The Human Genome Project (HGP) has been successful in capturing the imagination of the general public and the scientific community alike. The private-public project aimed at sequencing all the approximately 35,000 genes that define a human being. During and just after the completion of the project there was tremendous excitement generated by the promise of quick cures for the maladies affecting humanity. Time has told us that the promises are still to be met. But it has nevertheless caused a paradigm shift in the way pharmaceutical companies research and develop new drugs. It has given rise to a new angle in drug discovery and development, the "mics" angle. Information from genomics, proteomics, and bioinformatics is being used in target discovery, validation, and assessment of the efficacy and toxicity of compounds. The fusion of these components has given rise to Pharmacogenomics, which is the study of an individual response to a drug based on his genetic make-up.
Genomics is the study of analyzing genes and their expression patterns over time, to determine their influence on biological pathways, networks and physiology. Proteomics is on the same lines as genomics except that the analysis is of proteins. Sequences of DNA molecules that make up a gene are the master controls for all processes that take place within a cell. Proteins are the currency of the cell and any activity that takes place within a cell involves proteins. These are also the molecules implicated in disease and hence an obvious target for drugs and for diagnostics. Bioinformatics combines the knowledge generated from wet lab work on genes and proteins with complex computational analysis of their structure and interaction.
Flyovers
Traditionally, drug discovery started out with the identification of enzymes that are critical in the biochemical pathway of a particular disease. Biochemists and medicinal chemists collaborated to formulate a large number of low molecular weight compounds. These were then screened for efficacy. Suitable molecules were then moved through a complex process of cell culture, animal evaluation and human trials It costs upwards of US $1.7 billion and about 7 to 10 years to get a drug to the market. Even large pharmaceutical companies with the resources for this type of research are looking for ways to reduce costs and timelines. This is further compounded by the shortage of suitable targets to aim at.
An alternative to this is the use of Genomics and Proteomics data to design and develop new drugs. The HGP has caused the generation of huge amounts of data for possible targets to aim at, close to 35,000 genes and 100,000 proteins. The new process involves the identification of targets using bioinformatics, generate hits and identify leads for further development. The process can be further simplified using "biomarkers". They are biological entities such as genes and proteins that provide information regarding disease progression, drug efficacy and toxicity. They can also be used to stratify patient populations for effective clinical trials. Indeed pharmaceutical companies have recognized the usefulness of the biomarker and have incorporated biomarker discovery in their drug discovery pipelines. Biomarkers have been useful in the early stage clinical development of drugs. They have been used to measure the safety and efficacy of the drug. Data generated from biomarker studies has been used to take decisions on the further development of a drug.
Speed Breakers
As is with any new approach the biomarker route too has its share of problems. The initial investment required is huge and few are willing to take the risk. There are very few validated biomarkers that can be used for drug discovery research and development. The addition of biomarker discovery is further complicating the drug discovery and trial process. Results from biomarker studies on patients are variable and there is rarely a clear cut trend. The constant threat of misdiagnosis is also preventing people from investing further in this stream. There is a need to be able to analyze the interactions of large number of biomarkers to get a clear picture of the disease mechanism and the available technology is still not feasible for this. Apart from the monetary and technical challenges, there are also regulatory challenges as the regulatory bodies are yet to have a clear policy on this new trend in drug discovery and development.
The Road Ahead
A recent Frost & Sullivan study expects that investment in the field of biomarkers is only going to increase. Companies have recognized that although the initial investment is high, over the long run the amount of time and capital saved during the later phase of clinical development due to biomarker studies is significantly higher. The cost of failure of a drug at an advanced stage of development is far greater. Moving away from single target based diagnosis to a multiple target diagnosis is going to increase the reliability of biomarker data. Integration of high and ultrahigh throughput screening techniques such as DNA microarrays and protein arrays will reduce the complications associated with simultaneous biomarker discovery. The report also says that spinning-off of the biomarker as a separate diagnostic test or licensing for future use could be additional sources of revenue for companies investing in the biomarker discovery.
Highway Police
On the regulatory front, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMEA) have been encouraging companies to submit genomic data as part of the New Drug Application (NDA) process. The submission of genomics data is not compulsory but is part of the Voluntary Genomics Data Submission (VGDS) initiative of the FDA and EMEA. The VGDS helps regulatory scientists to be better prepared for any future submissions of NDA with genomics data. This will go a long way in reducing the delays caused during the review where genomics is an integral part of the drug development process. The FDA has also established an Interdisciplinary Pharmacogenomics Review Group to review VGDS. This group will work on policy development and upon request, will help interpret and evaluate pharmacogenomics data.
To further simplify the process the FDA and EMEA have agreed on a procedure for joint submission of VGDS. Previously companies had to produce separate VGDS, but with this new procedure the process has been streamlined. The spin-off diagnostics idea too has caught the eye of the regulators. The FDA recently brought out a draft paper titled "Drug-Diagnostic Co-Development Concept Paper". The aim of this paper is to gauge public opinion on the idea of drug companies developing kits to diagnose the possible response to therapy of the drug.
Indian outlook
India has a very competent pharmaceutical sector, which is known worldwide for its cheap and effective generic drugs. With the global pharmaceutical sector shifting focus to include genomics and proteomics in their product development, Indian companies too have started looking at integrating these new technologies into their processes. This has been further precipitated by the fact that India has become a signatory to the "Trade Related Intellectual Property Rights" (TRIPS) agreement. The protection offered by process patenting as against product patent regimes has been removed. This has meant that Indian pharmaceutical companies cannot afford to continue making cheap copies of someone else's innovative products. They have to incorporate research and development in their own processes and turn innovators themselves. Indian pharmaceutical companies began taking interest in genomics after the announcement of the Human Genome Project. Dr. Reddy's Lab has taken the initiative to include biomarker evaluation studies in the development of its new drugs. Triesta Sciences, a company based out of Bangalore is doing extensive studies on biomarkers in oncology.
In the future, genomic and proteomic data will be used extensively for drug discovery and development. We can hope for better drugs in the future, drugs that are tailor-made according to the person's genetic make up. For the pharmaceutical companies who take the risk and invest in the biomarker discovery the rewards will be better screening of compounds at an early stage of drug development leading to reduced chances of drug rejection at the advanced stage of clinical development. It will also lead to additional revenue generation and enhancement of the companies Intellectual Property portfolio. Biomarkers, will show the way forward.
The author is senior research analyst, Healthcare Practice, Frost & Sullivan. He can be reached through: sdedhia@frost.com)