Contributing author: Karen Briley-Saebo, Senior Director PET Imaging @ Antaros Medical
Biomarkers or ‘biological markers’, can help us to better understand both normal and pathological biological processes in the body. In the context of drug development, biomarkers enable us to evaluate disease pathogenesis, monitor treatment response, and can be used to stratify patient populations for enrolment into clinical trials.
Currently there are many different definitions for what constitutes a biomarker in the drug development industry. This lack of consensus on what a biomarker is and how it should be employed has somewhat limited the use of biomarkers in drug development research. This is especially true of imaging biomarkers, which can, among others:
- Provide information about mechanism of action
- Quantify changes related to treatment response, and
- Reduce study duration or the required number of subjects
This blog post will describe what imaging biomarkers are and how they can be used in clinical trials for drug development. We will also use the example of metabolic dysfunction-associated steatotic liver disease (MASLD) / metabolic dysfunction-associated steatohepatitis (MASH) to illustrate different types of biomarkers and the various ways they can be used.
What is a biomarker?
Attempting to establish a set of definitions and a consensus, the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) formed a joint task force to create the Biomarkers, EndpointS, and other Tools (BEST) Resource, landing on the following definition of a biomarker: “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention“.
This definition is broad and can encompass a wide range of measures, making it helpful to further subtype or categorise biomarkers according to the source or collection method, and/or by its intended purpose.
Types of biomarkers by source or method of collection
Biomarkers can be described by their source or method of collection. Currently, according to the BEST Resource, there are five different types of biomarkers:
- Tissue or histological biomarkers collected from tissue biopsy samples
- Circulating, liquid or serum biomarkers collected through blood or urine samples
- Imaging biomarkers collected using imaging methods
- Physiological or clinical biomarkers that are collected using tests usually found in a clinical setting
- Digital biomarkers that are collected using digital services
Categories of biomarkers by intended purpose
Biomarkers can also be categorised according to how they are used. For example, when levels of a biomarker change in response to an intervention, it can be classified as a response biomarker.
According to the BEST Resource, there are seven different categories of biomarkers, and it is possible for a biomarker to fall under multiple categories.
What is an imaging biomarker?
There is often some confusion around what exactly is considered an imaging biomarker. Terms like ‘imaging biomarker’, ‘imaging endpoint’, ‘contrast agent’ and ‘PET tracer’ are used interchangeably, and definitions may vary across different resources. The lack of clarity around what an imaging biomarker is and how it can support research has likely contributed to the underutilisation of imaging biomarkers in drug development. It is hoped that clarification will assist researchers in determining if imaging biomarkers can add value to their current drug development programs.
Imaging biomarkers vs. surrogate endpoints
A response biomarker obtained through imaging can be used as either a pharmacodynamic biomarker or a surrogate endpoint, depending on the specific context of use.
When a biomarker reflects biological activity of an intervention, it can be considered a pharmacodynamic and/or response biomarker. Importantly, a biomarker is not a direct measure of how a person feels, functions, or survives, as is measured using clinical outcome assessments (COA). Pharmacodynamic/response imaging biomarkers are extremely useful in drug development. They can be used in clinical trials to evaluate mechanism of action (MOA) and early indications of efficacy, among other things.
Therefore, the link between a biomarker and a clinical outcome must be established for it to be considered clinically meaningful from a regulatory perspective. Once this link has been established and the biomarker is expected to predict clinical benefit (or harm) by evaluating early changes in biological activity in response to intervention, it can be considered a surrogate endpoint. Depending on the level of evidence, from a regulatory point of view, a surrogate endpoint is further classified as being validated, reasonably likely, or candidate. The burden of evidence needed for validation of a surrogate endpoint is high, and consequently the majority of response biomarkers do not fall into this category.
Imaging biomarkers vs. contrast agents vs. PET tracers
There is sometimes confusion regarding what constitutes an ‘imaging biomarker’, a ‘contrast agent’ or a ‘PET tracer’. This can be important to distinguish in the context of drug development and clinical trials.
A contrast agent is a special type of dye used in conjunction with an imaging method, such as computed tomography (CT) or magnetic resonance imaging (MRI) that helps with visualisation be increasing the relative difference in signal intensity. Importantly, contrast agents are considered drugs and must be approved for a specific use case, which imaging biomarkers do not. For example, gadoxetic acid (Gd-EOB-DTPA, sold as Primovist® in the EU and Eovist® in the US) is a contrast agent that has been approved for detecting and differentially diagnosing focal liver lesions. It has also been used off-label as a non-investigational medicinal product to quantify changes in hepatocellular function and liver perfusion in drug development for chronic liver diseases.
A positron emission tomography (PET) tracer is a radiopharmaceutical made up on a radionuclide (label) attached to a tracer molecule that interacts with a physiological target. There are several PET tracers that have already approved by regulatory agencies, and many more that are still in development. For example, Antaros is developing a PET tracer for PDGFRβ to detect fibrogenesis.
Imaging biomarkers in drug development – MASH example
Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins in the liver, is considered one of the main prognostic factors in many liver diseases, including MASH. Both its presence and severity are correlated with the risk of developing cirrhosis and liver-related complications. There are many different biomarkers that have been proposed and investigated for measuring liver fibrosis in MASH.
Biopsies and histological markers
Historically for indications such as MASH, liver biopsy has been the ‘gold standard’ for assessing liver fibrosis. Histological biomarkers are assessed from the tissue sample and converted into a semi-quantitative score. The somewhat subjective nature of these scoring systems means that there is often intra- and inter-observer variability.
Liver biopsies have several other limitations; they require expensive, invasive procedures, which can carry a risk of severe complications. There is also risk of sampling bias, where the sample of tissue taken is not representative of the fibrosis across the whole liver. And importantly in the context of treatment decisions, liver biopsies give only a snapshot and not an insight into the dynamic changes during the process of fibrogenesis. This has given rise to a need for non-invasive tests (NITs) and biomarkers of liver fibrosis that can both reduce the need for biopsies and be better suited to enabling the development of treatments.
Circulating and serum biomarkers
Circulating, liquid, or serum biomarkers collected through blood or urine samples can be used for assessing liver fibrosis. These biomarkers can be ‘direct’, ‘indirect’ or form part of a combination panel.
Direct biomarkers are those that are related to ECM processes themselves, such as hyaluronic acid (HA), which is a glycosaminoglycan that is synthesised by hepatic stellate cells (HSCs). A commonly used combination panel is the Enhanced Liver Fibrosis (ELF) test, which combines three direct biomarkers including HA. Indirect biomarkers like alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicate alterations in liver function rather than ECM processes directly. FIB-4, another commonly used score is comprised of ALT and AST levels, as well as platelet count and age.
Imaging response biomarkers
One of the most used imaging response biomarkers for fibrosis in clinical trials in liver shear stiffness measured using magnetic resonance elastography (MRE) or ultrasound (US). MRE is a method that combines MRI with low-frequency mechanical waves to assess the stiffness of the tissue. The fibrotic scarring increases the stiffness of the tissue, and the shear waves travel faster through stiffer tissue.
There are of course other imaging response biomarkers that can be used to assess fibrosis. To revisit the examples from earlier, relative enhancement (RLE) with gadoxetate MRI has been associated with fibrosis. And the binding of a PDGFRβ PET tracer can serve as an imaging biomarker for detecting fibrogenesis.
A PET tracer that targets PDGFRβ can be used to evaluate early changes in PDGFRβ receptor expression following an intervention, which can indicate whether a drug has an effect on liver stellate cell activation. A decrease in expression post-intervention is indicative that the therapeutic is effectively reducing stellate cell activation and therefore likely reducing liver fibrogenesis. In the disease progression of MASH patients, stellate cell activation is an earlier marker compared to other biological processes, such as collagen-1 deposition and eventual fibrosis formation. By investigating changes PDGFRβ expression, it may be possible to detect at an early time point if the drug is effectively impacting the fibrogenesis.
In summary
To summarise briefly what has been covered in this blog post:
- There are several different types (e.g. circulating, imaging, etc.) and categories (e.g. response, predictive) of biomarkers that can be useful for understanding what is happening in the body within the context of drug development.
- Biomarkers are not the same as clinical outcomes, nor contrast agents or PET tracers, even though there is sometimes confusion between the terms.
- There are always strengths and weaknesses to different biomarkers, and while sometimes multiple biomarkers can measure the same thing, more often they are measuring something that cannot be measured in another way.
Blog disclaimer
The views and opinions expressed in this article are solely those of the contributing author/s. These views and opinions do not necessarily represent those of Antaros Medical.
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