A drug target that exhibits two separate functions in the inflammation response is the centerpiece of the lead program at Biotie Therapies Corp., Finland's first listed biotechnology company.

Vascular Adhesion Protein-1 (VAP-1) is an endothelial adhesion molecule expressed at sites of inflammation. It plays a role in the early recruitment of leukocytes in the inflammation response, and it contains a catalytic domain with semicarbazide-sensitive amine oxidase (SSAO) activity, which stimulates the formation of hydrogen peroxidase, a well-known mediator of inflammation.

The Turku-based company is developing compounds that target each of these activities. Its lead candidate, a murine monoclonal antibody called Vapantix which blocks the adhesion function, entered Phase I/IIa clinical trials in June. "We should have the preliminary results available during the first quarter of next year at the latest," Biotie's vice president for clinical development, Timo Varomaa, told BioWorld International.

"The reason we're pursuing a murine antibody in this day and age is we have the antibody in hand already," he said. Vapantix is indicated for treatment of acute, life-threatening inflammatory conditions, such as ischemia-reperfusion injury in myocardial infarction and stroke, and adult acute respiratory distress syndrome.

A humanized monoclonal antibody, which targets an overlapping epitope on VAP-1, is still in preclinical development. This candidate, called Huvap, is indicated for chronic conditions, such as rheumatoid arthritis, asthma, inflammatory bowel disease, psoriasis and other skin conditions. Varomaa said Huvap will not enter the clinic until 2002. "Before going for the clinical development, we wanted to be sure we would have an industrial-scale process," he said. The company has secured a manufacturing agreement with Boehringer Ingelheim Pharma KG of Ingelheim, Germany.

Biotie is also developing small-molecule inhibitors of the SSAO enzymatic activity. The origin of hydrogen peroxide at sites of inflammation is unknown, according to Veromaa. "We do have this humble belief [VAP-1] may be the sole source," he said. The company's screening program is aided by a model of the VAP-1 catalytic domain based on a crystalline form of the equivalent protein in the bacterium E. coli. "We would hope to have a lead candidate identified by the end of this year," said Veromaa.

Husband-and-wife team Markku and Sirpa Jalkanen, both well-known scientists in Finland, established Biotie in 1996. Markku Jalkanen is CEO of the company, while Sirpa Jalkanen retains her post as a professor of the Finnish Academy, based at the University of Turku.

The company is holding off from entering any alliances until it has first demonstrated proof of concept. "Our target is basically to get the first deal done in either late 2001 or 2002," said chief financial officer Jari Saarinen. Biotie has enough cash for the next two to three years, he said. It raised EUR17.1 million, net of expenses, when it floated 20 percent of its stock on the Helsinki stock exchange at the end of June, boosting its cash position to EUR20.8 million.

The company's second area of development is based on carbohydrate chemistry, or "biologically active linear polysaccharides." The lead program here is a low-molecular-weight synthetic form of the anti-thrombotic drug heparin, which is based on a precursor found in the capsule of the E. coli K5 strain. This is grown by fermentation, and the K5 polysaccharide is then subjected to a series of chemical modification steps to yield a replica of the anti-coagulant molecule, which contains repeating units of iduronic acid and glycosamine.

The company aims to develop a replacement for current formulations of heparin, all of which are derived from pig intestine. Apart from concerns stemming from the potential transmission of infective agents, the present method of manufacture is environmentally damaging and requires very large amounts of material: One pig is needed for each injection, according to Veromaa. The market for heparin is worth US$2 billion per year and is growing by 15 percent, said Veromaa.

In addition, he said, heparin is known to have anticancer activity, but its therapeutic potential in this indication has been limited because it can cause bleeding. The company is developing chemically modified forms of heparin in order to circumvent this problem. Biotie's third area of development is based on inhibition of the platelet collagen receptor integrin alpha-2 beta-1. This has potential in both thrombosis and in cancer, said Veromaa, but it is still at an early stage. The company has incorporated a molecular model of the receptor and its ligand into its screening program.

The VAP-1 therapeutic antibody program is the subject of patent litigation with Finland's largest pharmaceutical company, Orion Corp., of Espoo. The dispute stems from a previous research collaboration between Sirpa Jalkanen and Orion. The latter now contends that it should be assigned the rights to VAP-1 antibodies. Biotie is contesting this claim, and a preliminary hearing is scheduled for this month. "That is not impacting our clinical development at all," Veromaa said.

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