LONDON - Gene therapy company Cobra Thera peutics, of Keele, Staffordshire, is planning a funding round in May or June to raise #5 million (US$8.1 million), giving the company sufficient funds to await research results, which are due within the next two and a half years.

At the end of December, the company had #10.4 million cash and an annual burn rate of #4.8 million. But Cobra plans to start clinical trials of its lead product in the second half of 1999, and wants the comfort factor of knowing it will not run out of money before it has marketable data.

CEO David Bloxham told BioWorld International the company has "sufficient funds to last until the second half of 2000, based on current programs. The trials will be generating key results within the next 18 months, but we face the conundrum of the cash disappearing just as the results appear."

The lead product is a gene-directed enzyme prodrug therapy (GDEPT) for the treatment of cancer. An adenovirus, CTL102 is used to deliver a bacterial nitroreductase gene to cancer cells, prompting them to produce a nitroreductase enzyme. This enzyme converts the previously infused prodrug, CB 1954, into a cytotoxic agent, which kills the tumor.

Safety trials of CB 1954 have already been undertaken in 20 patients, with no adverse reactions to the drug and with plasma concentrations in the therapeutic range. Cobra is now awaiting approval from the government committee that oversees trials involving genetic constructs to carry out a trial in head and neck cancer using the gene to activate the prodrug. "We hope to do the real thing in the second half of this year," Bloxham said.

CB 1954 was discovered in the 1960s, not long after the cytotoxic agent cisplatin. Although it was more effective and safer in animal studies, CB 1954 had no efficacy in humans because the appropriate nitroreductase enzyme was not present. "This is the attraction of the GDEPT approach," Bloxham said. "It allows you to put in the necessary enzyme in the tumor cell to activate the cytotoxic effect. Using the adenovirus for delivery guarantees that the enzyme is produced intracellularly. This contrasts with using antibodies to target the tumor, where you can't guarantee delivery into the cell."

Cobra intends to develop GDEPT as a platform technology. "We believe we can develop a stable of products, by changing the promoter to change the specificity," Bloxham said. The first product has a promoter that will work in all solid tumors. This guarantees the production of the enzyme, but it could be generated in any cell, so that the prodrug must be injected directly into the tumor.

Two follow-up products will target enzyme production to liver tumors and epithelial tumors, respectively. "This will enable the prodrug to be delivered regionally, either into the lymph system or into the peritoneal cavity," observed Bloxham. It will also be possible to vary the enzyme that is produced.

Under current plans, the company will get clinical proof of concept using the generalized promoter during 2000. "This will be followed by expanding the program to the more specific products," Bloxham said. "That's why we would like to have more than one year's money to further develop the products and add value."

Cobra believes there are further advantages to GDEPT, including a "bystander" effect, by which the cytotoxin diffuses into the adjoining cells. This means that the virus only has to get into 20 percent of the tumor cells to achieve complete killing. CB 1954 is an alkylating inhibitor that kills cells at all stages of the cell cycle, whereas competing cytotoxic agents kill only dividing cells. In addition, CB 1954 can be used to treat tumors that are resistant to other chemotherapy agents.

"To date, all alkylating agents have worked in the first and second clinical phases," Bloxham said. "This means we offer a clean position for new investors, compared to other cancer therapies. Cytotoxics either work or they don't. There is no ambiguity and, in a 30-patient study, we can tell if it will work. We could get to a submission by 2003, and we do have the resources to get there, but not to market a product."

The company has not secured any significant collaborations.

"At this point we are involved in a lot of discussions and hope to do a deal in the next three months, but we are not talking about earth-shattering numbers," Bloxham said.

Cobra also is looking to generate revenue by building up its contract engineering business. When the company was established, in 1992, it invested in a manufacturing plant because it was not possible to source vectors elsewhere. This has cut the cost of clinical trials, and Bloxham estimated that it would have cost #500,000 to purchase the viral vector used in trials to date. Cobra has also produced plasmid DNA for the collaboration on DNA vaccines between London-based Glaxo Wellcome plc and PowderJect Pharmaceuticals plc, of Oxford.

"We are encouraged by the level of interest we have received in our manufacturing capabilities, and we want to be in custom manufacture, but it will be five years before we could expect to have a guaranteed contract for a product that was on the market," Bloxham said.

Cobra was founded in 1992 as Therexsys Ltd., but changed its name in 1998, following the acquisition of Cobra Biosciences Ltd., a company specializing in using adenoviral vectors to deliver genes in cancer treatments. To date, the company has raised approximately #30 million in three funding rounds.

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