New developments in clinical imaging

Clinical imaging can now be used to personalise diagnoses and to shed new light on the relationship between disease pathology and what the patient feels. Paul Matthews of GlaxoSmithKline talks to NGP about the benefits of these advances to developing new medicines.

“We can trace where that molecule moves in the body and literally watch it move into the brain”
-Paul Matthews, Head of GSK's Clinical Imaging Center

Developments in clinical imaging have been moving apace. The nature and course of diseases can now be followed at a molecular level in the human body, and new methods have emerged to make the development of medicines faster, better and safer.

Paul Matthews, Head of GlaxoSmithKline’s Clinical Imaging Centre (CIC) at the Hammersmith Hospital campus of Imperial College in London, UK, is on the frontline of this fast-moving field, as he explains: “We identify the major compound development targets and then develop imaging strategies to speed the early stages of moving a drug into the clinic, to make it faster, safer and more likely to succeed.

For example, neuroscience is an area where there are particularly important applications for positron emission tomography (PET). PET allows us to image where in the body a tagged molecule goes. With some special approaches, it helps to image interactions with the drug targets on cells.

“Why is that important? When we try to develop a new drug to treat a major brain disease, such as schizophrenia or depression, the first big issue to address is: does the molecule even get to the brain? Movement of molecules from the blood to the brain can be blocked by the so-called blood brain barrier.

“Pre-clinical models are not good predictors. To resolve this, we can simply take the molecule, label it with a positron-emitting isotope and administer that subject in micro-doses. We can trace where that molecule moves in the body and literally watch it move into the brain and define how much gets there.

“A second question for PET that follows from this is, does the molecule actually interact with its target and, if so, with what affinity? Knowing this allows a rational prediction of active doses.”

Realizing benefits

Matthews points out that in the “bad old days” – before many companies started using these techniques – a relatively common cause for the failure of a drug to move through early development was that it wasn’t getting to the targeted organ.

“Another practical issue is that if we don’t know what dose to give to a subject, we need to use many more subjects in the early phases of drug development. This takes more time and costs more money. Molecular imaging allows speeding of development. By limiting subjects exposed, it is safer for patients who are involved in the trials and it delivers higher value in the end.”

PET is not the only imaging method that can help drive drug development. The CIC also has an active, smaller group that uses advanced MRI scanning. Matthews emphasises that to gain confidence in potential clinical benefits, precise information is needed about pharmacological effects. “Consider what happens with weight loss. We know there’s an association between weight and poor clinical outcome with diabetes, heart disease and a variety of other medical problems. But when we use a drug to help people lose excess body fat, how do we know we are targeting the right sort of fat?

“Fat accumulates in different places in the body and it has different clinical consequences depending on where it is. If you have much fat deep in the body, around organs like the liver, it is a possible cause for clinical concern. On the other hand, if the fat is just under the skin, it may be perfectly compatible with a long, healthy life. With MRI imaging, you can differentiate fat loss deep in the body from that under the skin, and define what a weight-loss drug is actually helping to change.”

Collaborative science

The CIC was built through a collaboration between GSK, Imperial College and the Medical Research Council. The building sits on a plot of ground in the middle of the Hammersmith Hospital and is controlled and owned by Imperial College. The lower three floors are the CIC, the upper two floors house Imperial College clinical neurosciences, and the other half of the building is an MRC facility. The three partners work together in managing a common facility resource.

But it’s the non-physical element of the collaboration that Matthews finds exciting. “The development of new techniques that can be markers of disease or markers of response to treatment, is everyone’s concern, not just a GSK interest. We are developing programs that are actively engaging these partners in ongoing work.

“We set up a series of clinical research training fellowships, half funded by GSK and half by Imperial College. We have mentorship from GSK and mentorship from Imperial College. The Fellows have the opportunity of working with our cutting-edge equipment, well as in laboratories in Imperial, which is well-equipped, having the largest research income of any UK medical school.

“We also are developing joint scientific programs for example, in the areas of appetite regulation and neuroscience, which are jointly run by Imperial College faculty and our staff and common resources.”

Making advances

According to Matthews, imaging is a fantastic area to be in and offers a wealth of opportunities, both for the research community and for the pharmaceutical industry, because there are so many exciting developments on the horizon.

“In MRI imaging right now, what we’re beginning to be able to do is characterise the virtual histology of a tumor in the living body without having to do a biopsy. That’s important because it would potentially allow big decisions to be made about what kind of therapy to use with the tumor, how aggressive to be with it and what the prognosis might be. This is possible because MRI can probe many characteristic issues within minutes of an investigation. This is an emerging area. The range of molecules that are beginning to be studied is truly incredible.

“One of the emerging areas that our Head of Biology has been developing, initially with academic colleagues, is siRNA. siRNA is one of the most exciting new ways of delivering an entirely different kind of treatment to patients, one that would be targeted genetically very selectively to a bad protein, for example, in a cancer cell.

“SiRNA potentially allows therapeutic modification of a single protein, while not touching other parts of cell function. However, the problem has been to know how much of any siRNA administered actually gets into cells, where it goes and whether it is having any effects on the biology. There are new ways of using PET that promise an approach to quantitative measurement of how much siRNA is sticking in cells and where it’s going amongst the cells in the body. This should allow clinical scientists to move rapidly from the point of dosing to prediction of possible efficacy.”

Seeing the brain

The latest advances in clinical imaging that help illuminate the relationship between disease pathology and patient feelings are particularly relevant to Alzheimer’s disease and schizophrenia, as Matthews explains: “When we feel something or we have a thought, certain cells in the brain start working together. This cell network functions something like a computer to produce the thought or feeling. Changes in the way the brain functions determine everything about us, but in the past, the brain has been a black box, so no one could tell what anyone else was thinking or feeling unless they described it.

“In someone with Alzheimer’s, because the patient is impaired, they can’t tell us what is going wrong in their brain. We can only see the consequences. However, we can use functional imaging to look at the activity of the brain to define relatively precisely what systems are working when the subject performs a task. Perhaps more importantly, we can see what systems aren’t working. So when we ask someone with Alzheimer’s disease to try to remember something, we can define those parts of the brain that we need to modulate to make their thinking better.

“These techniques also allow us to make more specific diagnoses. There are many diseases in which the same symptom can be caused by many different things. Memory problems, for example, are not only caused by Alzheimer’s disease; they can also be caused by stroke, forms of Parkinson’s disease and depression. ”

Functional MRI can also be used to provide a useful marker of the effectiveness of any treatment that might be tried on the patient. Signals from MRI can be more sensitive than the responses verbally reported by subject. “This translates again to that critical issue in drug development: a faster, safer and potentially more effective route from a possible treatment toward something that will get out there and help patients.”

Cancer therapy

According to Matthews, imaging will play an important role in the future of cancer research. “Cancer treatment is very challenging areas for doctors and patients, because the drugs that are used are highly toxic. A remarkable thing is that even now, often the only way we have of assessing whether or not a particular treatment regimen is effective in a particular patient is to give the regime over weeks, sometimes even months, and see if it has had any impact on the tumor size or growth.

“This means subjecting patients to weeks or months of very difficult treatment, without being certain whether it’s giving them any benefit. It is potentially missing an opportunity to provide benefit using an alternative treatment. Imaging with molecular markers allows us to look at the way the cells are responding on a molecular scale. We can begin to get measures of whether the tumor is responding to the treatment within days.”

Matthews explains that by characterizing the types of tumor cells more specifically and looking at the kinds of molecules they express, we can target the chemotherapy better.

“In chemotherapy, you can’t administer the drugs every day, particularly if you’re giving a cocktail; they are administered in a schedule. For example, you give some drugs on Monday, you then repeat it on Friday, come back on the next Monday, next Friday, and so on.

“At this point, decisions about how long to wait between each of the cycles, how to administer the different drugs within the cycles, what order to give them and what delays to put between them are often just educated guesses. But what we can now do with some imaging tools is begin to use more rational ways of dose scheduling, bringing the science right to the bedside.

“This brings immediate benefits to patients. It provides them with more effectively directed therapy and reduces the amount of time that is spent on ineffective therapy.”

Matthews points out that this is also important for drug development because it means that assessment of new molecules can be done more quickly. “It is important for patients because we can end trials with a molecule that isn’t having any effect and get patients back on something that will be effective.

Matthews and his team are passionate about the opportunity to bring clinical imaging to the heart of drug development. He says GSK’s investment in the CIC is unique in the industry. The company has a big vision: “We are committed to sharing openly with the scientific community, including other pharmaceutical companies. The methodology can transform drug development, and it’s important for the scientific community to share in its development and ownership. This is what will bring the highest value to us as a company.”

Paul Matthews is Head of GlaxoSmithKline’s Clinical Imaging Centre (CIC). He is also VP of Drug Discovery within the company. CIC is a collaborative venture undertaken by GSK, Imperial College London and the Medical Research Council to create the largest new clinical imaging center in the world dedicated to the development and application of imaging techniques for drug development.