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Imaging Biomarkers in Drug Development: An Overview ofOpportunities and Open Issues

Sudeep Chandra,* Craig Muir, Matt Silva, and Steven Carr

Millennium Pharmaceuticals Inc. and Broad Institute of MIT and Harvard, Cambridge, Massachusetts

Received April 6, 2005

Introduction

The pharmaceutical industry faces unprecedented challengesin the coming years. The average cost and duration of drug development cycles have been continuously on the rise, withincreasing R&D costs over the past decade. It has currently reached more than $800 million and 13 years, respectively. 1 Inaddition, a recent article pointed out that while the number of compounds entering Phase I has increased over the past

decade, the number of compounds that have gone from PhaseII to Phase III has gone down. 2 Although estimates vary, only 5% of all molecules identified in discovery make it to humantrials, and within that pool only 1 in 5 compounds make itthrough complete regulatory approval. From a cost perspective,changing the rate from 1-in-5 to 1-in-3 would result in dramaticsavings. 3 The consensus view in the industry is that theavailability of robust biomarkers for drug efficacy and safety will reduce these failures and therefore have a positive impacton the drug development process. In this context, numeroustechnologic and experimental approaches have seen increasing value for intensive exploration and engagement.

Imaging, like proteomics and gene expression profiling, is atechnology that is generating significant interest in the medicaland pharmaceutical communities. A survey of clinicians in 2001ranked Magnetic Resonance Imaging (MRI) and Computer Aided Tomography (CAT or CT) as the most important innova-tion in the last quarter century. 4 In 2003, the invention of MRI was honored with a Nobel Prize. The pharmaceutical industry has embraced imaging slowly over the past decade. Imaging data is very convincing since visualization of a biological eventnoninvasively and serially within live species, in 3D and in colorprovides enormous opportunities for scientists to improveunderstanding of therapeutic interventions. In addition, as thesuite of imaging modalities in preclinical sciences has recently expanded to include Positron Emission Tomography (PET),Single Photon Emission Computed Tomogrpahy (SPECT), Infra-Red (IR), and others to accompany (MRI) and CT, the op-portunity to develop translational connections to the clinic hasexpanded. This should generate a significant benefit to thepharmaceutical R&D community and in turn to the patients.The current maturity of the tools dictate that we think togethermore about the role of imaging for fast and personalizedtherapeutic development which in turn may lead to betterpatient care and significant reductions in R&D costs.

Imaging: The Opportunity. The area of biomarker researchis diverse and complex. The concept of markers has been inuse for decades and covers various molecular markers including qualitative and quantitative detection of genes, proteins,metabolites, and labeled agents as well as intact organ levelsignatures of disease. So where is the value proposition for theuse of imaging biomarkers? Monitoring intact systems (cellsor whole animals), with minimally disruptive and noninvasive

imaging tools, facilitates some unique opportunitiess

such asserial measurements of pathology, 4- 7 and clinically relevantassays. 8,9 Imaging tools, in several instances, 10,11 have shownto provide often a direct patho-physiological connectionbetween disease mechanisms and therapy. The read-outsobtained with imaging technologies are therefore potentially the closest analogues to clinical outcomes. Additionally, therole of imaging in patient management and diagnostics is wellestablished. For in vivo read-outs, a direct noninvasive measuremay alleviate the need to collect tissue samples via invasivemeans. Above all, imaging allows visualization of the spatial-temporal selectivity of action, kinetics of distribution, andstaging the effectiveness of therapeutic modulation. The impactof this ability to directly and quantitatively observe the effects

of therapeutic interventions is difficult to overstate. A variety of imaging modes have recently been miniaturized to operate with higher resolution and sensitivity, 12- 14 thus facilitating intact whole-animal read outs similar to human patients. Utilizationof imaging markers in preclinical animal models is likely to addfurther validity and confidence to their adaptation in theclinical settings. Figure 1A,B shows an MRI image of a tumoron a mouse leg and a mCT of a rat paw, respectively. Thesefigures show the ability of small animal imaging devices toimage organ level pathology and the possibility of connecting these information to serial evaluation of disease status. Theability to develop quantitative assays of pathological markerson small animals allows researchers to generate first proof of biological activity of drug candidates along with the ability to

validate such observations using post mortem histology. 15Imaging technologies are therefore likely to play a significant

role in operations focused on translational medicine. This isa new organizational function that is beginning to appear inmany pharmaceutical R&D organizations. It is generally char-tered to encompass all aspects of the science required totranslate a candidate compound with promising in vitropotency and selectivity into a high value and well-annotateddrug candidate for clinical trials. Application of imaging in smallanimals (Figure 1) and in the clinic therefore offers a good fitto this branch of work. Figure 2 shows clinical utility of

Part of the Biomarkers special issue.* Corresponding Author: Sudeep Chandra. Dept of Imaging Sciences,

Millennium Pharmaceuticals Inc., 45 Sydney Street, Cambridge, MA 02139. Broad Institute of MIT and Harvard.

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simultaneous CT and PET to show the importance of measuring active glucose concentration from lung cancer patients. Thisstudy showed that glucose utilization in the tumors couldseparate responders from nonresponders in a clinical lung cancer trial and that such staging had prognostic value in termsof future survival rates. 16 The implications for patient manage-ment is clearly obvious. Such combination of molecular and/or functional data with pathology in clinical settings is thereforeexpected to favorably alter clinical study designs in the future.

The rapid evolution of novel molecular imaging agents inthe preclinic promises to provide yet another platform of novelreadouts from intact in vivo systems. 17 - 19 Such opportunitiesopen up new possibilities for basic researchers to interrogatedose response, predict early changes, and understand molec-ular events such as gene expression, enzyme activation, celltrafficking, and more from live animals. 20 - 22 The ability tointerrogate an intact system at a molecular level is intriguing and offers a connection between the global pathophysiology and underlying molecular modulations. Clinical translation of molecular imaging tools, specially using fluorescence or biolu-minescence, is perhaps still a few years away; but the potentialimpact is easy to imagine. For preclinical R&D, the ability to

use these molecular read-outs provides another set of impor-tant tools to assay the drug candidates en route to clinicalinterrogation. 23

The most significant promise of imaging biomarkers in thecontext of clinical trials could be in cost saving throughsmarter study designs that require less time, use enrichedpatient populations and provide better care for the patients. A variety of clinical studies have included and used imaging markers for bioactivity read-outs of agents, 24 - 28 pharmacoki-netic and dosing studies 29 and for prognostic indicators. 30 - 32

The two most notable applications in recent times were forGleevec and Etanarecept s where imaging provided valuable

information on drug activity earlier than some accepted

surrogates.33 - 35

The need for imaging biomarkers has to be carefully re-viewed and put in the context of cases where a spatially selective and temporally differentiated analogue of a diseasestatus can add value over molecular markers. In this context,imaging could provide the ability to avoid invasive procedures,or to report a signal earlier than other markers, or to serve asan initial screen that can be followed up with a more definitivemolecular and/or pathological validation.

The reader is encouraged to refer to many extensive reviewsof imaging applications in drug development to fully explorethe potential of the field. 10 - 12,19 - 21,23,35

Imaging: Open Issues. In this section, we discuss someissues that need to be carefully thought out such that theimaging opportunity can be capitalized more successfully within the pharmaceutical R&Ds. These issues are beyondisolated and appealing case studies and are common to all R&Dendeavors keen to adapt imaging as a valuable tool for drug development paths.

It is expected that imaging is going to provide key operationaladvantages and will provide cirtical path opportunities in theclinic. A recent workshop presented important ideas aroundusing imaging and developing more regulatory guidance in thisregards. 40 Among many, one area where imaging could poten-tially contribute would be to develop biomarkers, preferably closest to modulation of targets, which can predict clinical

Figure 1. (A) Single slice image of a Mouse leg with a tumorclearly delineated using Diffusion weighted MRI. These images

were used to demonstrate efficacy of a test agent in pre-clinicalscience (ref 15). (B) Micro-CT images of a mouse and rat jointshowing anatomy in exquisite details. Such images have beenused in the literature to study and quantitate bony erosions postarthritic disease initiation. (ref 38). Figure 2. Simultaneous CT and PET imaging for lung cancer

patients demonstrating the utility of imaging as prognosticindicator of successful therapy. The early 18FDG-PET imagesshow measurable changes in responders (Figure 2A) whosubsequently went on to achieve reductions of tumor size. In thenonresponder group, the 18FDG PET images showed little to nochanges and patients did not achieve significant tumor shrinkagein later interrogations. (Figure 2B) [reproduced with permissionfrom Weber et al. (ref 16)].

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outcomes in chronic (or refractory) diseases. Figure 2 shownhere is a great example of how imaging can contribute inclinical paradigms. The ability to use a molecular event s in thiscase radioactive glucose uptake and monitoring with PET sallows early classification of responders. This may provideavenues for identification of enriched subpoputations ORcareful retrospective demonstration of the efficacy of agentsin certain subgroups of patients. Connotations of exploratory studies in man to show biological activity in small pilot trials

have also been of interest to pharmaceutical companies andFDA. However, two important challenges remain to ultimately phase such clearly useful tools into the clinic. First, clarity onthe utility of such markers needs to be discussed. For example, would these markers be used for retrospective analysis of dataor do they need to be investigated for prospective selectioncriteria? Clearly, the requirements to establish the latter canbe quite different than the first. Second, if the imaging markersare not directly tied to the pathophysiological path of thedisease mechanisms then they are likely to generate estimatesthat loosely correlate with clinical outcomes s for example, CTrelated tumor size measurements and survival in colon cancerpatients. The correlation between the two is only 38%. 35 Carefulinterrogation of imaging biomarkers and their connectivity to

molecular pathways is going to be an important focus forestablishing biomarkers and small animal imaging laboratoriesare likely to play a major role in that effort. 23 Clearly, abiomarker development effort systematically targeted for imag-ing will allow characterization of specificity and sensitivity of imaging markers. That effort will require a careful collation of case studies and meta-analysis across studies for imaging basedread-outs.

As skill sets develop in the industry to use these markers,and integrate the design, utility, and adaptation of such markersto clinical trials, many more drug development programs willseek clinical imaging resources as well. Ability to developclinical imaging markers is likely to happen with establishedmedical centers where appropriate clinical imaging skill sets

and access to patients are available for pilot studies. The com-munity at-large needs to support such endeavors and assimilatenecessary skill sets, standardized ligands, analytical tools, andreporting systems such that a uniform code of evaluation canbe implemented in multicenter trials. Imaging measurementsneed to be standardized, cross validated across institutions,instrumentations, and their implementation procedures maderobust enough to ensure procedural reproducibility.

Outside of the clinical applications, development of imaging in small animals needs be a clear and well-aligned priority as well. Recent emergence of numerous high-resolution imaging modalities in the preclinical area will increasingly augment thedevelopment of improved animal models of human disease.In preclinical pharmaceutical research, the decision to advancea drug into development is often heavily reliant on pre-established animal models that often report activity of a specificdisease mechanism. For example, smooth muscle migrationin balloon angioplasty models of restenosis, 5 models of specificcancer lines that respond to specific pathways, 36,37 rheumatoidarthritis models in rats joints 38 etc. In most cases, these modelshave been set up years before diagnostic opportunities wereavailable or adapted in those study paradigms. Therefore, themeasurement tools and indices are often set up to report data without the need for clinically relevant read-outs. Examples of such mechanistic indices include intima-to-media ratio inrestenosis models post mortem or paw swelling in RA models.

In such studies, imaging read outs are often perceived asadditions to the armamentarium of assays being run togenerate more confidence around the efficacy of an agent.Indeed, some interesting examples exist demonstrating that thepharmaceutical R&D has been successful in using imaging inthat capacity. 5,38,37 But there is also a significant secondary opportunity.

Imaging is likely to provide an additional layer of efficacy studies with direct clinical relevance beyond the initial screens

of efficacy. By integrating the capability of noninvasive diag-nostics, post identification of leads, imaging could enabledevelopment and implementation of novel study designs suchthat the interrogations are clinically relevant and preclinically resource efficient. Along these lines, advanced models whichare more representative of human disease will find more utility especially for serial interrogations with one or more imaging modes. Also, such diagnostics will provide the ability tointroduce diversity and select for relevant disease phenotypesamong test subjects. In more advanced interrogations, com-bination therapies or selection of responders to treatmentscould be explored. Such detailed efficacy annotation willprovide more avenues for clinicians to use the pre-clinical datafor clinical trial design.

However, wide scale adaptation of imaging tools has beendifficult for drug development programs. One of the dominating arguments against adaptation of such clearly valuable tools hasbeen cost. In the pre-clinic, the cost of setting up an imaging instrumentaion, is often similar to other analytical instrumen-tation routinely used in drug discovery such as high field NMRand LC - MS/MS. In the past decade, therefore, departmentsof imaging have become quite prevalent within many phar-maceutical R&D organization. Moreover, as imaging readoutsprovide significant translational insights into the most expen-sive part of the drug development cycle, financial modelsindicate that the return on imaging investments are extremely favorable. The cost of running a clinical pilot study deservesmore detailed discussion and more evidence of direct utility

in prospective trial designs. It is currently well-recognized thatimaging case studies present a compelling argument to pursuemore characterization in the clinic. 39 The pilot trials couldreturn huge cost savings in the later stages of large scale clinicaltesting.

Another high barrier to rapid progression and adaptation isthe recognition of the need and ability to resource imaging functions appropriately. This tends to be even more importantsince centralized functions, like imaging, are often expectedto deliver on disparate studies across numerous target organs.There is a dearth of well-trained Imaging Scientists and Imaging Sciences Training Programs focused on biomarkers. Developing quantitative imaging markers that have been adequately testedfor reproducibility, validation, sensitivity, and specificity re-quires long method development cycle and is therefore chal-lenging. With this practical perspective, collaborative andinstructive interactions across functional groups are necessary.The R&D community must recognize that the field of imaging research is extremely diverse, and we all have to becomestudents and teachers of each other to embrace the op-portunity.

Imaging research groups in academia and industry need to work closer to take on such challenges. Once such readoutsare widely established, regulatory agencies will have higherlevels of confidence to understand, recognize, and accept suchread-outs as beneficial for the general patient populations.

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Ultimately, compelling scientific rationale and endorsementfrom regulatory agencies would be key ingredients for imaging research endeavors to gain more momentum. The regulatory agencies are clearly on top of it and have declared this to bean area of prime interest. 40,41 In conclusion, converting thehypothetical potential of imaging to an integrated and validatedtool in drug development will need significant alignment of resources and tight integration with translational researchmodels. Despite some additional R&D costs in the short term,

the opportunity is clearly going to benefit patient care and may favorably alter the escalating costs of drug development.

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