BioWorld International Correspondent

Norwegian firm Clavis Pharma A/S moved its lead compound, a modified version of the well-known cytotoxic agent cytarabine, into a dose-escalating Phase I/II trial, which is being conducted in the UK and Norway.

This represents an important test of its Lipid Vector Technology (LVT), which is designed to improve the performance of existing and new molecules through the attachment of a fatty acid molecule. Oslo-based Clavis Pharma, formerly known as ConPharma, was spun out of Norsk Hydro ASA, the Norwegian chemical and petrochemical group, in August 2001 to commercialize a decade's worth of research into the LVT platform.

Chain length and the position of a double bond within the hydrocarbon chain both appear to influence the performance of the modified therapeutics. The current trial involves an agent called CP-4055, an elaidic acid (C18:1, unsaturated fatty acid) ester of cytarabine, which has shown promising activity in human solid-tumor xenograft models. "With our lipid derivative, we saw complete tumor regression," Clavis Pharma President and CEO Ole Henrik Eriksen told BioWorld International.

Cytarabine (ara-C, Cytosar-U), which acts as an inhibitor of DNA synthesis, has a history of usage in combination treatments of chronic and acute lymphomas, but has not been effective as a therapy for solid tumors. The trial, scheduled for completion by the fourth quarter, will enroll patients with non-small-cell lung cancer, ovarian cancer and malignant melanomas. So far, four subjects have received doses. "Depending on what the level will be, it will take [about] 20 patients to get there," Eriksen said.

Cytarabine is a nucleoside molecule, and normally depends on transporter proteins in the cell membrane to gain entry into a cell. When linked to elaidic acid, however, it appears to take an alternative route. "We have shown that [it is] completely independent of those nucleoside transporters," Eriksen said. The attachment of the fatty acid moiety also appears to influence the drug's fate once it enters the cell and undergoes phosphorylation into its active form.

Eriksen said CP-4055 yields a higher sustained level of the active compound than unmodified cytarabine. "Somehow we limit the degradation."

Although CP-4055 has characteristics that are reminiscent of a prodrug, Eriksen said that LVT is not just a delivery platform. "We are making new chemical entities, which will have completely new properties," he said. Some compounds in its pipeline are active while still attached to a fatty acid molecule. Clavis' overarching strategy is to revitalize existing drugs that are known to be effective. "We will obviously target drugs that are doing well in the market that have deficiencies that we can attack," Eriksen said.

Next in the Clavis pipeline is another anticancer compound, which it aims to move into the clinic in the first quarter next year. "The second compound is doing well in solid tumors, but it has limitations with respect to dosing and toxicity that we think we can improve substantially," Eriksen said.

Oncology will remain the company's main therapeutic focus, while it will license out drug candidates for other indications. Two antiviral offerings are already on the block. An LVT-modified form of acyclovir has already completed a Phase I clinical trial, while a modified version of gancyclovir is in preclinical development.

Clavis raised NOK80 million (US$11.4 million) in a second funding round led by MVM Ltd., of London, last year. At current burn rates, that would last until mid-to-late 2004, Eriksen said. It aims to raise around €30 million in its next round, by which time it hopes to have two compounds in clinical development and one licensing agreement under its belt.