LONDON - Shares of Xenova Group plc fell by 25 percent when it said its lead anticancer compound, XR5000, had shown no effect in the first of four Phase II efficacy studies to report. Of 15 patients in the colorectal cancer study, two have shown stable disease, and 13 patients have had disease progression.

CEO David Oxlade told BioWorld International, "The difficulty is, of course, that people will draw conclusions that are inappropriate. This is one of a series of investigatory Phase II studies to identify where the drug is most effective and guide the future development program. It is probably not appropriate to say it didn't work in colorectal, so it won't work in anything."

Shares in Xenova, based in Slough, UK, closed down 26.5 pence at 79 pence when the news was disclosed Thursday. The price rose to #3.65 at the height of the biotech boomlet in March this year.

XR5000 is an inhibitor of topoisomerases I and II, two enzymes involved in the replication of DNA during cell division, and which play a key role in the proliferation of cancer cells.

Oxlade added that the reaction to the trial results ignored the fact that Xenova has two strong next-generation topoisomerases in preclinical development. The first, XR11576 has shown increased potency in preclinical studies compared with XR5000, is from a different chemical class, and has the potential for oral delivery. The requirement for prolonged intravenous administration of XR5000 caused problems with pain at the injection site in earlier trials.

The second follow-on compound, XR5944, is structurally distinct from XR5000 and XR11576, and has shown high potency in preclinical studies on several different human tumor cell lines.

"Since we have got two very exciting follow-on compounds it may be better to take them forward," Oxlade said. "We have got valuable experience with topoisomerase inhibitors."

Such a decision will depend on the findings of three further Phase II trials of XR5000, currently being carried out in conjunction with the European Organization for the Research and Treatment of Cancer. Oxlade expects to get the results of these studies, in glioblastoma and ovarian and non-small-cell lung cancers, in the third quarter.

Xenova also hopes lead compound XR9576 will be ready to enter pivotal Phase III trials by the end of 2000. XR9576 is a P-glycoprotein pump inhibitor that restores the sensitivity of cancer cells to cytotoxic drugs. The company announced positive interim pharmacokinetic data from Phase IIa trials of XR9576 with paclitaxel and doxorubicin in March and May 2000, respectively, and said early indications from the paclitaxel trial indicate a better response than would be expected with paclitaxel alone.

Imaging studies in a third trial with vinorelbine have shown that a single infusion of XR9576 results in P-glycoprotein pump inhibition in the liver for up to 48 hours.