other indications and other research fields. For the landscape of drug development this is an important change. Phase 2 trials can be efficiently executed at a single site with multicenter recruitment using both doctors but also direct-to-patient advertising. Data-rich early clinical phase trials with sophisticated and expensive methodology become feasible, e.g. taking advanced skin photographs, fMRI, PET etc. What do you need to engage these research communities? Again, the answer is strong collaboration between researchers, practicing physicians and above all the patients. The Netherlands is perhaps the ideal place for this, with a well-educated patient population who want to be involved in the scientific aspects of their disease and a tightly knit clinical research community. However, one questions remains. Why do we still need to perform multicenter trials in the way we did?

By: Robert Rissmann, Senior Clinical Scientist Dermatology