The promise of faster, cheaper and more efficient clinical trials is driving the adoption of pharmacogenomics across the pharmaceutical industry, and companies are stepping forward to provide contract services in this area.
One of the most recent entrants is US bioanalysis specialist Quest Pharmaceutical Services, which has created a molecular biology business unit that aims to tap into the growing market for pharmacogenomics testing in trials.
“The cost of drug development is getting higher and higher,” Ling-Sing Chen, QPS’ executive director of molecular biology, told PharmaTimes. “What we are providing is a new toolkit to help assess new drugs’ safety and efficacy and dramatically reduce the overall cost of bringing new products to market.”
Pharmacogenomics deals with the small genetic differences that help explain why some people respond positively to a drug, while others don’t respond, or may experience a side effect. Genetic differences also can predict variations in drug metabolism - how quickly or slowly a drug is eliminated from the body.
QPS has been building up its expertise in this area with an investment programme valued at several million dollars, which has mostly gone on the purchase of new equipment such as Biotage Pyrosequencing machines for genotyping for patient selection and stratification for clinical studies and Applied Biosystems’ TaqMan systems for expression analysis studies, developing and using biomarkers to monitor drug effects and toxicity.
The US Food and Drug Administration has also been instrumental in driving the adoption of pharmacogenomics in drug development, first issuing guidance on the inclusion of this type of data in applications to market new active substances in 2003, last updated in March 2005, as well as its Critical Path Initiative, which among other things focuses on the identification of biomarkers for diseases that can substitute for clinical endpoints and make trials shorter and cheaper.
In its draft guidance, FDA said that the promise of pharmacogenomics lies in its potential ability to individualise therapy by predicting which individuals have a greater chance of benefit or risk - thus helping to maximise the effectiveness and safety of drugs.
Prior to this, drugmakers were reluctant to use pharmacogenomics during FDA-regulated phases of drug development, because of uncertainties about how the data would be received by the agency. But this is gradually changing, according to QPS' vice president for commercial operations Jon Wallner, who now estimates that every major biopharmaceutical company is using the technology to some extent.
But in many cases developing this type of ancillary technology is not a core competency for pharmaceutical companies, who would rather focus their efforts on drug discovery and development, and they are increasingly looking to outsourcing as a means to add this capability efficiently.
Meanwhile, the field is now evolving, with some of the assays becoming so well-validated that the FDA is considering making the use of some techniques, specifically those related to drug metabolism such as cytochrome p450 genotyping, mandatory for all new drug applications.
“This is already in routine use at most pharmaceutical companies,” said Dr Chen.
But how is pharmacogenomics being used in the real world to guide the development of new drugs? One example can be seen in a project led by Jay Lozier of the FDA’s Center for Biologics Evaluation and Research, looking at what genetic factors determine if a haemophilia patient develops inhibitor antibodies to recombinant blood coagulation factors used to control the disease.
These antibodies can occur in up to one in five patients, but clinical trials of new and re-formulated coagulation factors tend to be too small to gauge whether the drug has this problem, so historical inhibitor rates are used as a benchmark.
“If we can define host genetic factors that explain inhibitor antibody development we will be better able to assess the significance of inhibitor antibody development in trials with small numbers of patients,” according to Lozier. Moreover, the knowledge could be used to develop new coagulation factor products without this tendency.
Another example of how pharmacogenomics can have an impact on clinical research is the use of UGT1A1 genotyping in clinical trials involving Pfizer’s Campto/Camptosar (irinotecan), a drug used to treat colorectal cancer which can cause severe, life-threatening diarrhoea and neutropenia in some patients.
Genetic polymorphisms in the UGT1A1 gene can be used to identify and exclude patients that will have a bad reaction to irinotecan, or alter their dosing, which is of immediate importance for companies developing new cancer agents for use in combination with the drug, said Dr Chen. This type of genotyping is already being used by oncologists to screen irinotecan patients, she noted, as well as in some other therapeutic areas such as HIV/virology.
Pillar of QPS’ business
Although the molecular biology department at Quest is still small in terms of headcount - currently accounting for just four staff members out of a total company tally of around 180 – its financial importance looks likely to rate much higher, eventually accounting for a third or even more of the overall business in five years’ time. The firm already has 10 clients on board for the molecular biology services and another 10 in negotiations, according to Wallner.
“We anticipate this will be a large contributor to our revenues in a short period of time,” he said, noting that this will in part be because of the growth potential of contract pharmacogenomics itself, as well as the commoditisation of other elements of the bioanalysis business, such as routine blood assays.
“We feel there’s a much larger opportunity for high-value specialised services like … pharmacogenomics, protein drug assays for biomarker studies, immunobiological testing and specialised pharmacokinetic work,” he said.
Meanwhile, Dr Chen believes QPS has a competitive position in the pharmacogenomics marketplace, estimated to be worth several billion dollars, because of the breadth of its service offering.
“Our advantage is that we provide genotyping and expression profiling and bioanalysis, and so can function as a ‘one-stop-shop’ in the marketplace. We offer a linear service for drug sponsors, including patient selection, efficacy markers and evaluation, drug concentration and phamacokinetic analyses, as well as mass spectrometry,” she noted.
Among the work ongoing at QPS is a programme looking at the pharmacogenomics of drug metabolism via acetylation, focusing on polymorphisms in the NAT (N-acetyl-transferase) 1 and 2 genes. Cytochrome P450 profiling is a staple of the business, and it also has a project with one client looking at using polymorphisms in the perilipin gene. This codes for a protein that helps body cells store fat and could be used to guide the development of drugs for obesity and possibly heart disease.
QPS officially launched the molecular biology business at two major meetings last month, namely the American Association of Pharmaceutical Scientists' National Biotechnology Conference in Boston and the annual meeting of the Drug Information Association in Philadelphia, USA.