Making a marked difference

Imaging biomarkers are contributing greatly to medical advancements by helping with the early diagnosis of disease and the development of drugs particularly as supportive elements for deciding whether drug candidates should be advanced, shelved, or abandoned. “Whereas molecular biomarkers measured in vitro provide information on biological pathways that are active in organisms under various conditions, in vivo imaging biomarkers add spatial and temporal character to investigations of drug mechanisms, disposition, and efficacy,” explains Van Cauter. “Nevertheless, questions remain whether their ideal clinical application as stand-alone surrogate endpoints for use in efficacy demonstration in late-stage clinical development will remain a largely attractive possibility or become a viable alternative to accelerate the drug development process.”

Adoption has been relatively slow with many imaging markers taking more than ten years to reach the market. Although this progress is frustrating, the hope is that they will be quicker to make their mark in the future. Two factors have contributed to the leisurely uptake of biomarkers according to Van Cauter. The first of these is the minimal acceptance by regulatory agencies for the use of biomarkers to support Investigational New Drug (IND) and New Drug (NDA) applications.  He identifies how this is due to the fact that for a single biomarker, there is not always a well-defined correlation with the disease/therapeutic intervention. “Typically, the correlation is not clear cut and a panel of biomarkers is required. This complexity has inhibited acceptance of biomarkers as an integral part of drug development by both pharmaceutical companies and regulatory agencies.”

Secondly, he explains that pharmaceutical and biotech companies are often focused on the use of positron emission tomography (PET) and optical imaging of small animals to support the drug discovery and development process. “I believe that this focus should shift towards the use of single photon computed tomography (SPECT) because there are many regulatory-agency-approved SPECT biomarkers in use for clinical diagnostic applications. This is not the case for PET where there is only one approved biomarker (FDG), or for optical imaging where the only approved biomarker is ICG. For SPECT on the other hand, there are over twenty approved biomarkers and over fifty have already been used in humans during IND studies.”

One observation that Van Cauter has made in the industry is that nuclear imaging is considered more advantageous than optical imaging. Currently over 7000 labs globally are using the nuclear molecular imaging modalities PET and SPECT in both pre-clinical and clinical studies, and mostly for clinical diagnostic applications. “Although optical imaging technology is coming on strong for small animal testing, the main disadvantage of it is that available technologies have limited penetrability into living organisms,” he explains. “Of course, this favours small animal work but complicates the translation to humans. The switch from optical to radioisotope techniques for humans requires therefore different new biomarkers, which may interact differently with target molecules.”

In contrast to PET, SPECT has not found general acceptance as a drug development tool. In Van Cauter’s opinion this is because there is a perception that since PET is the better technology for imaging humans, it must be the better technology for imaging small animals during the drug development process and for pre-clinical testing.  The reality is that SPECT imagers can produce equal if not better results: “While it is true that PET has better sensitivity than SPECT for imaging humans, today’s state-of-the-art multi-pinhole SPECT imagers such as Bioscan’s NanoSPECT/CT system, feature similar sensitivities and a much higher resolution than pre-clinical PET imagers.”

“For instance, the nanoliter resolution capabilities of a pre-clinical SPECT system such as NanoSPECT/CT, is ten times greater than for the best pre-clinical PET system. This ability to image small animals with the same visual acuity as can be achieved with human scanners enables researchers for the first time, to translate research results from mice to humans without introducing errors resulting from equipment shortcomings.”

Van Cauter is optimistic that the biomarkers will be more readily adopted in the future particularly due to the current state-of-the-art NanoSPECT imagers. He describes how these pre-clinical imagers can handle a wide variety of biomarkers, whether in vitro –validated (all I-125 biomarkers) or currently used for clinical diagnostics in the nuclear medicine field. “Moreover, these systems allow researchers to perform translational imaging, from small animals such as mice, to large animals and to humans. This ability combined with the wide choice of biomarkers already approved by regulatory agencies gives researchers the ability to use the same set of biomarkers, from disease target validation, to candidate drug validation, into clinical trials,” he concludes.

Bio:
Mr. Staf C. Van Cauter is EVP of Bioscan Inc, Washington, DC, US. Prior to joining Bioscan, Mr. Van Cauter was Corporate VP and CTO of Packard BioScience Company until its acquisition by PerkinElmer, Inc.