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Sep 15, 2005 (Vol. 25, No. 16)

Flanders' Biotech Sector Comes of Age

Proven Scientific Expertise and Range of Incentives Drive Growth

  • Two IPOs in May and June 2005 of Belgian biotechs, DevGen (Ghent) and Galapagos Genomics (Mechelen), which raised E30 million and E20 million, respectively, may be considered a bellwether of a rapidly growing Belgian biotech industry.

    Another sign that the regions biotech industry is reaching critical mass was attendance of over 400 at the regions first annual conference, Knowledge for Growth, held recently (kfg.flandersbio.be), at FlandersExpo in Ghent.

    Flanders, in northern Belgium, is the center of the nations biotech industry, home to 43 dedicated biotech and 70 mixed biotech companies.

    Twenty-five multinationals, including Johnson & Johnson, Pfizer, Bayer, Schering-Plough, Baxter, Monsanto, AstraZeneca, and Genzyme, have chosen to locate R&D, manufacturing, and marketing and sales in Flanders. With the seat of the European Union (EU) in Brussels, the region is centrally located within the EU.

  • Commercial Biotech Center

    Over the past decade, Flanders has transformed longstanding excellence in the academic life sciences into a flourishing commercial center of biotechnology, mostly in Ghent, Leuven, and Mechelen.

    A recent case study of biopharmaceutical innovation systems by the Organization for Economic Cooperation and Development (OECD), which examined eight European nations, confirms Flanders ascendancy in biotech, ranking Belgium first in innovation and industry, and second in science.

    Flanders has the second highest rate of clinical trial protocols per capita in all of Europe, and is home to Europes second largest hospital. The region currently employs about 20,000 in the life sciences, and after the U.K. and the U.S., has the worlds highest number of drugs in development.

    Flanders has also steadily increased investment in venture capital in biotech per capita, and now maintains the highest rate of investment among eight EU nations. Catherine Verfaille, Belgian native and a world-renowned stem cell researcher, recently announced that she is leaving the University of Minnesota to found a stem cell institute at Leuvens Catholic University.

    As one of the leaders in the early development of biotech, Flanders is where the first transgenic plants were developed, the first DNA sequence of a gene was determined, and where tissue plasminogen activator (tPA) was discovered.

    A study conducted by the Flemish government in 1994 showed that to commercialize its life sciences and move to the international markets, it needed to improve infrastructure. The Flemish government decided to invest $125 million over five years, doubling the areas research budget overnight, and re-evaluate the system every five years.

    To foster collaboration among Flanders four universities and 850 researchers, the Flanders Interuniversity Institute for Biotechnology (VIB), was founded in 1995 to facilitate technology, said Rudy Dekeyser, vice general director.

    We operate in a very hands-on manner by supplying seed financing, conceptualizing and writing a business plan, and assisting in the development of a team and in the due-diligence process, Deykeyser said. One of seven incubators in the region with 8,000 m2 hectares under construction, the VIB BioPark in Ghent is expanding.

    VIB focuses on human health (cardiovascular/angiogenesis, neurodegeneration, oncology, and inflammation), microbiology, and plant systems biology.

    Recently, Catholic Universitys Peter Carmeliets, M.D., Ph.D., group received the Galenus Prize for being the first to show the importance of vascular endothelial growth factor, or VEGF, in amyotrophic lateral sclerosis (ALS). Dr. Carmeliet is a co-discoverer of VEGF, a major figure in angiogenesis research, and recently showed that VEGF has an important function in the central nervous system.

    VIB has helped establish a number of biotechs, including DevGen, CropDesign, and Ablynx. In 2004, VIB and a number of biotechs set up FlandersBio to actively promote entrepreneurship and bring together companies doing R&D-based life sciences, research institutions, funders, and equipment providers, to attract other companies, investors, suppliers, and skilled labor, said its head, Els Vanheusden, M.D.

    Together, VIB, FlandersBio, and the Flanders Foreign Investment Office are collaborating to build the regions biotech capabilities.

  • Infectious Diseases

    The oldest Flemish biotech company, Innogenetics (Ghent), was founded in 1985, and focuses on diagnostics and therapeutic vaccines for infectious diseases. One of the worlds largest biotech companies in market value, and ninth largest in Europe, its specialty diagnostics for infectious disease treatment selection, genetic testing, and neurodegeneration, yield substantial revenues, over E70 million in 2004, and are partnered with Bayer, Roche, and others.

    Innogenetics is developing three polyepitope therapeutic vaccines for hepatitis C (HCV), hepatitis B (HBV), and human papilloma virus (HPV), and a vaccine for HCV using the E1 envelope protein, which provokes an immune response from both arms of the immune system.

    Results from Innogenetics Phase IIa with its HCV E1 vaccine confirmed a strong immune response in infected patients, stabilization of liver fibrosis after 17 months, and regression of fibrosis after three years. However, in June, the first of two Phase IIb trials surprisingly showed that the placebo group had slower deterioration of the liver than expected, so that the difference between the treated and placebo groups did not attain statistical significance.

    Dosing or length of treatment could be responsible, so we are extending the treatment period of the ongoing second Phase IIb trial by at least 15 months, says Luc Van Dessel, company spokesperson. In March, Innogenetics completed its first U.S. trial, a Phase I with its HBV vaccine, and raised E34.5 million in a private placement.

  • Nanobodies

    Ablynx, incorporated in 2002, is developing a new class of therapeutics based on unique single-chain antibodies, or nanobodies discovered by a University of Brussels researcher in the early 1990s in the camel family, said CEO Mark Vaeck. These small proteins are antibody fragments derived from the antigen-binding domain of naturally occurring antibodies in camels and llamas which naturally lack a light chain.

    Ablynx nanobodies have the affinity and selectivity of antibodies but are much smaller, have low immunogenicity, can be easily humanized because of their high homology to the human light chain framework, and are more stable than human antibodies.

    Because nanobodies are so small, they are able to penetrate organs and tissues better than full-sized antibodies, said Dr. Vaeck. Nanobodies can be produced in bacteria, unlike conventional antibodies, which must be made in mammalian culture, and can be engineered to have a short or long half-life.

    And unlike traditional antibodies, nanobodies can penetrate the brain-blood barrier and transport drugs to the brain, and can also be absorbed by the gut, said Dr. Vaeck.

    To produce nanobodies, Ablynx immunizes one of 20 llamas cared for by the University of Ghent with a target antigen, isolates B cells from blood, and clones the genes. To date, it has generated nanobodies for 20 disease targets, many in its areas of focuscancer and immune diseases; it also has generated leads in thrombosis, infectious disease, and neurodegenerative diseases.

    Ablynx candidates for rheumatoid arthritis, inflammatory bowel disease, and thrombosis prevention are in preclinical testing, should be in the clinic next year, and are partnerable.

    Ablynx programs for solid tumors, psoriasis, and Alzheimers disease are in earlier stage development. Ablynx has deals with Proctor & Gamble for a G-coupled protein receptor target, with Genencor for oncology, and Canada National Research Council for CNS disorders. It raised E30 million in June 2004.

    Tibotec and Virco (Mechelen), sister companies acquired by Johnson & Johnson in 2002, are developing therapeutics and molecular diagnostics, respectively, for infectious diseases. Tibotecs goal is to develop drugs for HIV, tuberculosis, HCV, and respiratory syncytial virus.

  • HIV Research

    Collectively, Tibotec represents 20 years of HIV research, said vp of lead discovery, Kurt Hertogs. It is developing three HIV drugs: TMC114, a next-generation protease inhibitor that can adapt to the changing shape of a mutant virus and targets two backbone areas of HIV that do not change.

    Two Phase IIb trials are ongoing with low-dose ritonavir; results of an interim analysis presented in February showed an unprecedented drop in viral load; Tibotec is in discussions with the FDA currently.

    TMC-125 is a next-generation non-nucleoside transcriptase inhibitor (NNRTI), also a flexible molecule, that shows good activity against wild-type and resistant virus. A long-term Phase IIb is ongoing in Europe, Canada, and the U.S.

    TMC-278 is a new NNRTI that has completed Phase IIa trials in analysis, and has begun a long-term Phase IIb trial.

    Focusing on viral pharmacogenomics, Virco has developed genotype and phenotype and virtual phenotype tests to predict when HIV drug therapy will stop working. The VircoType HIV-1 test combines genotype and phenotype testing in a rapid, low-cost test. The Antivirogram is an HIV-1 phenotype assay that uses fully replication-competant virus to assess susceptibility to RRTIs.

  • Regenerative Medicine

    Tigenix, founded in 2000 on the research of Frank Luytens, M.D., Ph.D., of Catholic University (Leuven), focuses on regenerative medicine, specifically, cartilage injuries and osteorarthritis (OA), for which no effective treatments exist, said vp of commercial development, Heico Breek, M.D.

    Tigenix is developing cell-based therapies, ChondroCelect autologous chondrocyte implants, and adult stem cell treatments for cartilage, bone, meniscus, and muscle repair, and locally delivered therapeutics.

    Older techniques use fibrous cartilage for repair, which does not work, said Dr. Breek. Tigenix technology enables the selection of a different cell population that produces stable hyaline-like cartilage resistant to mineralization and vascular invasion.

    Based on proprietary molecular profiling, Tigenix discovered 150 positive and 60 negative markers associated with the proper cartilage type, from which it selects the proper cells.

    Tigenix is currently conducting a prospective, randomized Phase III trial in 118 patients using its proprietary autologous cartilage cells; results are expected in early 2006. The primary end point is structural repair, and the secondary end point, symptom relief and function at 12 months.

    Tigenix plans to improve on ChondroCelect for future products by using a 3-D carrier, and to apply its stem cell technology to meniscal and other tissue repair. For therapeutics, it is researching signaling pathways as targets for OA drug development, and to stimulating cartilage matrix synthesis.

    Potential drug types include small molecules, polysulfated sugars (nutraceuticals), and chemokines. It is launching a private placement for E20 million, preparing to launch ChondroCelect in the U.S. and EU, and establishing a U.S. headquarters.

    ThromboGenics, Leuvens oldest biotech, is focusing on cardiovascular and stroke research. Founded in 1991 by Desiree Collen, who discovered tPA and licensed it to Genentech (S. San Francisco), ThromboGenics is developing microplasmin, (discovered from its tPA reseach), as a neuroprotective thrombolytic, and for treating eye diseases such as diabetic retinopathy and macular edema (with NuVue Technologies, Keene, NH).

    The firm is working with Geymonat (Catania, Italy) to develop placental growth factor (PlGF), an angiogenic growth factor, the focus of Dr. Carmeliets research, for cardiovascular applications.

    A homolog of VEGF, PlGF has more specific activity, targeted effects, and fewer side-effects than VEGF for pro-angiogenic treatments of ischemic heart disease and wound-healing. It is studying anti-PlGF for anticancer use, said Stuart Laermer, CBO. ThromoGenics subsidiary, Thromb-X sells embryonic stem cell reagents.

    "The critical factor in biotech locating in Flanders is not low costs and financial incentives," said Johnson & Johnson chief of medicinal chemistry, Jan Hoflack.

    "Its competitive advantage lies in its proven scientific expertise: top-level academic research and an educational system that has created a highly educated, skilled, and motivated workforce." A range of incentives including numerous types of cash grants and tax benefits are available for investment in Flanders.



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