Molecular imaging is becoming a very interesting growth area in drug discovery. There is considerable enthusiasm in the preclinical market to expand the use of molecular imaging and a more cautious approach in the clinical market. The size of the opportunity for suppliers of molecular imaging products and services is huge.
If the more than $12 billion spent annually by pharmaceutical companies for preclinical and Phase I drug discovery and the approximately $2.9 billion spent on translational research at academic and research institutions are combined, suppliers are competing for a share of a nearly $15-billion market.
Unusually, this huge market has limited technology risk since the imaging technologies are already well understood (Table). The development of additional molecular tracers/probes will require R&D but will not face hurdles in market acceptance. If instrument suppliers choose not to take the lead, there may well be an opportunity for other players such as contrast-agent suppliers and data-analysis software vendors to create integrated solutions that capture significant market share.
From a drug development perspective, molecular imaging can provide information on:
• Desirable or undesirable pharmacological effects of a drug on in vivo biochemistry and physiology
• Drug interactions with the desired target, including dose occupancy relationships and kinetic information
• The delivery of a drug to a specific target
• The absorption, distribution, metabolism, and elimination of a labeled drug candidate
We expect that the market for positron emission tomography (PET) techniques will grow at 15% over the next few years, with imaging agents growing even faster at 19%.
Spurred on by these robust growth rates, imaging equipment suppliers have been seeking new opportunities. Klaus Kleinfeld, former CEO of Siemens, predicted the increasing convergence of imaging, biotechnology, and IT would improve diagnosis and treatment of patients. Siemens’ commitment to this strategy was demonstrated by its acquisition of Bayer Diagnostics for $5.25 billion in 2006.
Two areas in which molecular imaging can have a significant impact on drug development are preclinical research and Phase I trials. Spending on these two areas accounted for nearly one-third of the total R&D spending across the pharmaceutical industry in 2006.
Not only are preclinical research and Phase I trials expensive, but inappropriate selection of compounds in these early phases can have disastrous consequences in later clinical trial phases. The story of drug development is also about failure. Out of a hypothetical 100 drug candidates that begin the process, only one will be successfully registered and available for patient care.
Between 30 to 40% of new drugs fail due to poor performance at the transition from animal to human trials (Phase I). Molecular imaging can play a role in completing the first successful toxicology in animal models to first in human testing in Phase I. Molecular imaging can impact between 8 to 22% of compounds in the later stages of preclinical research and Phase I trials. Even a modest improvement in these areas (e.g., 10–15%) could lead to a doubling of the number of compounds that successfully make it to market.
The explosion in potential targets generated by automated gene sequencing and improvements in high-throughput screening have led to a bottleneck in the in vivo validation of these targets. Earlier availability of this type of information allows researchers to make better decisions regarding which drug candidates to continue developing.
Several issues have emerged as key unmet needs in the preclinical research market:
• Dual technologies: Researchers are anxious to acquire imaging systems that enable structural and functional analysis in one experiment. Combinations of imaging modalities such as CT/SPECT and CT/PET are seen as the most likely to emerge in the immediate future, whereas the combination of MRI with a PET/SPECT system will take more time.
• Data analysis software: Most instrument suppliers offer only basic data-analysis packages that do not meet advanced market (e.g., the ability to overlay CT images with PET images) and improved decision-making requirements(e.g., database/data-mining capabilities).
• 3-D imaging: While multiple imaging technologies (SPECT, PET, CT, and MRI) can capture 3-D data, the current software to analyze and reconstruct images has low throughput and is extremely slow. Researchers want to image deep inside tissue and rapidly create detailed 3-D structures of regions of interest.
• Tracer availability: There are a significant number of imaging agents available to researchers today. However, there is a consensus that additional tracers that target more physiological functions are essential to drive continued growth in molecular imaging for preclinical research.
• Throughput and costs: Improvements in throughput result in lower per-image cost. New functional imaging systems such as micro PET and micro SPECT will garner greater share. These systems should also help address the need to share imaging systems with clinical groups.
With significant attrition in the transition from preclinical research to Phase I trials, the obvious solution to decreasing clinical failure rates is to make better selections earlier in the process. Phase 0, the administration of subpharmacologic or subtherapeutic doses of a drug candidate to humans who are closely monitored to generate preliminary drug safety and pharmacokinetic data, promises to improve the odds.
There are three technologies used for Phase 0—accelerator mass spectrometry (AMS), PET, and liquid chromatography/mass spectrometry/mass spectrometry (LC-MS-MS).
AMS is the most sensitive analytical technique ever developed that can routinely measure in the attogram range (10–18 grams) with the limit of detection in the zeptogram range (10-21 grams). See related story on page 30.
However, one of the limitations of AMS is that it does not appear to work for molecules with nonlinear pharmacokinetic profiles dependent on drug concentration, active metabolites, and protein binding. The process of labeling a target compound with radioactive 14C also requires specialized techniques. Only a handful of commercial companies have the capabilities to conduct AMS studies (e.g., Xceleron, Vitalea, Accium).
PET shows where a target drug candidate is deposited in the body. There are two approaches:
• In the first, the target drug is bound to a radiolabeled tracer and then followed by serial PET scans for several hours to determine its ability to reach the target tissues.
• The second approach is the injection of a radioactively labeled PET tracer and then monitoring how much of the tracer is displaced by the subsequently injected target drug.
There are currently two limitations to conducting PET microdosing studies. The first is the difficulty in chemically synthesizing the radiolabeled drug target. The traditional synthesis pathway utilized to make the target drug may not work when radiolabeled components are integrated. The second issue is the relative scarcity of FDA-approved tracers that can be utilized for displacement studies.
Ultrasensitive LC-MS-MS allows reliable measurement of drug concentrations in the low picogram per milliliter range. These assays use commonly available mass spectrometry equipment in association with sophisticated solid-phase extraction techniques to allow detection of trace amounts of drug. LC-MS-MS is generally available and does not require radioisotope-labeled material; however, the limiting factor is usually the reduced sensitivity compared to AMS.
Microdosing Is Promising
There has been a mixed response to Phase 0 for clinical trials among pharmaceutical and biotech companies. Only two trials are currently recruiting patients; both are sponsored by the National Cancer Institute. There appears to be greater interest in using microdosing among biopharmaceutical companies with European companies taking the lead.
Phase 0 studies are cheaper than full Phase I trials, and the ability of smaller drug development companies to report results in human subjects is a significant milestone with positive implications for valuation and potential deals with larger pharmaceutical companies.
Several large pharmaceutical companies, including GlaxoSmithKline (GSK; www.gsk.com) and Novartis (www.novartis.com), also have an active interest in Phase 0. GSK has made significant investments in AMS technology and plans to purchase two systems for use in the U.K. and U.S. GSK was also one of the early investors in Xceleron, which provides AMS on a CRO basis. Novartis has invested R&D funds to develop new tracers and has reported their value in identifying the progression of Alzheimer’s disease.
However, other pharmaceutical companies have greeted Phase 0 with considerable skepticism, even though almost all of the technologies it utilizes have been established in related fields. While some of this reluctance can be explained by the natural conservatism that accompanies any new approach, we believe there are also missing elements in the solutions provided by molecular imaging vendors that have retarded market acceptance. Many of the same issues in the preclinical market also need to be addressed for the clinical market.