LONDON - British Biotech plc said its oral anticancer drug marimastat, being developed in partnership with Schering-Plough Corp., has failed to reach the primary endpoint of longer survival in Study 193, a pivotal Phase III trial in advanced pancreatic cancer.

And, unlike a previous study in advanced gastric cancer, analyses of secondary endpoints did not reveal any significant benefits, with no overall difference in safety or the quality of life, in the two treatment groups.

The company's stock (LSE:BBG) fell 19.25 pence Tuesday, or 41 percent, to close at 28 pence.

Tony Weir, finance director of British Biotech, based in Oxford, told BioWorld International this result would have no impact on the overall marimastat program, or on the partnership with Schering-Plough. "This is the third set of results of 10 Phase III trials we are running in total. The rest are ongoing and will be completed. Advanced pancreatic cancer is very difficult to treat, and what these results say is that marimastat does not add anything to the standard cytotoxic treatment."

The randomized, placebo-controlled trial involved 239 patients. All received the cytotoxic gemcitabine, and were randomly allocated to receive 10mg of marimastat or placebo orally, twice daily. The combination of gemcitabine and marimastat did not show any significant improvement in survival. However, there was a trend indicating that patients with less extensive disease responded better to marimastat.

Weir pointed out the gastric cancer trial published in August was "close to a hit," although still negative. "What we can now see across the whole database is that patients with less extreme disease do respond." This is consistent with the mode of action of marimastat, a matrix metalloproteinase inhibitor (MMPI), which inhibits the enzymes implicated in breaking down tissues that surround malignant tumors, an important factor in tumor growth and spread.

The problem is that marimastat has tolerability problems, causing tendinitis after three to four months, meaning it is probably unsuitable for long-term use by early-stage cancer patients.

Schering-Plough has rights to all British Biotech's MMPIs in cancer. Since the deal worth US$60 million was signed in September, the focus has shifted to a follow-on compound, BB3644, which in animal studies did not show tendinitis as a side effect.

BB3644 has completed Phase I in healthy volunteers, and in November the partners began a Phase Ib trial in cancer patients to establish the maximum tolerated dose. "This is ongoing, and in effect, no news is good news," said Weir.

Four further marimastat studies are due to report in 2000. British Biotech is expecting negative results in two of these, a monotherapy study in glioblastoma and a combination study of marimastat and carboplatin in ovarian cancer. "These patients have a high tumor burden, and based on results to date we would be surprised to show an effect," said Weir. The company is more hopeful about two monotherapy trials in small cell lung cancer.