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  1. 1. whitepapers Charles River’s Corporate Vice President, William 1 BarBo, and Director Patrick mcconville discuss the drug discovery benefits of preclinical imaging for the discovery process future image d espite being a relatively new technology, discovery, drug development and clinical trials. number of time points. Furthermore, preclinical preclinical imaging has already begun to imaging offers the capability, in many cases, to play an important role in research and More eFFicieNt image multiple small animals at once, leading to an drug development, and that role will only become The increasing use of clinical imaging modalities even higher throughput with a much lower time more vital and more encompassing in the future. has been attributed to efficiency. For example, by investment. depending on the modality and the study param- having an Mri or ct scan performed on a patient, The focus on imaging endpoints in clinical eters, imaging has the potential to dramatically a doctor can quickly receive trustworthy data to trials further motivates the need for preclinical increase the efficiency of lead candidate selec- tion produce an accurate diagnosis and treat- ment plan, imaging as a tool for validating and optimizing by providing better quality and unique data. That which in turn helps patients avoid the costs, both imaging protocols used for a given agent or class of is why charles river has invested in becoming one physical and fiscal, of undergoing and recovering agents. By focusing on imaging earlier in a preclini- of the few companies in North america to offer from invasive exploratory surgery. in addition, the cal devel- opment program, the best-suited imaging Quantitative whole-Body autoradioluminography patient receives the benefit of starting treatment bio- markers can be determined and validated, (QwBa) as a tool for pharmaceutical clients to sooner, due to earlier detection and knowing quick- leading to tremendous increases in efficiency and evaluate drug metabolism and pharmacokinet- ics. ly whether a given therapy is working. in clinical cost savings in later-stage clinical development. it is also why charles river recently added the trials, early image-based indicators are being used in addition, preclinical imaging allows for the capability to offer clients the use of all of the major increasingly for effective enrollment of patients or combination of what have traditionally required in vivo imaging modalities, including Magnetic efficient switching of treatment paradigms, leading separate cohorts/analyses to gather more data resonance imaging (Mri), computed tomogra- to enormous time and financial savings for the from a single study. For example, imaging modali- phy (ct), positron emission tomography (pet) patient and the pharmaceutical company. ties can be combined in a single study, or a single and biophotonic imaging. in the world of drug discovery, the efficiency modality can be leveraged to obtain multiple physi- These tools can help better assess anatomy and benefits are analogous. one of the most important ological or functional parameters and end- points, disease morphology, physiological and func- tional goals of a pharmaceutical company attempting to in addition to anatomical information. increasingly, parameters (e.g., blood flow and tissue oxy- gena- bring a product to market (as well as one of the manufacturers are combining traditionally separate tion) and molecular and cellular processes (e.g., most important mandates for a contract research modalities, further facilitating this approach and cellular proliferation, metabolism and metabolite orga- nization) is to streamline the drug-discovery optimizing the power and efficiency of each study. levels). preclinical imaging enables the most phase of its products. The more efficient the pro- For example, charles river is routinely using com- powerful and clinically translatable methods for cess, the quicker a company can invest resources bined Mri (e.g., tumor vascularity) and pet (e.g., monitoring disease progression cur- rently pos- into the most viable candidate without wasting metabolism and cellular proliferation) readouts to sible. These imaging methods are also more easily them on less promising compounds. preclinical obtain the most powerful data for clients. The cli- applied than traditional methods in the newer, imaging is ideally suited to helping accomplish that ent then benefits by obtaining a powerful, multifac- more realistic models of human dis- ease that are goal. eted dataset from a single study that provides key becoming increasingly prevalent, such as models For instance, the time benefits of imaging over information about the action of their drug at the of invasive disease in the tissue of origin, as well surgery and terminal endpoints such as histology functional level, in addition to traditional informa- as transgenic mouse models. imaging biomarkers and ex vivo tissue biomarker analyses are substan- tion for efficacy readout (e.g., tumor growth rate). and surrogate markers are rapidly becoming the tial, due to significant reduction in the number of This enables earlier and more informed decisions most powerful methods that can be applied to drug animals required to capture information at a set in the drug- development process and enables 20/20 Pharma
  2. 2. whitepapers optimization of image-based biomarkers for use in coupled to tumors in non-relevant tissue sites, and The future of preclinical imaging as a broadly concurrent or future clinical trials. necropsy may not reveal the full extent of tumor employed technique is strong. in fact, the future of 2 burden in a relevant tissue. drug research and development is filled with tre- More accuRAte mendous potential for advancement because of the drug discovery The more realistic the models of disease, the better uNiQue data advent of preclinical imaging. currently, imaging the quality of data that can be gathered from them, Now that imaging technologies have evolved be- is used in almost every common human disease, and the more effectively the possible effects of a yond the ability to reveal anatomy and can detect and the development of increasingly sophisticated compound or device can be known. preclinical im- tissue function and molecular changes as well, and powerful imaging protocols, technologies and aging can help achieve optimal use of those more pre- clinical imaging offers unique capabilities tools is occurring at a rapid rate. while indus- realistic models in a variety of ways to provide over more conventional testing and measurement try trends show reliance on preclinical imaging more accurate and more unified data. methods. mostly in the later stages of the preclinical phase of First, preclinical imaging helps provide a more For instance, dynamic contrast-enhanced drug development, imaging is increasingly being comprehensive picture of the effect of therapy on a (dce) Mri is the only clinically proven method deployed earlier — saving time, money and effort disease. conventional methods of disease analysis for quantitatively measuring the vascular perme- on candidates that do not play out. This also helps run a greater risk of missing disease that has spread ability of a tumor. This is an important capability ensure familiarity with image-based endpoints in a to unanticipated areas of the body or changed in given the prevalence of vascular targets in a variety drug-discovery and development program, leading ways that are difficult to physically observe without of diseases, including the widespread focus on anti- to its most optimal use and ulti- mate successful the use of exogenous markers in ex vivo analyses. angiogenic and anti-vascular disrupting therapies utilization in clinical translation. with preclinical imaging, the entire body can be in oncology. dce Mri fills the need for a clinically one example of earlier deployment of imaging seen at once and disease can be visualized in its translatable method for quantitatively determin- is in vivo biophotonic imaging (or bioluminescence native state, mitigating the risk of overlooking ing vascular response to therapy. preclinically, imaging). in this modality, a luminescent protein certain results. second, preclinical imaging allows alternative methods to accomplish this largely rely or enzyme can be transfected into diseased cells the collection of data in real time, rather than after on sacrificing animals and using invasive methods that are then implanted into an animal or expressed the fact through terminal endpoints. This provides that can uncouple the readout from the disease in a transgenic animal. The light emitted from the the benefit of being able to observe the effect of property being measured, and therefore decrease implanted animal is then imaged. This can be used therapy on a disease at the moment of most inter- the relevance of the data gleaned from it. to track disease progression. in addition, expres- est: its living, native state. Third, preclinical imag- pet imaging is also becoming an increasing sion of the light emitting reporter can be tied to a ing permits researchers to follow a single animal area of focus for drug discovery and development conditional molecular process to enable imaging of over time to see how a disease changes. without because of its unique capabilities. in oncology, the the drug mechanism at the target level. This modal- imaging, researchers are forced to sac- rifice mul- two most clinically relevant pet protocols involve ity also allows the use of exogenous reporters that tiple animals at multiple time points to monitor use of fluorodeoxyglucose (Fdg) for quantifica- enable quantification of a molecular or cellular disease progression. No matter how similar a group tion of tissue metabolism and inflammation, and process. an increasing spectrum of these “smart” of rodents are assumed to be, they are still separate fluorothymidine (FLt) for quantification of cel- probes are becoming commercially available. animals with unique biological characteristics that lular proliferation. pet is also playing a key role in Biophotonic imaging also enables a high level could distort or dis-harmonize data. preclinical quantifying receptor occupancy for new targeted of throughput, offers results in less than a minute, imaging allows the circumvention of that obstacle therapies in several disease states. The future will and can therefore be more cost-effective compared by measuring relevant endpoints in each animal bring a broad suite of new commercially available with modalities like Mri and pet. Furthermore, over time. This also helps further the principles of designer pet tracers, each a biomarker for a critical bioluminescence imaging can be conducted humane care, as it reduces the number of animals disease process. Many of these are already being in vitro, before the use of animals. This allows necessary for a study. used in clinical trials and preclinical studies. screening assays to determine how cells react, so an example where imaging provides greater ac- These examples illustrate the ability of imag- that more efficient judgments can be made before curacy is in metastasis models. There is increasing ing to meet needs where traditional methods have moving on to an in vivo stage, which again furthers industry focus on preventing or treating metastasis. not. increasingly sophisticated imaging technolo- a responsible approach to research from a humane- however, metastasis models do not allow an ac- gies, probes and biomarkers will further drive this care point of view. curate determination of the full extent of meta- uniqueness. Through imaging, researchers can in summary, the opportunity for development static tumor burden using traditional life span or obtain information in vivo that cannot be obtained and enhanced application of preclinical imaging is necropsy based endpoints. charles river is leverag- in any other way. This is exactly why preclinical enormous because of its potential to increase the ing the power of optical imaging of reporter tumor imaging is necessary to accelerate the drug devel- efficiency and accuracy of the discovery process. cell lines in these models, which enables tracking opment process. technological advancements — such as the avail- of individual metastasis appearance and growth/ ability of multiple integrated modality imaging response to treatment. in contrast, using traditional the Future oF systems — will soon see preclinical imaging grow endpoints can limit accuracy, since survival may be precLiNicaL iMagiNg at unprecedented levels. 20/20 Pharma

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