Human Genome and the Molecular Diagnostics Market

Chris Chamberlain, Global Head, Medical Genetics, Roche Products Limited, UK

Chee Gee See, Biomarker and Genetics Programme Manager, Roche Products Limited, UK

Molecular technologies will drive the expansion in market size and the range of applications in the molecular diagnostics market.

The unravelling of the main bulk of the human genome in 2000 led to a feverish explosion of ideas of how genetic information could be used to improve the identification and management of human disease and enhance human health through improved therapeutics. Target-based drug discovery immediately received a shot in the arm for more molecular-based approaches. In part, these ideas re-evaluated the massive costs involved in the drug discovery process and streamlined the targeted strategies already employed by pharmaceutical and biotechnology development companies. The agreed estimate of 26,000 to 30,000 genes in the human genome has probably 3,000 to 5,000 gene targets which are potentially amenable to pharmacological intervention, the so-called druggable genome. However, 5 years after the initial euphoria, all pharmacological-based disease intervention is still restricted to a select group of around 500 targets. The challenge for the post-genome era remains to break through this select group and to capitalize on the potential of the druggable genome.

Coupled with empirical sequence data on the human genome has been the recent surge of basic biological information and the advent of various genomics-enabling platforms to test disease hypotheses. Taken together, this continues to be a powerful cocktail for new discoveries. Constantly improving genomics technologies such as RNAi have satisfactorily validated targets that would have taken much longer (and at greater cost) with traditional knock-out transgenics, and sometimes with the added bonus of detecting both on and off-target effects.

A new approach

The search by pharmaceutical and biotechnology development companies for newer, safer and more efficacious pharmacological compounds has also led to a renewed appraisal of the value of diagnostics. The pressure to be first-to-market for safer, more efficacious and cost-effective medicines has meant that, increasingly more companies are integrating diagnostics across their pipelines in parallel to drug development. It is clear that this approach makes a significant difference. Arguably the most notable historical milestone can be traced back to the early nineties. In 1991, when Roche acquired patent rights to the Polymerase Chain Reaction (PCR) technology from the Cetus Corporation, PCR was not positioned or envisaged for diagnostic purposes.

With inspirational foresight, Roche quickly developed and launched the PCR-based Amplicor system as standard kits for clinical diagnosis within a year. With a strong licensing strategy for its newly acquired PCR technology and a very carefully engineered commercial emphasis, Roche launched in 1992 the Amplicor system for detecting pathogens of two sexually transmitted diseases, Chlamydia trachomatis and HIV. The matching of an appropriate diagnostic tool to the critical need of the clinical environment ensured that this was a timely delivery that was readily accepted. Current refinement of the Roche Amplicor system now not only detects HIV presence but also provides ultra-sensitive measurements of the viral load of individual patients ensuring that physicians are able to clinically manage their patients’ personalized treatment regime. Roche has therefore optimally utilized the combination of a clear diagnostic tool with its drug portfolio, making a significant material difference both to the patient and pharmaceutical company.

Another example of a pharmacodiagnostic partnership is the Aventis/ Pharmanetics story. Aventis has had approval for Lovenox, a low-molecular weight heparin for treatment of dangerous blood clots in the arms and legs, in the US and Canadian markets since 1993. The decision by Aventis to invest $5 million to tailor the development and regulatory approval of Pharmanetics’ Enox test for the point-of-use of Lovenox created the potential to double the $1 billion per annum sales of Lovenox. Concurrently, following the approval for the Enox test in August 2002, 90% of Pharmanetics’ revenues in 2003 came from sales of the Enox test itself. The commercial potential in such pharmaco in vitro diagnostic partnership is therefore huge. The Aventis/ Pharmanetics story is a good example of how such partnerships can generate huge opportunities, although sadly the current relationship between the two companies has fallen on hard times.

Within the in vitro diagnostics industry, molecular diagnostics is the fastest growing segment. In little more than a decade, the clinical market for molecular diagnostic products has surged from $50 million to over $1 billion in the US, and is anticipated to reach a global market of $35 billion by 2015. These are astonishing exponential figures and they are an indication of the profitability of the molecular diagnostics market. Even more indicative is the market belief that a major portion of this will be attributed to advances in genetics, genomics and proteomics. It is therefore clear that molecular technologies will drive the expansion in market size and the range of applications in the molecular diagnostic market. Driven by the perceived commercial benefits pharmaceutical companies are increasingly interested in developing tests that can be used to guide the eventual prescription of their drugs. Take the case of Herceptin. Herceptin is indicated for metastatic breast cancer and in late May 2006 also gained UK approval for early-stage breast cancer. Herceptin treatment is seriously considered only when a patient scores a +2 or greater on the pre-requisite Her2/ neu protein over-expression diagnostic test. The Her2/ neu diagnostic test is therefore a targeted clinical test as it indicates to the physician as to who should be appropriately considered for Herceptin. In this respect, the Her2/ neu diagnostic test selectively identifies a subgroup from breast cancer patients who may benefit from Herceptin and equally importantly, identifies those patients for whom Herceptin will not be useful. Herceptin is the epitome of personalized medicine in its fundamental approach. The commercial cost of segmenting the breast cancer market by following this approach is more than offset by the superior effectiveness of providing the appropriate drug to the appropriate patient and at the appropriate dosage – the dogma of the safety and well-being of the patient coming first.

Whilst Herceptin is a good example of the use of a specific molecular diagnostic test in combination with clinical utility, relatively few companies are devoting their resources to developing molecular technologies for use in the actual clinical setting. The high costs in validating any such molecular diagnostic tests to the FDA and the extended lag-time from initial introduction to eventual adoption by the clinical community are key factors in discouraging many companies from taking this plunge. Instead, most of the developmental interests for such molecular diagnostic tests lie in the discovery and research arena, where the FDA hurdle is considerably lower. In the research environment free from regulatory constraints and associated costs, both diagnostic and pharmaceutical-based companies can actively exploit the rich coal seam of the molecular diagnostic market. This is the arena where sequence data from the Human Genome and Proteome Project is making an enormous impact. For example, single nucleotide polymorphism (SNP) data from both the Human Genome project and the HapMap project has been and continues to be exploited in the design and construction of microarray chips used for whole-genome association studies. Affymetrix has been an astute leader in this area and has produced GeneChip mapping sets now extending to 500,000 SNPs. It is envisaged that genetic association tools such as these GeneChips will continue to be major players in the next few years. As long as there is a demand in discovery research for the identification of key genes involved in common disease etiology, this is an area of the market where growth is likely to continue. SNP information on key genes involved in drug metabolism or transport has also been exploited in the design of microarray chips for pharmacogenetic studies. This is an area where pharmaceutical companies in their quest for safer, more efficacious and cost-effective medicines require indicative answers as to how subjects are metabolizing or excreting their drugs or to discover if there may be genetic reasons for pharmacokinetic outlier effects. Again, the market indications are that tools for pharmacogenetics will potentially provide rich pickings for the diagnostic market.

Even more informative are expression microarrays which are used to interrogate and compare transcripts from case-control studies. Developments in proteomic platforms now also allow the comparison of proteins from such case-control studies. Taken together, these molecular diagnostic tools allow pharmaceutical companies to either generate or validate biomarkers in their drug development programs. The incisive molecular diagnostic partner will continue to seek out these specific requirements to match the need.

The need to trim down the massive costs involved in bringing a drug successfully to market and the high attrition rate in the drug development pipeline are two reasons biotechnology and pharmaceutical companies are increasingly looking to molecular diagnostics to provide early leads and guidance as to a program’s likely fate. The incredible synergy that can be found in such pharmacodiagnostic partnership is likely to grow as we clock up more mileage on the human genome data. Such a synergy is clearly exemplified by the Roche-Affymetrix partnership in the design, execution and marketing of the AmpliChip diagnostic kits. Making use of Affymetrix’s expertise in microarrays and Roche’s PCR technology, this is an ongoing partnership that seeks to create diagnostic tests both for research and clinical use. As targeted medicine and personalized healthcare become more relevant topics for consideration, these could be the low-hanging fruit that molecular diagnostic companies should keep a watchful eye on.

Authors' note: Clinical data available upon request

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