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