BioWorld International Correspondent

LONDON - Xenova Group plc said it discovered a novel DNA-targeting agent, XR5944, with potency that far exceeds that of the two major classes of DNA-interactive cytotoxics used in cancer chemotherapy.

Such is the excitement that the company held a conference call for analysts last week to describe the preclinical data and announce the initiation of a Phase I trial funded by partner Millennium Pharmaceuticals Inc., of Cambridge Mass.

CEO David Oxlade told analysts, "We hope to convey to you a sense of why both Millennium and Xenova feel really quite excited about the potential of this compound, which looks like a new class of potential cytotoxic, albeit at a very early stage of development."

Currently there are two major classes of chemotherapeutic agents that work by interacting with DNA - alkylating agents and topoisomerase inhibitors. Michael Moore, research director of Slough-based Xenova, said that "not withstanding the pivotal role of these compounds in the clinical armory," there are problems with their use, including drug resistance and the limited mechanistic differentiation between the drugs, which tend to work by bringing about DNA strand breaks.

When XR5944 entered preclinical development it was assumed to be a topoisomerase inhibitor. However, Moore said, subsequent data have shown otherwise. In fact, XR5944 represents "a new class of DNA-interactive molecule, which is highly potent and mechanistically different from existing compounds in the topoisomerase class, and which surmounts several drug resistance mechanisms."

In the preclinical studies, XR5944 was very potent in human tumor cell lines, including cells that exhibited multidrug resistance to topoisomerases, and active in human xenograft animal models of colorectal cancer and small-cell lung cancer.

In the SCLC model, the maximum possible dose of a topoisomerase inhibitor led to a slight delay in growth of the tumor. In contrast, XR5944 initially prompted tumor stasis, and when the dose was increased there was complete regression, with no palpable tumor left.

While it was originally thought XR5944 was an inhibitor of topoisomerases 1 and 2, it is now understood to interrupt RNA transcription, and Xenova is working with academic groups to fully elucidate its mode of action.

XR5944 is the second compound in the family. XR11576, also partnered with Millennium, is expected to complete Phase I in the near future. Oxlade said Millennium is particularly interested in XR5944 because of the complete cures seen in animal models.

The two compounds, along with XR11612, which is still in preclinical development, were licensed to Millennium in December 2001. Millennium is providing funding of up to $20 million for clinical trials to the end of Phase II. Xenova retains most rights to the compounds outside North America.

The Phase I trial is an open-label, dose-escalation study in patients with advanced solid tumors, to evaluate safety, tolerability and pharmacokinetic properties.

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