As pharma R&D costs escalate and productivity declines, there is a clear need to address the problem of the high attrition rate of compounds as they go from discovery through the various stages of drug development. Translational medicine may be the way for pharma and biotech to transform their fortunes. The concept—known also as experimental medicine or discovery medicine—has different interpretations, depending on company location and culture. But, most major pharmas now have a translational medicine group whose goal, broadly speaking, is to create a more direct connection between basic research and patient care.
Translational medicine focuses on a better biological and physiological understanding of human disease and applying this at every stage of the drug discovery and development process.
Often it is about using tools and technologies in a more patient-centered way, which can include going earlier into man. It can also be about focusing more upon bridging the gap between in vitro, in vivo (animal), and in vivo (man) studies and creating better animal models, especially those that can mimic chronic human diseases.
Translational medicine is further concerned with changing a company’s culture and organization, ensuring, for instance, that there is more direct communication between clinicians and basic researchers.
Using Biomarkers in Cancer Research
Andrew Hughes, Ph.D., global director of discovery medicine at AstraZeneca (www.astrazeneca.com), describes the company’s approach to translational medicine in the area of oncology. “We want to address the question of how our drugs actually work in man,” he says. This means a number of specific and practical approaches are being taken.
For instance, it’s important to get the optimum dosing schedule for a drug; a good drug may not realize its potential if it is given on the wrong schedule. Another consideration is the need to determine efficacy in man as early as possible, as well as deciding whether the drug will be used alone or in combination.
AstraZeneca is also interested in understanding the mechanisms of resistance to anticancer drugs better. Additionally, there is a keen interest in looking at the various types of cancer and using the underlying science to prioritize decisions on potential drugs. Recognizing that 40% of patients do not benefit from their prescribed cancer medication, personalized medicine is another area of concern.
Central to all of these is the oncology group’s use of biomarkers. “We have made kill decisions based upon biomarkers,” explains Dr. Hughes. The group uses biomarkers to answer questions and make decisions at an earlier stage on whether the drug hits the target, whether it affects disease phenotype, and whether it actually has clinical benefit.
He admits, however, that validation of biomarkers is a challenge. “It can take three to four years to validate a biomarker. First, the method of measuring it must be fixed and then the variability of the measurements determined. Then we need to find out how the biomarker is modulated by the drug in question.”
Pharmacokinetics and Pharmacodynamics in Neuroscience
The translational medicine concept is being adopted enthusiastically in the CNS and psychiatric therapeutic areas, where the attrition rates can be particularly severe. More attention to pharmacokinetics and pharmacodynamics (PK/PD) in the preclinical stages of drug discovery may help overcome some of the challenges posed by translational medicine in this area, says Johan Luthman, Ph.D., head of neuroscience at Serono (www.serono.com).
“The industry now has the techniques needed for these studies but doesn’t use them as much as is possible to answer questions such as whether the drug is getting to the brain.”
It would be worth putting more effort into investigating PK/PD interactions both in vitro and in vivo, he adds. For example, rather than focusing just on drug dosage, Dr. Luthman believes more should be learned about drug exposure and free drug concentration.
Using Early-stage Results in Later-stage Development
Keith Wesnes, Ph.D., chief executive of Cognitive Drug Research (CDR; www.cognitivedrugresearch.com) sees translational medicine as identifying information at one stage of drug development that can affect selection of a candidate at a later stage.
CDR has a battery of computerized tests that assess the effect of a potential drug on cognitive functioning in Phase I and beyond. This can give an early indication of a compound’s efficacy, as well as its safety.
Dr. Wesnes developed a model in which injection of the drug scopolamine into healthy volunteers temporarily produces the cognitive deficits of Alzheimer’s disease and related conditions. This model has been widely used for evidence of safety and efficacy of drugs in Phase I. “It can provide early evidence that a compound is doing what it is supposed to, which is an important aspect of translational medicine,” he says.
CDR has also developed a sleep deprivation model, which is applicable to Phase I testing of drugs for sleep disorders, including sleep apnea, narcolepsy, and shift work sleep disorder. The CDR approach is being used to test new classes of drugs, such as nicotinic agonists, for their cognitive enhancing properties.
This model has led to promising Phase II results on a drug in this class being researched through a collaboration between Targacept (www.targacept.com) and AstraZeneca for age-associated memory impairment. The CDR battery of cognitive tests has also been used in a recent Phase I study of a nicotinic agonist from Memory Pharmaceuticals (www.memorypharma.com).
The company’s approach is also proving valuable in testing the next generation of psychiatric drugs for any residual cognitive effects which can otherwise impair the patient’s everyday functioning. “Companies feel this all adds value for they can enter Phase II knowing much more about their products, which helps attract partnerships and new investment,” points out Dr. Wesnes.
Experiments During Clinical Trials
Meanwhile, Gerard Dawson, Ph.D, CSO of pIvital, sees experimental medicine as a way of testing efficacy of potential drugs without going into patients—using volunteers instead and working outside of the GP network. This kind of work is beginning to be done between Phase Ib and Phase Ia, especially in the CNS and psychiatric areas and more recently, obesity.
In anxiety, for instance, he says, “instead of a person with anxiety going away and returning for us to ask them how they feel, we can create a challenge in the lab that will create anxiety. It is an experiment rather than a clinical trial.” There are already a few of these experimental paradigms in existence whose validation the UK Medical Research Council has funded.
“But, industry needs more validation than this,” adds Dr. Dawson. pIvital has therefore been involved in getting academia and industry together for this purpose. A precompetitive consortium has now been formed of eight companies who are validating experimental medicine methods. “We are bridging the gap between industry and academia, providing them with the necessary infrastructure and expertise. In this way we can hone and shape the models, as well as pool knowledge on what is and what is not useful.”
These new experimental medicine paradigms can never replace clinical trials but they will, hopefully, generate better drug candidates going into Phase II.
Challenges in Translational Medicine
The general lack of validation of technologies used in both preclinical and clinical studies, particularly where biomarkers are concerned, is a big challenge in translational medicine, according to Dr. Luthman. “Validation of biomarkers, including the surrogate biomarkers that are accepted by the regulatory authorities, takes a massive effort,” he explains. Indeed, it is more common to discard a biomarker than to validate it.
The problems with validation can be traced back to a general lack of understanding of the complex biology of human disease, which is particularly challenging in neuroscience. This could be overcome, perhaps, by having researchers talk more to clinicians. Serono uses a process called back translation where they talk to clinicians about hard-to-understand processes, such as defective remyelination in MS, and use information to do trials in animals that mirror what might be done in man.
Furthermore, the traditional pharma company set-up cannot make translational medicine a success, says Dr. Luthman. “We need to break down all the barriers across functions like clinical development and experimental medicine in our industry. Getting the right organization is probably the biggest challenge.”