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The discovery of the individual as business model

The move towards personalised medicine has made considerable progress, in particular in the field of oncology, where it is leading to the close integration of diagnostics and therapy as well as to the development of profitable new business models, some of which have controversial exclusive legal claims.

“All cancers are different.” The finding that tumours are often characterised by thousands of mutations that can differ considerably within one single type of tumour has led to the establishment of the International Cancer Genome Project. The goal of this project is to “acquire a comprehensive description of genomic, transcriptomic and epigenomic changes in different tumour types and/or subtypes that are of clinical and societal importance across the globe”. As a result, it would then become possible, and indeed desirable, to offer individual oncology patients a differentiated therapy that is adapted to his or her specific cancer profile. The concept of personalised medicine has not made anywhere near the same progress in any other large field of indication. Any advance made depends decisively on reliable diagnostics that can provide information as to whether and how a particular patient responds to treatment.

Roche as the pioneer of personalised medicine

Personalised medicine means the end of the blockbuster concept, which is a way of trying to treat large patient populations as homogenous groups (“one drug fits all”, all being every individual suffering from the same disease irrespective of individual, genetically-based differences in drug response). However, although personalised medicine signals the end of blockbuster drugs as a concept, it does not signal their demise as an economic force: Large corporations depend on such blockbuster drugs, “as they generate in excess of a billion dollars in revenue each year”. One such blockbuster drug is Herceptin, a therapeutic antibody produced by Roche. Herceptin was developed for the treatment of women with metastasing breast cancer. However, clinical studies involving a broad patient collective revealed that Herceptin only afforded a minor advantage in terms of survival. Therapy with this particular antibody (which is directed against the human epidermal growth factor receptor HER2/neu) showed a positive treatment outcome only in women overexpressing the HER2 gene in the tumour. Women therefore need to be screened for HER2 overexpression prior to treatment with Herceptin in order to ensure that they will respond to it. The same applies to gastric cancer patients undergoing treatment with Herceptin, which has been approved for the treatment of metastasing gastric cancer since 2010. The revenues achieved with the sale of Herceptin increased from 4.7 US$ in 2008 to an estimated 6.5 billion US$ in 2009. It is estimated that Herceptin will generate revenues of 7.3 billion US$ in 2012 (Financial Times Germany, 2nd October 2008).

Roche Diagnostics in Mannheim © Roche

Roche considers itself to be excellently positioned for developing the combination of therapy and diagnostics needed for personalised medicine. The Swiss concern not only owns one of the top-selling and most profitable pharmaceutical producers in the world, it is also the global leader in the field of in vitro diagnostics thanks to Roche Diagnostics, the Mannheim-based company that is Roche's third largest location in the world.

F. Hoffmann-La Roche Ltd. is far more rigorous than any other pharmaceutical concern in its approach to personalised medicine as a driver of innovation in a changing healthcare industry, and refers to this side of its business as: "Personalised Healthcare", PHC. The company focuses on the molecular level for both its pharmaceutical and diagnostics research and development. Roche's PHC concept involves the close cooperation of teams focusing on the development of innovative medicines and diagnostic tests, as Dr. Horst Krämer, Project Leader Roche PHC Communications, explains. This enables the unrestricted exchange of information in the early development phase of pharmaceutical agents and diagnostic test methods and technologies, and in consequence saves time and money as the company works towards clinical validation and commercialisation. Here, this parallel development is explained using two examples in Roche's oncology pipeline:

  • The tumour suppressor protein p53 is a key protein for DNA repair and cell growth, which also plays an important role in the growth and suppression of tumours. This is why p53 has been at the centre of development and research activities in the pharmaceutical industry for several decades. p53 is inhibited by the oncogene MDM2, which results in enhanced tumour growth in people suffering from sarcomas, leukaemias or breast cancer. The MDM2 antagonist RG7112 developed by Roche enables p53 to exhibit its suppressor function and prevent the further growth of tumours. However, cancer can only be effectively treated using RG7112 on the condition that the p53 gene is not mutated, which is the case in around 50 per cent of all cancer patients. The therapeutic use of RG7112 requires a test to identify patients with a wild-type p53 gene. In order to carry out this test, an AmpliChip p53 array was developed in parallel to the clinical development of MDM2 antagonists. The AmpliChip p53 arrays recognise the mutation state of the p53 gene.
  • BRAF is a protein kinase that plays a key role in the MAP kinase signalling pathway involved in cell division and cell differentiation. In addition to a BRAF inhibitor (RG7204), Roche has developed a diagnostic test that identifies a single mutation in the BRAF gene (BRAFV600E) using the polymerase chain reaction method (RT-PCR). The BRAF inhibitor is currently undergoing clinical testing in a European Phase III study for the treatment of advanced malignant melanoma. Patients with a mutation in the tumour stand to benefit from this pharmaceutically active agent, which is expected to receive marketing authorisation in 2012.

Exclusive, profitable genes

The fact that the otherwise useful orientation towards personalised medicine is also used for highly questionable business models is illustrated by a case involving BRCA genes, which was described by Helga Nowotny, Vice President of the European Research Council and Prof. em. at the ETH Zurich, and Giuseppe Testa, head of the stem cell epigenetics laboratory at the European Institute of Oncology in Milano (Nowotny H, Testa G: Die gläsernen Gene, SV 2009).

Mary-Claire King, Professor of Genome Sciences and of Medicine, Seattle © University of Washington

The American geneticist Mary-Claire King discovered in the 1990s that around five per cent of all breast cancers are hereditary and around two thirds of these are caused by mutations in the BRCA1 and BRCA2 genes.

While King and an international consortium of scientists were focussing on the further investigation of the two breast cancer genes, the company Myriad Genetics in Salt Lake City, a spin-off of the University of Utah whose goal was to establish the genealogical trees of Mormon families, sequenced the two genes, filed patents and developed a diagnostic test for the identification of mutations in these genes. Myriad Genetics issued an exclusive licence to market all test methods for potential therapies that resulted from this discovery to the pharmaceutical company Eli Lilly, itself concentrating on establishing a proprietary genomic database with all BRCA1 and BRCA2 sequences of patients tested with this diagnostic test. Massive advertising campaigns were run to inform doctors and women with breast cancer about the availability and potential of this test. The company's website says: "Less than 5% of people at risk of hereditary cancer know their genetic results. Myriad provides the answer." Women without a hereditary risk of developing breast cancer were also tested prophylactically and their gene sequences stored in the database that has since become a rather valuable resource for the identification of genetic variants for the development of new drugs at the same time as providing the reference framework required to do so. Independent scientists and other companies were unable to carry out application-oriented research on hereditary breast cancer due to the company's exclusive property claims.

Genes are not a human invention

Recently, this situation has been changing. The Public Patent Foundation and the American Civil Liberties Union of New York City sued the US Patent Office and Myriad Genetics over patents on the BRCA1 and BRCA2 breast cancer genes. The American Department of Justice published a brief on this lawsuit on 29th October 2010 that will most probably turn out to be fundamentally important for the field of biotechnology both in the USA and in Europe. The crucial sentence in the “amicus curiae” brief reads: “The unique chain of chemical base pairs that induces a human cell to express a BRCA protein is not a human-made invention.” The brief thus invalidates more than a dozen key patents held by Myriad on the BRCA1 and BRCA2 genes because “isolated DNA” is a product of nature and not an invention.

Breast cancer cells, fluorescence microscopy © Lutz Langbein, DKFZ

It was no surprise that patent attorneys called the Department of Justice's brief "absurd, disturbing as well as contrary to sound patent policy". As expected, large American biotech companies disagreed with the Justice Department. As the American biotech industry's greatest lobbyist, Jim Greenwood, President of the Biotechnology Organisation (BIO), condemned the report: "If adopted, the Justice Department's position would undermine US global leadership and investment in the life sciences, harm US economic growth and competitiveness at home and abroad and be counterproductive to the Administration's own initiative to fight cancer and develop renewable sources of energy" (quoted from Science 1st November 2010).

Since previous gene patents are mainly held by American biotech and pharmaceutical companies and by big universities that are closely linked to industry, it can be assumed that German biotech companies will not suffer unduly from this new stance on the patenting of genes. In fact, quite the opposite is true: since the brief only stipulates that natural genes cannot be patented, but that the patenting of applications or modifications of gene sequences is unaffected, research and proprietary developments relating to disease-causing genes should only be stimulated if companies such as Myriad and research institutions such as the University of Utah can no longer impair such research.

An article in the Germany weekly DIE ZEIT on 4th November 2010 stated: "...all companies are now able to develop own methods on the basis of a genetic trait... It is still unknown when the US Patent Office will implement the Justice Department's brief in practical terms. However, when they do, the gold rush in the biotech sector, far from grinding to a halt, will reach new heights."

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