A biomarker is a characteristic of a biological process that occurs naturally or during pathogenesis, and it can serve as a function of therapeutic intervention. Biomarkers are an essential part of drug discovery, all the way from pre-clinical discovery to clinical validation and implementation, and the importance of biomarkers in decision-making continues to increase.
Better informative biomarkers can increase the likelihood of drug advancement or approval, and implementing biomarkers increases the success rate in drug development.
Clinical decision making is relying more and more on the importance of biomarkers. However, biomarkers validated to high standards, and biomarkers that reflect biological and pathological processes accurately are still a growing area. Such biomarkers are needed to develop treatments faster, and to improve and guide clinical trial design by selecting and de-selecting patients.
The value of using biomarkers in clinical drug development is profuse, and the results are often significant improvements in trial design, evaluation, and outcome.
The table below summarizes the different uses of biomarkers across the spectrum of clinical development, from pre-clinical research through early- and late-stage clinical development. In many cases, biomarkers form the basis of clinical decision making, making them necessary and highly valuable tools.
Table 1. Clinical utility value of biomarker implementation.
Protein biomarkers are often used for various applications during drug development, including initial mechanism of action, on- and off target effects, proof of concept and in guiding dose-selection for clinical trials. An essential fact of drug development is that biomarkers of ECM remodeling provide tools for evaluating changes to the ground substance in the organs. This is because collagens and other ECM proteins make up the main bulk of organs.
In fact, more than 50 different diseases are associated with changes in the tissues of organs, tissue formation or degradation, leading to tissue changes that affect tissue function. For example, dysregulated tissue homeostasis is a common feature associated with fibro-inflammatory diseases. It is implicated as both a cause and consequence of disease and outcome, is associated with up to 35% of deaths in the western world and is projected to increase. To be truly efficacious, and not just symptomatic, drug developers should also focus on treatments that affect the organs and reverse the organ damage conflicted in the ECM.
Figure 1. Quantifying pathological tissue turnover distinguished from healthy tissue turnover. During normal tissue homeostasis, there is a balance between tissue formation and degradation, necessary to preserve tissue function. In disease affected tissue the balance is distorted, which can lead to impaired tissue- and organ function. These processes can be quantified by biomarkers reflecting ECM turnover, but advanced assays measuring specific neo-epitopes are needed which accurately quantify both tissue formation and degradation, in order to quantify the balance.
The process of tissue formation and degradation is constantly ongoing but turns pathological when deposition of newly formed proteins exceeds the degradation or vice versa. These tissue changes can be monitored non-invasively in blood tests, however, it is important to know exactly what the applied biomarkers reflect. Specific neo-epitope generated biomarkers serve as a more accurate measure of ongoing tissue modulation as compared to epitopes that are generically generated, which impacts the information and utility that can be derived thereof (figure 1).
Biomarkers accurately reflecting ECM turnover can be used as measures to quantify ongoing tissue remodeling in diseases, which provide crucial information on disease status, risk of progression and risk of adverse outcome.
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