Noninvasive Imaging in Drug Discovery and Development.

What will be the long term utility of these technologies in therapeutics development? Where in the discovery - development timeline do these technologies belong? What are the current uses of these technologies in the field?

What will be the long term utility of these technologies in therapeutics development?

Over the past few decades, multiple new technologies have been introduced into the field of drug discovery and development. In each case, their introductions began a sequence of euphoria, predictions of revolutionary impact, dismay and doubt and, finally, a proper role in the process. Accuracy, reproducibility, ruggedness and applicability to the drug development process were initially unanswered questions. Is non-invasive imaging a different story? Consider that anatomical and functional imaging technologies have seen clinical use for decades. Anatomical technologies such as x-ray, CT (x-ray computed tomography), ultrasound and MRI have become diagnostic staples of current clinical practice. Functional imaging modalities have found broad clinical use in cardiac function testing and in oncologic disease diagnosis and staging. Noninvasive imaging is a mature technology with proven clinical applicability. What is new is the ability to extend this technology to in vivo specimens as small as a mouse, with species scaled sensitivity and resolution comparable to the clinical setting.

The obvious opportunity, then, is the direct translational applicability of these technologies. With the existing clinical infrastructure, it can be a straightforward process to introduce imaging endpoints early in a clinical development plan. Proper late stage use of imaging endpoints in the preclinical environment not only provides critical clinical planning data, but also firmly establishes a link between the preclinical safety and efficacy database and early clinical data.

The less obvious role, then, becomes imaging’s involvement in the discovery process. Drug discovery programs, particularly those aimed at unique, novel targets, proceed with a hypothesis of the relationship between target, target modulation and impact on disease. Since functional imaging presents the opportunity to measure physiological processes in the intact, living animal, it can clearly play a role in demonstrating target validity and cross species comparability.

Where in the discovery - development timeline do these technologies belong?

The discovery – development timeline has very different requirements as the compound selection process progresses. In early lead discovery, the number of compounds screened can be on the order of 105 or 106. While high throughput screening is impedance matched to these numbers, imaging technology is not. Animal handling, image collection times and image processing all contribute to the limited throughput of imaging technology. Imaging is not an appropriate general screening tool. It does, however, represent an ideal platform for early systems biology measurements. A drug discovery program is a triad of therapeutic, disease and target. Novel targets resulting from genomic or proteomic studies often have an uncertain relationship to a specific disease. Additionally, a perfectly acceptable target from a biological perspective is of little value if it is not drugable, that is, if its action cannot be modulated by an external therapeutic. Imaging is an ideal platform to assess these target biology questions. By focusing functional imaging endpoints on presumed target effects, the validity of the target can be probed in normal and diseased models, across species and, potentially, in early clinical trials. The longitudinal, whole system datasets generated by noninvasive imaging provides a platform for investigating the time course relationship between target, disease state and therapeutic. Such data can be extremely valuable in interpreting early clinical results.

On the other end of the timeline, the translational potential of imaging technologies is evident. As development programs mature, key questions of pharmacodynamics, efficacy and toxicity often emerge. These key questions and the data generated to answer them often determine the success or failure of the program. Is the dose-response curve in man similar to that in the preclinical model species? What is the dose relationship between preclinical models and clinical disease state? What stage of disease, if any, is optimal for therapeutic intervention? Is a side effect as likely to be seen in man as in the toxicology species? What are my clinical patient selection criteria? How uniform is my disease population? A well designed preclinical imaging program has the potential to establish quantifiable endpoints upon which to answer these types of translational questions.

What are the current uses of these technologies in the therapeutics discovery field?

Noninvasive imaging techniques are seeing increasing utilization in the therapeutics discovery field. Interest in the technology has been spurred by the FDA Critical Path initiative and Exploratory IND guidelines. Large Pharma is making investments in preclinical and clinical imaging centers to facilitate the inclusion of imaging endpoints throughout the development process.

In oncology research, preclinical imaging is being used both for early efficacy verification and for later stage clinical planning. Using primarily functional imaging (optical, PET), researchers are establishing noninvasive imaging endpoints as measures of efficacy in primary tumor treatment and metastatic disease.

Anatomical methodologies (CT, MRI) are being used to assess efficacy in bone diseases and other anatomically defined diseases. CT, in particular, has been used to assess compound efficacy in osteoarthritis, osteoporosis, and bone healing.

Compound distribution and pharmacokinetics are areas of concentration for nuclear methodologies. These methods provide unique, continuous distribution datasets that can be extended into the clinic. Using appropriately labeled compounds, targeted antibody therapies can be rapidly assessed in preclinical and clinical settings. Labeled small molecules can provide early clinical distribution data to support compound selection, i.e. Phase 0 studies in man. Labeled small molecules are also seeing wide application in CNS research, where brain receptor occupancy studies are being used to establish clinical dosing regimens.

Summary

Noninvasive imaging technologies are seeing increasing utilization in the drug discovery and development process. Across therapeutic areas, across program timelines, imaging endpoints are showing promise as quantifiable measures of compound efficacy and disease response to treatment.

J. Paul Shea, Ph.D., completed his doctorate in 1983 at the University of Washington (Medicinal Chemistry). He held a postdoctoral position (Molecular Toxicology) at Vanderbilt University until 1985, when he joined the Metabolism and Pharmacokinetics Department at Bristol Myers Company. In 1990, he became a Senior Consultant, Metabolism and Pharmacokinetics, Arthur Dr. Little, Inc. He assumed the position of Vice President of Clinical Development and Vice President of R&D with Molecumetics, Ltd., a small molecule drug discovery company, in 1996. He became the Vice President of Clinical Development of PETNET Pharmaceuticals, Inc. in 2002, Vice President of Quality and Regulatory Affairs at CTI Molecular Imaging, Inc. In 2003 and joined MPI Research as Director of Molecular Imaging. In 2007, Dr. Shea joined QSA Global, Inc. as Vice President, Auriga Medical Division. He has published many articles on the specific application of molecular imaging to the process of drug development.