Accelerating drug discovery and development through in vivo imaging

Driven by scientific advances and strong competition and economic forces, the pressure to accelerate drug discovery and development is increasing, especially in the phases leading up to and during early human clinical testing. Fortunately, scientific evidence is mounting rapidly that in vivo molecular imaging can help save time and money—without sacrificing quality or integrity—in every aspect of drug development, from drug target validation, to preclinical animal studies through every stage of human clinical trials and beyond.

Researchers at the Tufts Center for the Study of Drug Development (CSDD) in Boston have reported that the costs to bring a drug to market had risen from an average of $231 million in 1991 to more than $802 million in 2004. In addition, the extended development time reduces the remaining time on a drug patent—an important factor in each pharmaceutical company’s ability to recoup its drug development costs. Tufts researchers recently reported that market exclusivity for patented drugs has dropped from about 8 years in the 1970s to about 2 years as of 1998. Tufts researchers say that increasing the speed of new drug development could save hundreds of millions of dollars, and imaging is emerging as a solution right at the outset by increasing the efficiency of drug target validation and preclinical animal studies.

1. More Specific Drug Target Identification and Validation:

As a result of the human genome project, drug companies currently have hundreds of thousands of potential drug compounds, however less than one of every 10,000 will eventually emerge as an FDA-approved treatment. “Molecular imaging at early, preclinical stages can quickly reveal which compounds have possibilities” (Timothy McCarthy, PhD, Pfizer Global Research and Development).
The tracer approach used in PET and SPECT is especially valuable in early stages of drug research, where researchers can directly label a drug lead to see where it goes. For example, researchers looking for a drug to treat psychiatric conditions such as depression or schizophrenia need to know first whether a potentially useful compound can get across the blood-brain barrier. If it cannot, there is no use developing the compound any further. In addition, PET and SPECT tracers can reveal molecular changes brought about by the drug. This change is an extremely important capability in light of new cancer therapies, where changes on the molecular level occur long before becoming visible in anatomic imaging. “And as the drug candidate progresses in the development process, you can go from monitoring the kinetics of the drug candidate to monitoring the effects of the drug on the disease target” (Ward Digby, PhD, director of molecular imaging in advanced research at Siemens Medical, Hoffman Estates, Ill). Again, this ability weeds out non-viable candidates early in the process. Imaging can also show increased cardiovascular function in response to treatment with new drug candidates, or provide statistical data to help quantify response to neurological agents—for instance, showing increases in dopamine (associated with Parkinson’s) or serotonin uptake (associated with Alzheimer’s).

“The pharmaceutical industry does not want to spend a lot of money developing a compound into a drug when it cannot go where it is intended” ( Dr. D. Mozley, Senior Staff scientist, Eli Lilly Corporate Center)

2. Speeding-up Pre-clinical Testing: PET and SPECT enable real- time ADME

For those drug candidates that can reach their disease targets in a living subject, imaging helps to reduce costs of the next step: preclinical studies on absorption, distribution, metabolism and excretion, or ADME studies. These studies are currently conducted by injecting a drug candidate into animals, usually rodents, and then sacrificing a certain number of the animals at each step in the ADME process. The animals are then sectioned, examined and measured with scintillation counters, or through whole body radiography, to see where the drug ended up.
It’s a manually intensive process that requires several groups of animals—six to ten animals per group and seven to ten groups—to avoid random variations in the data. By attaching nuclear medicine tracers such as SPECT and PET tracers to potential drugs, researchers can follow a prospective therapy through live animals to see ADME characteristics in real time. This means that one needs fewer animals to see how drugs work. In addition, in vivo imaging provides biodistribution information within the hour as compared to extensive post-mortem evaluation procedures. No longer does one have to use many animals for statistics, so it is quicker, cheaper and, as a side-effect, it also saves animals. “Imaging at the ADME stage results in significant cost savings” (Eric Milne, MD, professor emeritus of radiology and medicine at the Univ. of Calif. at Irvine). “Preparing a transgenic mouse can cost anywhere from $150 to $3,000. You do not want to kill that mouse. You would like to follow it day by day while you are treating it, and that is what molecular imaging allows you to do.”
Mice can be imaged with the same radio-tracers, used in the clinic for humans, but at dose levels adapted to the smaller subjects. As a result, successful pre-clinical studies in animals quickly translate to clinical studies on humans. Provided that small-animal imagers are indeed able to image small subjects with the same utility as humans in the clinic, the ability to use the same tracers in human clinical trials as those used in pre-clinical animal testing, can result in significant efficiency improvements and time and cost savings in clinical trials.

3. More Efficient Clinical Trials: NanoSPECT™ and HiSPECT™ bridge the gap between pre-clinical animal testing and clinical human trials.

Bioscan’s recent introduction of ultra-high resolution in vivo SPECT imagers, the NanoSPECT and HiSPECT scanners, are enabling researchers to image of mice with the same functionality as humans. Namely, images in mice and humans can now be obtained with the same relative resolution and similar image contrast. This advancement is made possible by a proprietary multiplex, multi-pinhole SPECT technology enabling the imaging of mice with a spatial resolution of less than one mm and with an image contrast improvement of one order of magnitude. “These improvements in small animal imaging were required to enable researchers to gain as much information from imaging mice as from imaging humans with existing clinical SPECT cameras” (Dr. Nils Schramm, staff research scientist, Federal Research Center of Juelich, Germany). As a result, pre-clinical trial experiments on mice carried out with NanoSPECT and HiSPECT systems can now be carried over to humans using the same SPECT-labeled drug candidates and imaged with existing SPECT clinical cameras. With HiSPECT, it is even possible to use the same clinical camera to image both humans and small animals with the same molecular imager and with the same molecular tracers. This ability is near-optimal for researchers attempting to bridge the gap between pre-clinical and clinical testing.

As a result of these dedicated translational imaging products, SPECT imaging has an important role to play in both the pre-clinical trial stages, as well as the three stages of human clinical research leading up to submission of a prospective drug to the FDA for marketing approval. Early on, for example, in Phase 1 of the clinical trial process, imaging helps assess toxicity by showing bio-distribution and individual response to the drug. “There is a therapeutic window between toxicity and therapy, and it is different from one person to another. Because imaging uses small tracer doses that have no physiological effects, it may allow an earlier and safer move to Phase I clinical testing in humans. While this does not give any information on the ultimate clinical benefit, it does show whether the drug is hitting the target” (Dr. McCarthy, Pfizer). In vivo molecular imaging permits earlier determination of whether a given compound will work in humans. By using imaging to look at response earlier in humans, money can be saved by abandoning drugs that do not translate to the human model in favor of those that do.

To most researchers working in drug discovery and development, it is becoming increasingly clear that in vivo small-animal imaging has the potential to revolutionize drug development by providing non-invasive drug lead optimization and pre-clinical testing tools that easily translate into clinical hypothesis testing. In addition, “the net result of pre-clinical animal testing could benefit the public need to enhance human clinical subject safety by limiting the number of volunteers who will be exposed to drugs that will ultimately fail and ensuring that those who are, receive the proper dose” (David Mozley, MD, Eli Lilly & Company).