Prof. Geert Jan Groeneveld: the revolution in neuropharmacology is underway

Neurodegenerative diseases will become increasingly important in the coming years due to decreasing mortality from cardiovascular diseases and cancer. The good news is that (genetic) research into these diseases is yielding more and more targets for therapy. As Groeneveld puts it: ‘It’s becoming increasingly clear that the non-hereditary forms of these neurodegenerative diseases are also caused — or partly caused — by genetic defects. The speed at which new genetic mutations are being discovered is increasing and shows no signs of slowing down.’

Biomarkers and neurodegeneration

The lecture focused largely on clinical drug development in neuropharmacology, driven by a central question: how can we demonstrate that a novel drug for a very slowly progressing neurodegenerative disease actually works, and that it affects a process that we may have only recently come to understand and which has never before been measured in humans? As already revealed by the title of the lecture, biomarkers provide the answer.

Groeneveld illustrated his point with research conducted by CHDR’s Neurology group, which he led for many years. This research was conducted in a subgroup of patients with Parkinson’s disease (PD) in whom the activity of the enzyme glucocerebrosidase is reduced due to a genetic mutation. The compound the team investigated aimed to increase glucocerebrosidase activity.

To demonstrate a pharmacological effect of the drug, the team used a measure of glucocerebrosidase activity in white blood cells. However, before they could use this measurement as a pharmacological biomarker, a lot of preliminary research first had to be carried out by CHDR’s Research & Development lab, for instance on the natural fluctuation in the activity of glucocerebrosidase in white blood cells. In addition, it was necessary to screen a large group of PD patients in order to select the subgroup with the genetic mutation. Thanks to all this groundwork, the pharmacological effect could be demonstrated, and the compound is now in the next stage of development.

Ongoing research

Groeneveld also spoke about the pain research he conducts at CHDR, partly in collaboration with the Leiden University Medical Center. This research is also concerned with developing biomarkers to map the pharmacological action of new drugs, as well as thoroughly defining subgroups of patients. In conditions such as neuropathic pain, the focus is not so much on genetic differences, but rather on defining subgroups through better phenotyping.

In the booklet published to accompany the lecture, Groeneveld further argued for a ‘leaner’ version of Good Clinical Practice (GCP) requirements, which could reduce the cost of drug development. ‘I think it’s feasible to provide scientific evidence that a lean GCP interpretation is not inferior to the current “fat” version. This may encourage regulators to change. I foresee potential for a collaboration between regulators and academics to carry out these studies,’ says Groeneveld.