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Imaging, a potential step-change in drug development

Radiolabelled versions of a drug can clarify go/no go decisions and improve the quality of life for patients enrolled in clinical trials

July 2014

Drugs Imaging Pharma Research IMA Lab

In an editorial in Drug Discovery Today, in January 2014, Roger Gunn and Ilan Rabiner explain the usefulness of using imaging techniques as part of the process for testing new pharmaceutical products.

Clinical trials are becoming larger and more complex, and developing a drug from concept to market costs staggering amounts due to the time needed to develop the drug and the risk of drug failure.

Estimated clinical approval success rates range from 8% for CNS drugs to 24% for systemic anti-infectives. Drugs that fail at a late stage of development – or even worse, at the approvals stage – mean that companies waste a huge amount of money and time.
Unfortunately, go/no go decisions are difficult to make, and this is true for both small and large biopharma companies.

How can imaging play a role in translational medicine? Understanding more about a drug’s mechanism of action and its likelihood of success at an early stage of development not only facilitates the decision-making process but also provides information that could be used to improve the drug or its mechanism of delivery.

Researchers can create radiolabelled versions of their drug candidates and then track the passage of the molecules using positron emission tomography (PET).

PET provides a direct measurement of the concentration of the native drug in the vicinity of the target site and by accounting for any off-target binding it can directly assay the free concentration of the drug: this is extremely valuable, since it is one of the key drivers for target engagement.

These measurements facilitate predictions of the drug concentrations to which the target is exposed at a given dose. This approach could be particularly useful in assessing drugs in development for neurological conditions that will need to cross the blood-brain barrier to reach its target in the brain, or for oncology drugs that need to reach the depths of a large tumor.

The findings could facilitate a go/no go decision, or suggest that the drug would need to be formulated into a targeted delivery system. Imaging techniques can be performed as part of first time human studies (Phase 0 or 1) in small groups of subjects that receive the radiolabelled drug. Such trials look at pharmacokinetics in different tissues within the body and provide confidence that the drug exposure levels in target tissues are likely to be appropriate.

To be effective, the drug needs not just to penetrate the tissue of interest, it also needs to bind to the right target. The combination of PET and a radiolabelled form of either the candidate drug or a competitive binder, which produces a measurable specific signal, allows for the determination of target engagement of the unlabelled drug These measurements are achieved by using this imaging probe to measure the number of unbound target receptors in the absence and presence of different doses of the unlabelled drug candidate.

The pharmacological effects consequent on drug binding to a target can be related to the levels of target engagement, which, in turn, enables the levels of target occupancy needed for pharmacodynamic effects to be determined. Pharmacodynamic effects can be imaged by targeting second messenger systems.

Before imaging can be accepted as an important tool in translational medicine, however, there are five key barriers that need to be broken down: lack of knowledge, perceived high cost, lack of access to imaging facilities, lack of validated PET tracers and lack of integration between disciplines.

"In summary - write Roger Gunn and Ilan Rabiner - we strongly believe imaging has a powerful potential role in drug R&D. As well as clarifying go/no go decisions, it can also improve the quality of life for patients enrolled in clinical trials. […] Imaging helps to make clinical trials shorter, smaller and more targeted, potentially bringing drugs to the markets more quickly and more cost-effectively. What is now needed is for the sector to stop hiding its light under a bushel and aggressively take part in the general drug discovery economics debate."

Source:
http://www.drugdiscoverytoday.com/view/36462/drug-discovery-today-januar...