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European Biopharmaceutical Review

A Secret Weapon


Developments in magnetic resonance imaging, bringing higher magnet strengths and more sophisticated analysis methods, are establishing the technology as a desirable alternative for the discovery of biomarkers and early proof of concept studies.

One of the most important unmet needs in drug discovery, as well as the delivery and monitoring of new medicinal entities, is the development of new biomarkers that can be used as surrogate endpoints to assess a therapeutic effect. Beside genetic and invasive methods, imaging techniques are recognised to be essential tools for drug discovery, development and evaluation. Most prominently, positron-emission tomography (PET) is utilised in this context to radioactively label and study drugs and targeted molecules in the organism in question. However, magnetic resonance imaging (MRI) presents an alternative, as it is non-invasive and can be used for longitudinal studies without being limited by radiation exposure.

MRI techniques to assess tissue states are continuously evolving and so is the potential impact of MRI on pharmacology. MRI is of most value at three distinct stages in the process of drug discovery: understanding disease; investigation of mechanisms of drug action; and providing quantitative markers of drug action, or endpoints, in candidate compounds for the clinic.

Understanding the Disease and Target Identification

Since its inception in the 1980s, MRI has quickly become indispensable for clinical imaging. MRI is a versatile tool to assess tissue composition and function, and by manipulating magnetisation allows different tissue features to be probed. Due to this flexibility, MRI is increasingly used to diagnose diseases and to monitor disease progressions and the success of interventions.

In neurology (for example stroke, multiple sclerosis, epilepsy, Parkinson and Alzheimer’s diseases), MRI plays a crucial role in detecting diseases before clinical symptoms appear, allowing more effective treatment. In addition, it allows differentiating of diseases with similar symptoms (differential diagnosis) and monitoring disease progression. In musculoskeletal imaging, the goal of MRI is to detect damages to joints at the interface of general tissue and bones (muscle, menisci, bone, tendon, ligaments, spine and so on). MRI is particularly important in these disorders because of the various image contrasts available to shed light on the type and origin of the damages. Cardiac magnetic resonance imaging has become a routinely used imaging modality for the diagnosis of ischaemic heart disease and non-ischaemic cardiomyopathies, and can provide non-invasive evaluation of reperfusion therapy through comprehensive evaluation of wall motion, global function, perfusion and viability due to its excellent spatial resolution, reproducibility and safety.

MRI also plays an important role in the diagnosis and management of cancer. MRI is used non-invasively to obtain information on the location and extent of cancer, as well as assessments of tissue characteristics (such as hypoxia, apoptosis, necrosis and tumour vasculature) that can monitor and predict treatment response.

Target identification and elucidation of mechanisms of action can also be tackled using MRI. The development of molecular imaging methods, such as MR spectroscopy (MRS), has allowed the further elucidation of multiple mutations and dysregulatory effects of pathways leading to oncogenises. It is of crucial importance to develop imaging methods to optimise the design, dosage and schedule of novel therapeutic and pharmacological approaches. For example, an aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. MRS provides an excellent tool to monitor these processes and the effect of anticancer drugs as choline, phosphor, ATP and other metabolites are measured with this technique, both in vivo and in vitro (1).

Another emerging field of pharmacological MRI is functional MRI (fMRI) in neurology. Functional neuroimaging has the potential to improve the decision-making process in the development of new drugs. It probes the neuronal activity following a behavioural task and the alteration of neuronal activity following a drug administration. With the high cost of failure of compounds in later stages of development, there is a need to establish, early in humans, reliable measures of drug activity and efficacy in the brain. fMRI is helping us to understand therapeutic mechanisms and can provide clinically relevant markers of disease responses to drugs. Thus, for the field of diseases in the central nervous system (CNS), fMRI can add additional information to evaluate drug effects on cognitive and sensory brain functions.

In addition, measuring blood flow not only in the brain, but also in other body parts (for example heart, kidney), using contrast agent techniques or arterial spin labelling, provides information about the level of metabolism and blood vessel integrity. These methods provide valuable information for the effect and efficacy of drug actions.

Functional Biomarkers: from Preclinical Models to Patient Stratification

The biomarker concept is an important one in drug discovery because of the need to measure the relevant responses of drug intervention. For imaging biomarkers to be useful, they need to identify patterns that can be correlated with biological events with the aim of validating novel drug targets and predicting drug responses. Specifically, clinically relevant biomarkers are needed to inform the therapeutic development of candidate drugs and in demonstrating significant drug effects for the purposes of regulatory approval (2). For example, MRI could become a powerful tool in patient stratification. By differentiating diverse patient populations based on clinical imaging, and then carrying out clinical trials within those stratified patient populations, the significance of results could be greatly enhanced – with the added benefit of shorter, smaller, more focused trials.

In the near future, fMRI is likely to be of great value to the pharmaceutical industry in early proof-of-concept studies for novel therapies. Imaging biomarkers, especially those with clinical relevance, would be used to prioritise the application of resources in drug discovery. For example, the correct choice of dose in large, and by implication costly, late-phase clinical trials can be crucial to their success. At a given dose, fMRI can be used to demonstrate a drug effect in the CNS that correlates with behavioral reports such as those reported in treatment of depression. Robust fMRI imaging biomarkers, because of their application in humans, could potentially provide much more relevant data than animal models, and thus better inform the subsequent design of clinical trials (3).

However, pharmacological fMRI in animals can complement and provide more extensive physiological data than human investigations. fMRI can provide comparative measures between animal and human, potentially validating an animal model or assessing the relevance of an animal model once the compound is tested on man.

It is important to remember, however, that in addition to interspecies differences, there will necessarily be methodological differences between pharmacological studies performed in small animals and man. Probably the most significant of these, in influencing data interpretation, is the need for anaesthesia in most animal studies, which produces its own fMRI-pharmacological interactions (4). This places limits on the usefulness of preclinical animal models with fMRI in drug discovery and, therefore, highlights the value of pharmacological fMRI studies for drug development in man.

Bigger and Better

As already discussed, imaging, combining high-resolution spatial information with specific functional and molecular information, is making important inroads in producing new biomarkers. High field magnetic resonance imaging is capable of detecting subtle morphological, functional or even metabolic changes based on the detection of endogenous contrast. To overcome the inherent sensitivity limitation of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), increasingly stronger magnetic field strengths are being used to boost signal to noise. MRI systems based on magnetic field strengths of 7T and higher have recently been introduced to further increase the sensitivity and specificity of clinical magnetic resonance applications.

Currently, more than 50 ultra high field MRI systems have been installed worldwide in clinical research centres exploring new techniques that can be used for the noninvasive, in vivo tissue characterisation and opening up a range of possibilities with implications for medical diagnosis and treatment (5).

When looking at brain anatomy, for example, the potential to improve spatial resolution to a range of 100-200μm will enable visualisation of different layers of the cerebral cortex, with impact on the diagnosis of diseases such as early dementia, epilepsy and small-vessel stroke, as well as understanding of vascularisation, myelin pathology and other phenomena. Furthermore, microbleeds can be identified, oxygen saturation quantified and vasculature mapped via techniques such as susceptibility weighted imaging. In addition, studies have already shown huge benefits for body imaging, for example in prostate and breast imaging.

In terms of brain function, the enhanced signal-to-noise ratio (SNR) enables higher resolution (sub-millimetre) functional imaging. This leads to the possibility of columnar-level imaging, providing insights about the ‘neuronal code' within specific brain regions. In addition, the increased contrast optimises the relative impact of physiological noise, aiding our ability to probe the mechanisms associated with behaviour, learning and brain development.

Another key advantage of moving to ultra-high field is the improvements seen in (functional) spectroscopy – brought about by the higher sensitivity and specificity (spectral dispersion). As a result, it is possible to reliably identify many metabolites that are invisible with standard MRI. This opens up many opportunities for oncology, psychopharmacology and other disciplines.

Conclusion

MRI is already an important weapon in the arsenal of the biotech community. The ongoing interest from the biotech and pharma communities in applying MRI to drug discovery indicates that the role of the technique is likely to continue to expand greatly over the coming years. Most of the major corporations are embracing this technology via academic collaborations or by establishing it in-house. The continued evolution of this technology to higher field strengths, coupled with more sophisticated analysis methods, enables ever more subtle understandings to be elucidated.

References
  1. Glunde K et al, Choline metabolism in malignant transformation, Nature Review Cancer 11: pp835-848, 2011
  2. Frank R and Hargreaves R, Clinical biomarkers in drug discovery and development, Nature Review Drug Discovery 2: pp566-580, 2003
  3. Wise R and Tracey I, The role of fMRI in drug discovery, Journal of Magnetic Resonance Imaging 23: pp862-876, 2006
  4. Austin V et al, Confounding effects of anesthesia on functional activiation in rodent brain, Neuroimage 24: pp92-100, 2005
  5. van der Kolk A et al, Clinical applications of 7T MRI in the brain, European Journal of Radiology, 2011

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Ross McLennan is the CEO of Brains Unlimited, an internationally-focused company based in the Netherlands that operates a state-of-the-art imaging centre providing research and education services to both academia and industry. Following a PhD in Genetics, Ross has followed a career in managing and facilitating large initiatives at the junction of academia, healthcare and the biotech industry. Previous roles include Programme Manager of the Translational Medicine Research Collaboration, linking Scottish Medical Schools with Pfizer, and involvement in the set up of the Wolfson Molecular Imaging Centre in Manchester, UK.
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