The R&D process in steps
Each new medicine follows the same precisely defined development path right across the pharmaceutical industry:
1. Target biology
Target evaluation
In this first phase we look at new biological points of action in the body that are involved in processes of diseases. These points of action are also called ‘targets’. They form the starting point for the screening of potential medicines. Ideas for new targets may arise from internal research and via external sources, like scientific literature. With the present biotechnological knowledge we have a better understanding of the way cells should function as well as what goes wrong in case of a disease.
New genes and proteins and their functions are being
detected and quickly become new targets for therapeutic intervention. In addition, we start looking for biomarkers, i.e. proteins or metabolites that are influenced by the target of interest and, may reveal a possible therapeutic effect or mechanism. Our technology platform and the excellent skills of our biotech partner Innogenetics and GENFIT help us develop our targets.
Assay-development and hit finding
The next step is the development of measurement systems or ‘assays’ for the selected target. They are the starting point for our search for chemical compounds that are able to influence the target involved. With robots we test large numbers of chemical compounds on a possible effect. The
screening robots work day and night and are able to test thousands of compounds a day. If a compound is recognized with a certain activity we have a ‘hit’.
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2. Chemical design and synthesis
Hit-to-lead
Based on the hits discovered in HTS, new variants of a compound are designed of which we change the chemical structure. A minor change in the chemical structure can lead to a major improvement of the biological activity of a compound. For the optimization of molecules we use advanced three-dimensional computer models. Thanks to the introduction of automated synthesis techniques, the number of chemical compounds that are synthesized each year has increased considerably. Our automated synthesis facilities are capable to create tens of thousands of chemical compounds each year for further screening.
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3. Lead optimization
On a yearly basis we test thousands of chemical compounds for their biological activity and availability. We call these compounds ‘verified hits’. For the investigation of the verified hits we have a great number of tests to our disposal. As we proceed further in the discovery process, the complexity of the tests increases: from a membrane or enzyme, to a single cell and from a cell to cell tissue, in which the effect of a compound is established. The remaining compounds are further tested in vivo (animal experiments). We investigate, for instance, the compound’s effect on the animal’s behaviour or on physiological parameters such as blood pressure. The biological availability is determined by studying the uptake of the compound by the body and its ability to reach the correct destination, in other words: its site of action.
In this phase of research a considerable number of compounds will be eliminated. Based on the test results, medicinal chemists will further “fine-tune” the chemical structure of the lead compounds. In the end only a few of the verified hits remain. They show an effect over a certain time in the right place. These remaining compounds are called ‘optimized leads’.
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4. Preclinical drug development
Lead profiling and safety examination
Before a compound is administered for the first time to healthy volunteers we have to be absolutely sure that no harmful side effects will occur. Therefore a number of safety and toxicology experiments are carried out. Detailed efficacy studies in different disease models supply us with better information about the way a compound behaves in the body. The route of a compound in the body is examined as well as the amount and the speed of absorption. We want to know how the compound will be spread over the different organs, how the liver breaks it down and how it is excreted by the body.
In this phase of research we do pharmacological, toxicological and metabolic studies. Depending on the results we decide whether to develop the compound in clinical studies. In this respect the development and validation of biomarkers started in target biology may help us prioritize these compounds. A positive decision means that a new ‘clinical candidate’ is available.
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Clinical Development
Clinical drug development can be subdivided into four phases:
Phase I
Trials on healthy human volunteers, aimed at measuring safety and tolerance, rather than efficacy with an initial approach to dosages. These trials are usually
executed in hospitals under close supervision of physicians.
Phase II
Testing the effectiveness of the compound, measuring benefits against potential risks, and more precise defining of administration dosages. The compound
is tested in 100 to 300 patients who are in need of treatment and have volunteered for the tests. All patients are carefully monitored by independent
physicians.
Phase III
Worldwide large-scale trials are carried out on thousands of patients, principally in order to confirm the effectiveness and safety, and to meet the requirements
of the health authorities. Our product is compared to other existing drugs or to a placebo. All study results have to be brought together in a registration
file which we submit to the health authorities for registration. After approval, which usually takes one to three years, the drug is officially registered
and we can introduce it for commercial use.
Phase IV
Additional trials are aimed at fine-tuning the use of the medicine in practice, in accordance with the approved labeling of the drug.
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