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Reducing attrition in drug discovery: The role of biomarkers

20 June 2011  •  Author(s): Sheraz Gul, Vice President & Head of Biology, European ScreeningPort GmbH

The development of most diseases is often attributed to the dysfunction of the activities of key proteins involved in biological processes and their modulation by a therapeutic agent is considered to offer the potential to alleviate the disease state. However, prior to discovering a therapeutic agent, it is usually necessary to identify and validate that a particular protein is the underlying cause of the disease. It is often the case that a single target is implicated as being the cause of more than one disease. This suggests that particular focus needs to be paid to validating these targets for drug discovery purposes as many experimental drugs that are designed to modulate the activity of a specific protein often fail to exhibit efficacy during clinical trials. The role that biomarkers can play in reducing attrition observed in drug discovery will be discussed in this article.

The discovery of therapeutic agents in drug discovery is a time consuming, expensive and risk averse process. A recent analysis that can be generally applied to the drug discovery process suggested that more than 24 target-to-hit projects are required in order to deliver a single marketed therapeutic agent1. Further analysis was made by categorising the attrition in relation to each of the well known milestones of the drug discovery process. Approximately half of the experimental drugs failed to progress from Phase I to Phase II suggesting that despite the rigorous evaluation of the experimental drug in the pre-clinical stages, safety related issues were a major contributor to their attrition. Of those that did not have any safety related issues, two-thirds of the experimental drugs still failed to progress from Phase II to Phase III, suggesting that they did not demonstrate efficacy in the primary disease indication. Likely reasons for this attrition include the possibility that the experimental drug undergoes metabolism, its mechanism of action may vary, use of sub-optimal experimental drug dosage, and in some cases the presence of slow and/or non-responding patients. Even if the experimental drug is shown to act upon the intended target in patients but does not lead to efficacy, it is also possible that the target is not a valid one for therapeutic intervention2. Thus, a large number of experimental drugs have been developed to modulate the activities of their respective targets and progressed to the clinical stages of drug discovery, fail to demonstrate efficacy.

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