Pharmacogenomics – goldmine and dynamite
Author: Dr Martin Pfister - Consultant
The right drug for the right person - with Pharmacogenomics, this dream could come true. Scientists in both the academic and industrial setting follow the theme of promises of riches that the intersection of genomics/proteomics with the sciences of pharmacology and toxicology might bring. This marriage of tradition and future claims to deliver tailor-made medicine on the basis of the patients’ genetic make up. However, individualized diagnosis and treatment does come at a price. Why Pharmacogenomics will nevertheless be a major driver of the diagnostic market will be shown in the following article.
The hope: A goldmine for the diagnostic industry
Although a number of factors like environment, diet, age, sex, lifestyle, and state of health all can influence a person's response to medicine, understanding an individual's genetic makeup is thought to be the key in creating personalized drugs with high advantages: optimal efficacy and safety. The completion of the Human Genome Project laid the foundation. If just 5% of the human genome with approximately 30, 000 genes and approximately 100, 000 proteins will have diagnostic significance, about 1500 gene- and 5000 protein-based tests could be commercialized. Thus, with the study of variable drug responses against the backcloth of genetic variability, an almost inexhaustible goldmine can be exploited. The maturation of the DNA-microarray technique in the next 5 to 10 years will provide the possibility to routinely study hundreds of hereditary gene characteristics like predisposition relevant single nucleotide polymorphisms (SNPs) of a patient on one array in parallel with just one small sample. This will revolutionize the way diagnostics and possible subsequent individualized treatments can be accomplished. The most promising diagnostic products to emerge in the pharmacogenomics markets are found among the following disease groups:
· Cancer (better defined and more sensitive detection) · CNS disease (schizophrenia, Alzheimer’s disease) · Diabetes (both, type 1 and 2) · Asthma (leukotriene influence)
The Pharmacogenomics market today comprises three fast-growing core segments:
· oncology testing, · single nucleotide polymorphism (SNPs) and · (viral) genotyping.
Important tools to streamline the high volume gene expression analysis will be, as suggested, DNA microarrays. Even though this technique has to live up to its expectations, first-movers like Affymetrix have begun to shift from research-only applications onto clinical routine settings. Major limitations of the DNA array technology are mainly a matter of quality, standardization and catalogued arrays with relatively high costs. However, the DNA microarray marketplace is changing rapidly. HBS Consulting sees the entire DNA array market in 2002 - including the actual arrays, as well as instruments and supplies - at approximately $499 million. We expect the market to reach about $1.78 billion in 2007 with the SNPs analysis having a major impact on that market.
With molecular tests, the field of Pharmacogenomics, becomes important in two ways. First - the new market promises to transform the art of medical diagnosis and treatment into a predictive science. Second, for the development of new drugs, Pharmacogenomics will play a pivotal role – from the analysis of a lead structure, the clinical trials to the prescription of safer drugs with known metabolic characteristics.
Both manufacturers and users of molecular diagnostics have high expectations for Pharmacogenomics, which promises no less than to transform the art of medical diagnosis and treatment into a predictive science.
The race to catalogue as many of the genetic variations found within the human genome as possible has already started. These variations can be used as a diagnostic tool to predict a person's drug response. The most famous example is Genentech’s Herceptin (trastuzumab) which was originally not developed in connection with genetic testing. It turned out, that this therapy can only be used to treat breast cancer in 20-30% of breast cancer patients that over-express the HER-2 protein. A prior knowledge of HER-2 genetic status is thus an absolute requirement for trastuzumab therapy. The drug in turn is highly effective in this group. In combination with the genetic test for HER-2, Genentech was able to sell the product at a premium price, even compared to other cancer therapies. The drug generated in its first full year (2000) sales of $280 million on the US market.
For Prozac, pharmacogenomic profiling has demonstrable benefits. Approximately 10% of the population contains the drug metabolizing enzyme CYP 2D6 (cytochrome P450 2D6 enzyme) in a slow-metabolizing form. For another 7% of the population, the enzyme exists in a super-fast acting form. For a patient with the slow-metabolizing form of the gene, continual use of Prozac can result in toxicity and potentially lethal side effects. Likewise, a patient with the super-fast acting form of the enzyme would not benefit from a standard dose of the drug, and may require substantially larger doses to achieve the clinical effect. Therefore, a Pharmacogenomics derived product may actually improve profitability, even if it addresses a limited patient population.
Yet another factor was analyzed as important: Even if the market of a personalized drug will be smaller than that of a traditional drug, the treatment of a genetically characterized patient group will be more exclusive for the manufacturer and the best insurance against competition from generic drugs. Many more trastuzumab-like examples are likely to emerge within the next years – leading to new disease and/or drug response markers that may ultimately change the practice of medicine. Not only for clinical pharmacologists, the value of a DNA-chip, capable of diagnosing various alleles and polymorphisms for genetic characteristics and polymorphisms (SNPs) would be invaluable in determining drug and dose regimes.
Market Influences.
Traditional diagnostic companies are operating in an industry that is currently growing at a rate of only 3 to 5% per annum overall, and need to seize new opportunities to ensure their survival. Numerous partnerships have already been established that will help companies to use the driving force of developments like Pharmacogenomics and to stock their (technological) portfolio on the spot. The very first cooperation has been DAKO and Genentech creating the first theranostic test/drug combination with HercepTest and Herceptin. Others followed such as the Roche/Affymetrix alliance and collaborative development efforts between Abbott Diagnostics and Pyrosequencing. Roche Diagnostics is also developing pharmacogenomic tests with deCODE Genetics using its Icelandic genealogy database, in conjunction with its phenotypic and genotypic databases, to enable diagnostics development.
While the pharmacogenomic approach might work for diseases of high unmet need, it is unlikely to be a valuable strategy in areas where a number of effective and relatively cheap therapies are available. On the other hand, one has to examine areas of therapeutics, where a choice of treatment exists. It does not make any sense to test individuals for treatment response, where there is not a genuine choice of treatment. Thus, new molecular diagnostic tests should be available well before their therapeutic siblings or at least in parallel with some form of therapy. The potential economic reward will be huge: profits would come from sales of both the drug and the companion diagnostic test.
We have selected the following markers as of interest for commercialisation within the next 3-5 years:
As for all potential applications, it will be useful to look at the current economic and practical environment. In the hypertension market for example, there is currently a choice between at least six classes of antihypertensive drugs with many drugs within each class. The more drugs patients take, the greater the risk of cumulative side effects and non-compliance. If a test could circumvent some of the need for common multiple prescriptions and repeat consultations, it would become economically viable.
It is generally accepted that the clinical validation and approvals required to move Pharmacogenomics into routine diagnostic testing will take 5 to 10 years. Diagnostic companies, capable of providing automation on the scale from low- to high throughput, along with strong capabilities in genomic discovery and bioinformatics are likely to become the dominant players. Roche Diagnostics, Abbott Laboratories, Applied Biosystems and Celera Diagnostics are well-positioned biotechnological companies bearing the most promising potential in that sector. The adoption of pharmacogenomics within the pharmaceutical sector as well as amongst the consumers, the patients, the physicians and the payers will generate a major market impact for the diagnostics industry as a whole.