How finding out what a drug does in the body earlier can make research more efficient
The research and development of new therapeutic entities is not only time consuming and complex, but also an incredibly expensive venture. With the average time for new drugs to come to market around 10 years at a cost of up to $1bn, innovations that can improve efficiency in this process and lower costs are widely sought by industry and the wider healthcare community.
One way that is being explored in fulfilling this need is the use of imaging sciences – an area of research that has seen a revolution in its development over the past 25 years.
This has included major advances in equipment, available probes and analysis techniques, providing good opportunities for wider use of imaging by bioscience companies using such tools as positron emission tomography (PET) and magnetic resonance imaging (MRI).
As for what benefits these instruments offer, PET scanning enables researchers to label molecules, ligands and development compounds with small amounts of radioactivity so their journey through the body can be traced. This allows for imaging of biological systems at a molecular level, meaning researchers are able to discover if the compound reached its intended target.
With more advanced PET techniques, the measurements of the concentration of proteins, enzyme activity or the receptor occupancy of drugs at their targets can be taken. PET imaging techniques are constantly evolving, bringing new opportunities for the application of imaging and expanding the biological space in which measurements can be made.
PET scanning is a useful tool in its own right, but when combined with MRI and computed tomography (CT) scanning, its utility is amplified considerably. Both MRI and CT scanning offer high quality anatomical imaging that, when combined with PET, allows the researcher to see where the drug is interacting with the body. In addition, by employing techniques such as functional MRI (fMRI) one is also able to compare the direct functional effects of those interactions.
Importantly these techniques are non-invasive which means they can be utilised in human subjects in-vivo early on in the drug development process. Being able to determine which compounds reach their targets and the responses they innervate means that developers can determine which compounds demonstrate good properties as drug candidates.
Imaging cannot guarantee 'winners' but its strength is in rapidly identifying 'losers' that should be discontinued much earlier on in the development process. This ability reduces the number of drugs discontinued at later stages in clinical trials – a far more costly failure for pharma companies.
Imaging sciences can also be utilised to provide valuable information on lead compounds moving into early stage development and proof of concept studies. The results of the imaging studies can be used to determine likely dose levels which give the desired pharmacological response, increasing the chance of gaining beneficial results in later clinical trials and decreasing the likelihood of adverse events.
Neurology is a key therapy area where imaging can make a significant contribution, such as in the development of compounds to tackle neurodegenerative diseases, eg stroke. In this area, the need to determine if the molecule has reached the intended target in the brain is essential, as the efflux pumps in the blood brain barrier (BBB) prevent many novel compounds from reaching the brain and the BBB may be compromised as part of the disease progression.
The data generated from PET imaging can give drug developers early confidence as to whether the molecule has reached the intended site of action in the brain in pharmacologically active concentrations.
If the intended mechanism of action is in the brain but no brain penetration is observed, this allows researchers to make an informed decision on the continuation of the compound in development.
New treatments for Alzheimer's disease (AD) are currently an area of intense interest. PET probes which can measure beta-amyloid, a protein which is suspected of contributing to the disease as it builds into plaques, are already being deployed to investigate the effect of novel AD therapeutics. MRI scanning is also vital in measuring structural changes in the brain, where a reduction in grey matter volume is determined as the disease progresses.
Alongside treatments for Alzheimer's disease, the ongoing search for a new biomarker in schizophrenia is also seeing significant contributions from the imaging sciences.
Another area which has huge potential to benefit from imaging is oncology. In this field, new probes to measure the cellular processes angiogenesis (new vessel development) and apoptosis (cellular death) are being developed as these are the mechanisms of action for new anti-cancer drugs and can therefore provide key information in their development.
The potential for value of imaging sciences in early stage drug development is huge. Allowing researchers to make informed early decisions on drug candidates could shave millions of pounds off development costs. Non-invasive trials of novel compounds in humans not only relieves the need for animal modelling of biological systems, but will allow the progression of a new compounds to the market to become more targeted, saving both research costs and time.
Andy Brown is a senior imaging scientist working in imaging applications at Imanova, centre for Imaging Sciences. Imanova is an independent company owned by collaboration between the MRC and three of London's leading universities.