“We know contrast”
Hubertus Pietsch and his MR & CT Contrast Media Research team work right at the core of Bayer’s radiology business. The researchers keep an eye on Bayer contrast media safety and efficacy. They improve contrast media application protocols and evaluate the impact of new technologies on existing products. As one of very few manufacturers worldwide, Bayer still invests in the development of new products.
Radiology.bayer.com (rbc): What does your team focus on?
Hubertus Pietsch (HP): Our work is based on three pillars. Number one is research on marketed products. A current example is a test series on aspects of efficacy and safety of x-ray contrast media. We are looking very closely at potential skin reactions and late reactions. We continuously look into our products and monitor application data. We publish quite a lot about that.
The second pillar is about new contrast media, for MR and CT. Their development is in different phases. I don’t want to spill the beans, of course, but there is one project we are currently pursuing with very high speed. These new compounds are important and I find their chemistry fascinating. Fortunately, the Bayer labs have the power to both synthesize and evaluate these new molecules. We are also working on concepts for contrast media for new imaging techniques, called Magnetic Particle Imaging. Together with a scanner manufacturer and other partners we explore the potential of this technology for diagnostic imaging. We were able to attract third-party funds from the German Federal Ministry of Education and Research.
rbc: Are you synthesizing all new molecules in your own lab?
HP: Not all of them. We usually work closely connected in a project team with our chemists from medicinal chemistry who is producing the substances. But we do the main work of the substance characterization in our lab.
rbc: What about pillar number three?
HP: The third pillar is key opinion leader and customer support. We share our lab with our clinical partners, sort of as their extended workbench. Our aim is simple: we want to exchange experience and investigate clinical questions in a pre-clinical setting. We just had Japanese radiological colleagues as our guests for two weeks. They do excellent work and we were lucky to publish a joint paper on our work.
rbc: What was this particular joint project about?
HP: The colleagues were checking a hypothesis published by Matthew Davenport and his team that has stirred some controversy about Primovist®. The Davenport paper describes the occurrence of transient acute self-limiting dyspnea in patients receiving gadoxetate disodium. This basically means that the scans of patients receiving Primovist® showed breathing artifacts which were not observed before.
Davenport speculated that the contrast medium was responsible for that. The study had some limitations, so we rechecked the hypothesis in an animal model. We found no significant changes between Primovist® application and the control group in dogs, meaning that the contrast medium did not have any influence on breathing in this animal model.
This process is typical for part of our work: Some questions can simply not be answered clinically. In this case, we define a set-up and try to solve the problem in a non-clinical setting, in a study without patients.
rbc: From a more general perspective, where is contrast media development heading?
HP: Contrast enhanced imaging has become a permanent fixture in radiology and I believe it will stay this way. New techniques will lead to new insights and eventually to new indications. Contrast media will continue to play a big role.
However, enhancement rates are not where they should be. If you look at CT imaging, enhancement rates are between 40 and 50 percent, in highly developed countries even 60 percent. In MR imaging we also find quite interesting differences – the UK has an enhancement rate of 20 percent, Germany around 40 percent.
Regarding the use of contrast media and training of radiologists and radiographers, there is still a lot to do.
rbc: What about new indications?
HP: Our contrast media can find broader application and add value to new indications, for instance during therapy monitoring, which does provide added value.
Therapies have come to be very efficient, so if a tumor is diagnosed early, patients do not die from the primary tumor, but maybe from its metastases.
We really need stratification not only in the sense of how many metastases are there, or how big they are. There are more interesting properties imaging could visualize, like oxygenation, cell density or blood permeability. Contrast media with more diagnostic efficacy – for example with higher relaxivity – can help to detect smaller tumors and metastases.
rbc: What will new machines lead to?
HP: Contrast media need to adapt to the technological development. Regarding CT, I can think of many things. Radiation absorption could for example rise for lower kV settings, which would lead to a decrease in radiation dose.
It would also likely decrease adverse events from contrast media. Clinicians might say that an adverse event rate of five to eight percent is not a lot. However, it is a worthwhile aim.
In the long-term view, I believe that the coming 15 years will belong to MRI, just as the last ten years were characterized by CT hard- and software innovation. New MR machines largely depend on computing power, which doubles every two years. MRI technology will benefit from this – it will become faster, cheaper and more widely available. Then we will probably reach out to other indications and MRI availability will rise. I believe this process is far from finished and that we are about to see interesting developments in the near future.
At the moment, MR contrast media are not specific enough, except for gadoxetate disodium. We need better efficacy of MR contrast media.
rbc: What indications are you thinking about?
HP: There are many examples, like compounds that specifically bind to thrombi in the body, or to lymph nodes, or to atherosclerotic plaques. Another option might be neurodegenerative diseases in the brain that cannot yet be found with contrast.
These indications can be addressed once the contrast media or the machines get better. Being as precise as possible was our aim from the very beginning of contrast media research.
rbc: Does cost matter?
HP: We have to keep a balance between a molecule’s usefulness and its cost. So the price of our basic substances like Gadolinium or iodine is of course an issue. We apply contrast in the range of grams – five to ten grams for MRI, for CT imaging we use ten times as much. In x-ray imaging we produce something like 1000 tons of contrast a year. In MRI we are somewhere in the low double-digit zone.
The complexity of a substance’s synthesis also plays a role. We need to think about upscaling synthesis for a production site. A small lab is not sufficient; we need a huge site like our X-ray contrast production facility in Bergkamen in Germany.
rbc: How will imaging fit into future diagnostic algorithms?
HP: There will always be in-vivo imaging. I don’t think we will see something like Star Trek’s tricorder though, it is too complex. Still, the future will likely bring a lot more in-vitro tests, probably using substances like bioliquids or RNA/DNA snippets, which will help to stratify patients. Laboratory medicine development moves incredibly fast. This will push diagnosis forward. These lab tests will then give hints whether an MRI or a CT is indicated. This process is likely to be a lot cheaper than starting with imaging first. I just read a publication on breath analysis as the basis for further diagnosis. In-vitro tests and imaging will be closely connected.
About Hubertus Pietsch
PD Dr. Hubertus Pietsch is Head of MR & CT Contrast Media Research at Bayer. He is a trained veterinarian. Before he switched to Bayer in 2002, he did biomedical research at the Berlin-based Max Delbrueck Center for Molecular Medicine.