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Imaging in drug research: a developing picture.

WITH MOUNTING R&D COSTS and many late-stage compound failures, there is an increasing demand in the biopharma industry for new methods that can accurately predict, as early as possible, whether novel agents will be effective and safe. As a result, companies are actively pursuing new technologies that can provide more reliable data upon which to base go/no-go decisions. One of the tools that has been proposed and successfully utilized for this purpose is imaging technology, which includes a range of modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), in vivo optical imaging, and ultrasound. With its ability to deliver non-invasive and quantitative cellular and molecular information that can access the mechanisms of drug action, imaging stands out as one of the most promising and flexible technologies for improving the drug development process.

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Already a gold standard in some areas of clinical medicine, imaging has more recently risen to prominence in preclinical drug development. Many large pharmaceutical companies, and an increasing number of smaller biopharma companies, rely on imaging at critical stages of their preclinical development cycles. The entire drug development cycle has the potential to be affected by imaging in profound ways. This will occur by increasing the availability, accuracy, sensitivity and specificity of predictive disease-based biomarkers that can be translated between the preclinical and clinical phases of drug development. Biomarkers are measurements that reflect progression or activity of a disease. Imaging-based biomarkers include any anatomical, physiological or molecular parameters detectable by one or more imaging methods used to establish the presence and/or severity of disease. (1) The next few years will better define specific therapeutic areas, disease models and classes of agents in which specific imaging protocols will begin to be used as gold standards through image-based surrogate markers. Surrogate markers are biomarkers that can be used as substitutes for clinically meaningful disease endpoints. (1)

Taking Imaging from

The Anatomical to the Functional

The most prominent imaging technologies in use today were developed initially as clinical tools for disease diagnosis through imaging of deep-tissue anatomy. These early developments have led to clinical imaging becoming a standard in some areas of disease monitoring and treatment management. However, these standard applications are still largely founded in the realm of anatomical imaging. For example, in clinical imaging, MRI, CT, ultrasound, and PET are used as standards of care in assessing tumor growth or successful growth inhibition after oncologic treatment in a number of indications. Anatomical MRI is increasingly becoming a standard method for assessing lesion progression in stroke and multiple sclerosis.

In the preclinical stages of drug development, anatomical imaging has also changed the way that go/no-go decisions are made. For example, in oncology, imaging is now routinely used to quantify tumor incidence and burden over time in small animal models. This occurs especially in models where traditional methods cannot reliably access the tumors--e.g., metastasis and deep-tissue tumor models such as transgenic tumor models. In this way, imaging is being used to drive decisions early in discovery based on assessment of anti-cancer therapy-based tumor growth inhibition. MRI, CT, ultrasound, and optical imaging are particularly well-suited for this approach. In neurodegenerative disease models, including stroke and brain trauma models, MRI is used to generate primary end points for decision-making. This includes anatomical imaging of lesion volume, but also T2 and diffusion mapping for detection of tissue changes at the cellular level. T2 MRI may also be used as a primary end point for anatomic assessment of hemorrhage in neuroprotective therapeutic approaches.

As the field matures, the same tissue properties that enable diagnosis via anatomical imaging are increasingly being leveraged as tools for tracking disease progression and response to treatment via imaging of tissue function. Today, imaging protocols and agents have been developed to enable spatial resolution of both the tissue itself (anatomical imaging) and the physiological and functional properties of the tissue (functional imaging), even down to the cellular and molecular level (molecular imaging). This has enabled non-invasive access to pharmacological parameters including blood flow, tissue permeability, metabolism, tissue density, cellular proliferation, and tissue oxygenation. Imaging of physiological and molecular level function can provide a more direct measure of a drug mechanism of action, enabling more predictive measures of drug activity. As medical research enables us to increasingly understand the critical stages of the disease process and better targets for treatment, mechanistically targeted image-based biomarkers can be identified and developed for more reliably testing drug action.

Earlier Go/No-Go Decisions

Through Imaging Biomarkers

Currently, the dominant areas of focus for imaging in drug research are in the late-stage of preclinical development through to the clinical phases. Today, there is significant preclinical imaging focused on developing and validating image-based biomarkers that are intended to be applied for use in clinical trials. Additionally, preclinical imaging is used to optimize future clinical trial design, such as choice of imaging time points for a specific candidate molecule and treatment regimen. During this process, it is important to correlate the intended imaging biomarker readout with efficacy (using positive controls), active versus inactive dosage levels for the test compound, and responsive versus non-responsive models.

Even today, functional imaging biomarkers are contributing to early decision-making. Some of the more promising clinically translatable approaches are shown in Table 1. As biomarkers go on to be used as true surrogate end points for outcome, earlier and more accurate development decisions will be facilitated, translating to substantial cost savings, as well as development of better therapies.
Table 1: Promising clinically translatable approaches for early
decision-making in drug development

Imaging Protocol   Function Assessed       Therapeutic Area

FDG PET            Glucose metabolism      Oncology, inflammatory
                                           disease

FLT PET            Cellular                Oncology
                   proliferation

Dynamic contrast   Tissue vascular         Oncology
imaging (CT, MRI,  permeability, vascular
Ultrasound)        surface area and blood
                   flow

Diffusion MRI      Tissue cellular         Oncology, stroke,
                   density                 multiple sclerosis

NaF PET            Bone metabolism         Oncology, arthritis,
                                           osteoporosis

IH MRS             Cellular viability via  Oncology, Alzheimer's,
                   metabolites such as     Huntington's
                   NAA, choline


As more and more success is achieved in preclinical biomarker development and validation and subsequent clinical translation, focus will increasingly shift from using preclinical imaging as a tool for clinical image-based biomarker development and support to making or supporting earlier preclinical go/no-go decisions. Increased understanding of where (therapeutic class, model choice) and when (timing relative to treatment and disease progression) to apply specific image-based biomarkers will be a key aspect of this trend. This will naturally lead to earlier use of preclinical imaging in the discovery and development process and consequential cost and time savings.

New Trends in Biomedical Imaging:

Translation from Pharmacology to Toxicology

Unforeseen toxicity has been a large contributor to late-stage candidate failures, even in advanced clinical trials. In toxicology there is, as a result, also an unmet need for new technologies that can better predict toxic side effects or accurately confirm safety in the earlier stages of the development cycle. While imaging has not yet played a major role in safety pharmacology and toxicology studies, there have been recent efforts to apply preclinical imaging in this way.

Many of the same physiological parameters that can be quantified in imaging drug efficacy can be applied in imaging toxicology. Image-based quantification of toxicity mechanism may allow earlier and more informed go/no-go decisions based on safety As with pharmacology anatomical imaging is leading the way in toxicity applications, including CT- and MRI-based imaging of teratology and reproductive toxicity, for example. Image-based methods for assessing cardiovascular function, including those provided by MRI, CT and ultrasound, are finding applications in cardiovascular drug development. These same methods may soon play a role in increasing timeliness and accuracy of cardiovascular safety assessment.

In collaboration with academia and the FDA, the industry is now beginning to look at how imaging can fulfill unmet needs in safety testing, within the confines of regulatory guidelines. An example of a new initiative in this area is a consortium being launched by HESI (Health and Environmental Sciences Institute; www.hesiglobal.org), which is focused on translational imaging in preclinical safety assessment and environmental hazard identification. This group will develop strategies for multi-center evaluation and use of image-based safety biomarkers to guide safety biomarker development in collaboration with the FDA and other regulatory agencies.

The earlier that drug companies can establish the efficacy and toxicity profiles of a drug candidate, the earlier accurate go/no-go decisions will be, leading to a more efficient drug development process. This goal will become closer to realization as reliable biomarkers and surrogate markers, including those provided by imaging, are used earlier in the development cycle. This process will be facilitated by continued successful translation of imaging applications from anatomical to functional endpoints, for both efficacy and toxicity assessments.

Acknowledgement

Thank you to Juha Yrjanheikki, Managing Director at Cerebricon, Ltd. (a Charles River company), for his perspective on imaging in central nervous system disease.

Reference

(1) Biomarkers and Surrogate Markers:An FDA Perspective Russell Katz. NeuroRx. 2004 April; 1(2): 189-195.

Patrick McConville is director of imaging at Charles River Laboratories. He can be reached at pmcconvilie@crl.com. Vinod Kaimal is a scientist at CRL. He can be reached at vkaimal@crl.com.

Patrick McConville, Ph.D., and Vinod Kaimal, Ph.D.

Charles River Laboratories
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Title Annotation:IMAGING IN R&D
Author:McConville, Patrick; Kaimal, Vinod
Publication:Contract Pharma
Date:May 1, 2010
Words:1541
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