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European Biopharmaceutical Review

Eye for Success

Widespread incorporation and acceptance of novel technologies or assays into scientific disciplines relies on both demonstration of consistent datasets and timelines. Depending on the specific technology and potential crossover into multiple discipline areas, acceptance may take many years and cross multiple generations of professionals. As a result, when it comes to novel technologies, it is essential to look closely at the preceding work to understand its temporal development path and readiness for application in any given discipline. A challenge in this regard is often the lack of peer review monographs and other publication/ data sharing media that scientific professionals can use to determine validation and verification of reproducibility.

The misconceptions of novelty are often encountered when it comes to the development and application of molecular imaging (MI) – particularly relating to the utilisation of MI in drug development. From its earliest days, the power of MI has been its unique ability to connect molecular biology with real-time cellular functions, creating new ways to monitor and record the molecular processes in an organism. This allows researchers to evaluate real-time target engagement and other objectives, defined through applicable study design.

Molecular Opportunities

Identification of a few key milestones in the development and application of MI can help to provide a better understanding of its development. Such landmarks include 1924 when the first use of radiotracers occurred in animals; 1950 when iodine-131 was ‘radiolabelled’ onto human serum albumin for imaging the blood pool within the heart; and 1961 when the first cyclotron for medical use was installed at Washington University Medical School. Imaging platform technologies, such as single photon emission computed tomography (SPECT), positron emission tomography (PET) and computed tomography (CT), were also introduced roughly in the timeframe of the 1960s. Likewise, the first SPECT and PET images of human neuroreceptors took place more than 30 years ago.

MI associated technologies and applications have been undergoing continual refinement and improvement since their inception – today, there is significantly improved resolution and computing power, as well as data analysis tools. The importance of these advances cannot be understated. Appreciable improvements in the ability to process and analyse imaging data have led to progress in the understanding of these datasets, allowing researchers to better guide programme decisions.

Complementary Solutions

In parallel with the advancements in MI has been the continued increase in pressure from every corner of society to improve the efficiency and effectiveness of the drug development process. Questions abound from patients, advocacy groups, shareholders and even regulators, all asking how we can make it faster, easier and cheaper to develop effective drug therapies. It is generally accepted that significant changes to the established drug development process take time to be implemented. These variations can be of multiple types: technological advancements, accepted modifications to study design, increased use of in silico among in vitro assays, alterations to the regulatory requirements for safety assessment, or others. While each of these categories has their own inherent evaluation process for acceptance, the application of MI provides opportunity for review and critique of traditionally accepted means, providing the chance for strong scientific and professional assessment.

Given its demonstrated utility in many scientific disciplines, including drug development, MI is uniquely positioned. There is every reason to believe that now is the time for this important technology to take its place as a key driver in helping the pharmaceutical industry to make better decisions about drug candidates in a faster and more cost-effective manner.

MI has been shown to provide insight into development efforts throughout all levels of the development paradigm. Early-stage attempts are often assisted in answering questions as critical as target engagement, while late-stage development and/or post-market approval efforts have also been facilitated by the application of MI. There has been a significant increase in the number of clinical trials using SPECT or PET imaging since the late 1990s. Furthermore, there has been a substantial increase in the number of preclinical drug development programmes utilising an imaging solution in their development efforts to provide a translational endpoint, bridging preclinical efforts to the clinical attempts.

The opportunity MI currently brings to the drug development community is not one that entirely abandons the established designs of traditional preclinical studies. Rather, MI complements and can improve upon them, given the capabilities of today’s platforms and significantly improved informatics solutions. Successful programmes often include an imaging endpoint or solution designed into the programme, in conjunction with more contemporary techniques or assays to strengthen the programme as a whole.

Today’s MI offers significantly improved precision/resolution and study designs featuring single model repeated measures in which a single test subject undergoes imaging sessions at multiple intervals, as opposed to terminal cohorts. These advantages provide robust datasets, while helping to reduce total test subject need on study – therefore reducing expenses and facilitating all stages of drug development to limit continual development efforts and the associated costs.

Biodistribution Data

A common model of early-stage drug development studies focuses on the absorption, distribution, metabolism and excretion of drug candidates. An emphasis is often placed on biodistribution data, reflecting where and in what concentration a new compound accumulates or deposits in an organism. The standard approach is to design studies to collect excreta, blood/fluid and tissue following the euthanasia of study animals to evaluate distribution. Tissue dissection and analysis can be an effective method for helping determine many things that take place within a test animal during a trial, although datasets are typically expressed at a whole organ level. This approach is less than ideal when one needs to understand distribution to a level of precision that allows for understanding at a target organ level. For example, a drug under development for the treatment of renal clearance would require an understanding of distribution or accumulation within the kidney that would be able to discern between capsule, cortex, medulla, or something as focal as the nephrons, in order to obtain a meaningful dataset.

Biodistribution studies using appropriately labelled test material and imaging platforms allow researchers to generate datasets which are then processed with sophisticated informatics, allowing for coregistration of the detected radiolabel activity with CT imaging, or other structural/ anatomical imaging, to precisely identify the locations of distribution. Such data is often compiled and processed with historical data that has been used to generate well-defined anatomical atlases – which can include multi-segmented individual organs – to understand distribution within differing anatomical areas of interest.

MI biodistribution studies are often designed to include a cohort of test subjects that will undergo processing and analysis through quantitative whole body autoradiography (QWBA). This allows for the evaluation of distribution of test material; when biodistribution studies are designed with a MI solution and paired with applicable QWBA cohorts, the dataset generated allows for significant gain in resolution of the locations of distribution, compared to standard tissue dissection and counting methods. This approach provides researchers with a greater understanding of properties comprising their test material, and potential toxicity or potential effectiveness in treating their desired indication.

Wider Application

It would be a mistake to conclude that MI has made the long-term animal study obsolete, or that every study must have a major MI component. There are always going to be programmes that, either due to targeted pathologies, a compound’s mechanisms of action, or other factors, will have study objectives satisfied with non-MI based approaches.

However, contemporary MI solutions offer the drug development community an unprecedented set of tools capable of dramatically ‘de-risking’ clinical drug development. Studies evaluating biodistribution MI and autoradiography represent a very precise and cost-effective method to understand the biodistribution kinetics of test material. They can provide resolution orders of magnitude greater than traditional methods, delivering a more accurate picture of distribution both in vivo and ex vivo.

MI is becoming more widely applied and accepted in the drug development industry. Studies initiated using PET/SPECT have increased five-fold in the past 10 years. More recent advances are allowing for the co-registration of imaging data generated from modalities such as magnetic resonance imaging with MI data, providing a tri-modality solution to researchers – allowing structural and functional analysis of the same test subject. Given the realities facing drug developers, and the solutions offered by imaging technology today, we can apply this expertise into drug development programmes, making it beneficial to those patients in need of new and improved therapeutics.

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Scott Haller is Director of the Translational Imaging Center at MPI Research. Previously, he was a director of multiple laboratories at Borgess Research Institute in Michigan, US. Scott has an MS in Virology and Immunology from Western Michigan University, and is well published in peer-reviewed journals. He also continues to serve as a visiting scientist.
Scott Haller
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