Positron Emission Tomography (PET) - Shining a light on human disease
As the experience and advances in Positron Emission Tomography (PET) imaging grows, so does the belief that this technology can have a key role to play in ushering in an era of personalised medicine while also offering an enormous contribution in reducing the attrition rates in the pharma industry as a whole.
Highly valued for its ability to detect and stage cancers and for its nascent role in identifying Alzheimer’s disease and other neurological functions, Positron Emission Tomography (PET) has demonstrated its broad ranging applicability at the earliest stages of therapeutic drug development in preclinical and clinical testing, and now, as a reimbursed, cost-effective procedure of molecular imaging.
With continuing advances in Positron Emission Tomography technology, this imaging technique is poised for growth and is positioned to become an indispensable tool at the lab bench and in the daily practice of medicine. PET provides a non-invasive, safe means of looking inside the body. It allows understanding of normal physiology and that of diseases, while evaluating the effects of existing or experimental drugs.
It offers the potential to bridge the gap between basic biological research, animal studies and human trials, to expedite new drug development, to identify safer and more effective therapeutic agents, to diagnose pre-symptomatic disease and to select appropriate patient populations for clinical testing and drug treatment.
To foster the goals of translational medicine – defined as the development and application of new technologies where the emphasis is on early patient testing and evaluation, PET can contribute critical information that will shorten the path from animal testing to the bedside. PET offers unique capabilities and advantages for pharmaceutical R&D. It enables quantitative, in vivo activity interrogation within tissues throughout the body.
Positron Emission Tomography provides information on biochemical and physiological processes that complements morphological information. Pioneers of clinical PET imaging research at centres such as Hammersmith Hospital, London and Uppsala University, Sweden (now part of GE Healthcare’s commercial imaging network) have facilitated the growth of PET tracers now widely used in the early stages of drug development to confirm drug performance at the molecular level to understand the biological basis of disease, to validate and refine drug targets, to evaluate surrogate endpoints of disease activity, and to assess the pharmacokinetics and pharmacodynamics (PK/PD) of drug candidates in animal studies and early stage human trials.
Specifically, PET could be used for the rapid quantitation of response to multiple permutations of drug combinations and dose strengths in a range of disease types. In clinical testing, PET is playing a valuable role in demonstrating whether a test compound reaches and interacts with its intended target, documenting its physiologic effects in a small number of patients, assessing its dose-related ADME properties, and predicting the safety profile and potential side reactions and toxicities of a drug. Radiolabelled drugs are used in microdosing studies to gather information related to drug occupancy, as researchers cannot rely on clinical manifestations of drug activity.
For example, a drug may saturate the target without achieving a clinical effect, or, alternatively, it may be unable to reach an effective concentration without producing intolerable side-effects and toxicity. Using a PET tracer, the binding of aprepitant (EMEND, Merck) to brain NK1 receptors was quantified by measuring blockade of binding of the PET tracer to NK1 receptors in the corpus striatum. Nearly complete brain NK1-receptor blockade provided maximum antiemetic efficacy of aprepitant in humans.
The PET study was the basis for the FDA approval of the EMEND dose. If the therapeutic window that spans the two extremes is too narrow, a company may decide to abandon a project or reassess the chemical structure of the drug candidate. Therefore, the use of PET has provided drug development teams with the information needed to make these types of decisions earlier in the process, as early as Phase I clinical testing.
In preparation for late stage trials, PET can help the pharmaceutical industry with informationdriven patient selection by identifying individuals and sub-populations in whom a drug is more likely to be effective, safe, and well tolerated. This could tip the balance in favour of successful trial outcomes and, in so doing, perhaps may entice companies to invest in R&D targeting of rare and historically more difficult diseases.
PET also supports the development of linked diagnostics/therapeutics designed to identify appropriate patients for treatment. In fact, the FDA and other regulatory agencies are encouraging companies to include more high quality imaging data through the submission of Exploratory INDs.
Beyond the surface
The main priorities of the Pharma industry, which is under mounting pressure to improve productivity and reduce the cost of drug development, are threefold:
-To discover effective compounds with novel mechanisms of action.
-To move these compounds more rapidly through the developmental pipeline and fail ill-fated drugs as early as possible.
-To improve the odds for successful clinical trial outcomes and minimise the possibility of late-stage and post-marketing product failures due to poor efficacy or unanticipated toxicity.
In other words, the ultimate goal is to accelerate and improve the efficiency of drug discovery and development. The emerging recognition that imaging techniques have value across the spectrum of drug development is highlighted by improved technology and labelling methods, reduced cost of and greater access to instrumentation.
In the future, the synergies realised when PET is used in combination with other imaging techniques and with novel types of biomarkers now in development will further drive interest in this evolving technology. In neurology, examples of the power and commercial potential of molecular imaging for diagnostic applications include DaTSCAN™ (GE Healthcare), a SPECT imaging agent approved for use in Europe that binds to dopamine transporters on neurons in specific brain regions to detect neuronal degeneration.
It can be used to differentiate between Parkinson’s disease-related dementia and other forms of dementia, such as Lewy body disease, helping physicians select the most appropriate drug therapy for individual patients. Pittsburgh Compound B (PiB), developed at the University of Pittsburgh in collaboration with researchers at Uppsala University in Sweden, is being evaluated in clinical studies for its ability to detect amyloid plaque in the brains of patients with pre-symptomatic Alzheimer’s disease.
Earlier detection of Alzheimer’s disease could enable the use of safer and more effective therapies to slow or halt disease progression (Figure 1).
In oncology, the use of radioactive glucose (FDG – see sidebar, A PET primer) has allowed the rapid expansion of PET. It is now widely used and reimbursed in the US for diagnosis, initial staging and restaging of many cancers, and was recently accepted for the monitoring of breast cancer treatment and in cancer radiation therapy planning.
An example of how PET can be applied in oncology drug development emphasises the critical distinction between structural and functional imaging. After treating a test animal or patient with an anticancer agent it is common practice to evaluate the size of the tumour for shrinkage several weeks after treatment. Often, though, tumours may exhibit no change in size on structural imaging, yet an assessment of tumour cell function using FDG may reveal that its cellular metabolism is no longer upregulated, implying that drug treatment has stopped tumour growth.
PET can also be used to distinguish between correlates of cell proliferation (using FLT), hypoxia (using FMISO) and apoptosis (using Annexin-V), differentiating between the ability of a drug either to downregulate proliferative activity, induce apoptosis or reflect the Oxygen level of a cell. A new agent undergoing clinical trials, F-Angio, is a radiolabelled RGD peptide with high affinity for the v/3 integrin receptor present on the surface of the neovasculature of tumours.
It is tested for the detection of cancer metastasis and the aggressiveness of a tumour based on its angiogenic activity, and possibly may serve as a biomarker for the response to chemotherapy of metastatic cancers. In cardiology, patients at high risk for coronary heart disease and heart failure can benefit from imaging procedures looking at the density and activity of adrenergic receptors with MIBG, whose imbalance may predispose patients to heart failure, thus detecting early stage disease that may be more amenable to prophylactic and therapeutic interventions.
PET: present and future
The use of imaging techniques such as PET has more often been applied after identification of a drug target to study target expression and distribution in specific tissues. However, the emerging focus on personalised medicine is changing how Pharma formulates its development strategy. Rather than focusing on a disease, companies are beginning to define projects in terms of specific targets. For Gleevec (Novartis), for example, the target is not CML, but rather bcr-abl expressing CML. The target defines the disease.
Similarly, in the area of CNS disorders, the basis of a project may not be Alzheimer’s disease or Parkinson’s disease, but rather targets that represent the disease pathology. This new perspective places a great deal of importance on biomarker development and creates abundant opportunities for the application of PET. It also necessitates the development of novel radiotracers that can be used for target validation, the stratification of subpopulations within a disease area, and patient selection for clinical trials.
Today, high-performance chemistry with dedicated equipment has firmly established F-18 as a PET diagnostics mainstay. New tracer production also continues to simplify. The next advance is software-controlled synthesis using versatile chemistry platforms composed of pre-loaded cGMP cassettes. As chemistries and methods for radiolabelling drug compounds improve, PET will be able to make an even more valuable contribution to drug development.
As illustrated in the examples provided here, PET offers unique advantages for drug development, clinical diagnostics and patient management. It is a non-invasive, quantitative tool for imaging human physiology, detecting disease and measuring biochemical changes associated with pathology or drug treatment. Advances in genomics and proteomics leading to new in vitro diagnostic tests will stratify populations into ‘risk groups’ that may benefit from imaging.
PET technology and the emerging recognition by the pharmaceutical industry of the valuable role that molecular imaging can play throughout drug discovery and development, will continue to expand the growing interest in PET. As experience with PET increases, so will the knowledge that this imaging tool can contribute to earlier diagnoses and earlier interventions, with data-driven decisions regarding drug targets and drug compounds as well as patient selection for drug testing and drug treatment, and that it has a key role to play in ushering in an era of personalised medicine.
Advantages of PET
A notable benefit of PET is the ability to administer a radiotracer repeatedly in the same subject over a short time period. This facilitates time course studies and baseline versus drug treatment assessments without the need to account for intersubject variability. In animal studies, subjects can serve as their own controls, thereby improving the statistical quality of the data and reducing the
number of animals needed for a study. Furthermore, PET allows researchers to determine the impact of treatment on a target tissue without having to wait for the animal to die. In humans, PET offers particular advantages for assessing the impact of CNS drugs, as samples of brain tissue can only be evaluated post mortem. In oncology, key criteria for evaluating drug effects and establishing treatment protocols include the length of time a drug exerts a therapeutic effect and the time until maximum effect is achieved.
These parameters are difficult to determine using traditional biomarkers, and tumour biopsies only provide a view of the effects of a drug at a single time point. PET enables direct imaging of the target tissue, repeat assessments and quantitative data output. Above all, PET is a rather safe imaging technique. The high specific activities of positron emitting tracers (typically greater than 1 Ci/micromole), means that subjects are administered with radiolabelled drug compounds at sub-pharmacological doses (typically <10 nmol).
This has particular advantages for drug development, as information about tissue kinetics, regional distribution and target occupancy can be acquired with only small amounts of drug. This may allow for the study of trace doses of a compound in humans earlier in the drug development process and contribute to earlier decision making on whether to pursue a particular drug candidate. DDW
Dr Jean-Luc Vanderheyden is Leader of Molecular Imaging at GE Healthcare, responsible for the design and development of the company’s molecular imaging strategy. Prior to this he was Vice- President of Research and Development for Theseus Imaging Corporation in Boston where he designed and led the execution of a novel apoptosis imaging agent that reached phase II clinical studies. He was also Director of Nuclear Medicine Research and Development for Mallinckrodt/Tyco Healthcare and a visiting Associate Professor in Nuclear Medicine at University of Massachusetts Medical School. Vanderheyden holds a PhD in chemistry from the University of Cincinnati, is a pharmacist, and graduated from the Universit Libre of Brussels, Belgium.