On the 11thof March, Prof. Geert Jan Groeneveld delivered his inaugural lecture as Professor of Clinical Neuropharmacology at Leiden University Medical Center (LUMC). During his lecture, titled ‘The importance of the biomarker - and how unravelling neurological diseases leads to new targets for drug research’, he discussed his expectations for a shift towards and an exponential increase in targeted treatments for neurodegenerative diseases such as ALS, Parkinson’s and Alzheimer’s Disease, due to increased knowledge of the genetic background of these diseases. He linked this development to the work he does at CHDR, which is quantifying drug effects in early phase clinical trials using specific methods and biomarkers that are developed and validated in house. The unravelling of neurological diseases leads to new targets for drug research, and each of those targets leads to new drugs, which will have to be investigated using pharmacological biomarkers.
Groeneveld mentioned a program CHDR conducted on behalf of sponsor Lysosomal Therapeutics as an example. The most common genetic risk factor known to date for Parkinson's disease (PD) is a mutation in the GBA gene (GBA1), which leads to reduced activity of the lysosomal glucocerebrosidase enzyme. Lysosomal Therapeutics developed a compound, LTI-291, that enhances glucocerebrosidase activity. The expectation was that this compound would reduce disease progression of patients with Parkinson's who have a mutation in the GBA1 gene. To identify these patients for the clinical trial, we did a large‐scale GBA1 screening in collaboration with a consortium of neurologists across the Netherlands. Approximately 15% of the Dutch PD patients was shown to have a mutation in the GBA1 gene. To subsequently investigate whether the drug worked in those patients and what the correct dose would be, we validated a biomarker for the clinical trial: the concentration of glucosylceramide, a substrate of glucocerebrosidase, in peripheral white blood cells. We showed that LTI-291 treatment indeed influenced the concentration of glucosylceramide in the cells, indicating that the drug works in these patients, and leading to its further development at a large pharmaceutical company.
According to Groeneveld, this potential drug was one of the first resulting from the genetic revolution of neurodegenerative diseases, but it will certainly not be the last. These new, targeted treatments may only be effective in part of the patients. For example, a drug targeting a mutation in the GBA1 gene may only be effective in the 15% of PD patients that has this specific mutation. Groeneveld therefore anticipates a division of patients into -genetic- subgroups, which all require specific treatments. The methods and biomarkers he develops must evolve along with this revolution, so efficacy can be investigated as early as possible in the clinical development trajectory. This contributes to a higher efficiency of drug research and thus to a cheaper development process, and if all goes well, eventually cheaper medicines. And that is the piece of the puzzle that Prof. Groeneveld plans to add to this exciting transition that awaits us.