By Mary Welch

Staff Writer

Despite not reaching statistical significance in its primary endpoint, officials at British Biotech said they are "encouraged" by the Phase III data on marimastat, its oral matrix metalloproteinase (MMP) inhibitor.

"We are encouraged for several reasons and, after speaking with several cancer specialists in both the UK and the U.S., we believe that the quality of the data warrants us going to the regulatory officials posthaste," Elliot Goldstein, the company's chief executive officer, told BioWorld Today. "We want to show them the data. We know the drug is safe. It's been tested in more than 2,000 people. It's an unmet medical need. We will go to the regulatory agencies with our package of data and full analysis and meet to discuss the next steps."

The stock market echoed the company's support of the drug. Its stock (NASDAQ:BBIOY) gained 81.25 cents Tuesday, or 21 percent, to close at $4.687.

The Phase III randomized placebo-controlled study involved 369 patients, all of whom failed surgery. To be included in the study, patients had to have an anticipated life expectancy of more than three months and have had not more than one regimen of prior chemotherapy.

Patients received either 10 mg of marimastat twice daily or a placebo. The primary endpoint was improved cancer survival. The protocol called for an arbitrary trial cutoff when 85 percent of one group died (72 people). The trial, which started in October 1996, stopped in February when 85 percent of the placebo-controlled group had died. At that point, the placebo group had a survival rate of 14.1 percent, with the survival rate of the marimastat-treated patients at 22.7 percent.

"Obviously there was a visible and important benefit in taking marimastat," Goldstein said. "It was not statistically significant but close. Instead of p=.05, we reached p=.085. It was frustrating."

However, patients continued to receive marimastat. At the end on June, 35 patients from the original trial were still alive. Twenty-five had received marimastat; 10 were on the placebo.

"And that is statistically significant," Goldstein said. "We had arbitrarily set a cutoff date for the trial, but if you look at a longer period of time, the difference between the placebo and marimastat strengthens. At the end of June, our survivability rate was p.=.048."

In a statistical side note, Goldstein said nine patients counted in the study never received treatment because they were too ill. Six were slated to take marimastat, three the placebo. "One even died the day they entered the study but because they were part of the intent-to-treat, we had to count them in the overall results," he said. "If you remove those nine, we would have reached statistical significance in our primary endpoint."

Marimastat is a broad-spectrum agent with potent inhibitory action against MMP enzymes implicated in breaking down tissues that surround malignant tumors, an important factor in cancer growth and spread.

In a subgroup of the trial - those whose cancer had not metastasized - marimastat showed statistically significant results. At the predefined clinical cutoff, patients treated with marimastat showed a statistically significant benefit (p=.027) in progression-free survival vs. the placebo group. In those whose cancer had spread, there was little difference. Those patients without metastases also showed a survival benefit in favor of marimastat of p= .033 - again statistically significant.

"There is a strong trend in favor of survival on marimastat," Goldstein said. "If you keep looking for something positive you can find something. Our results aren't statistical quirks. We believe our results are consistent and meaningful and show that marimastat slowed cancer growth."

Bolstering the Oxford, UK, company's discussions with regulatory agencies is the nature of the disease. It is the leading cancer killer in Japan, fifth in the Western world and eighth overall. Less than 20 percent of patients live past five years.

"If this were a drug for hypertension and we got these results - who would care?" he asked. "You'd have to have a treatment that would beat the pants off all the others. But here you are dealing with people who had surgery and it didn't work, and maybe had chemotherapy and it didn't work. There is no approved therapy."

The company hopes to have meetings with regulatory agencies within the next six to eight weeks, Goldstein said. Negotiations in Japan will be handled by British Biotech's Japanese partner, Tanabe Seiyaku Co. Ltd., of Osaka. In 1996, Tanabe signed a deal potentially worth $74 million to market marimastat in Japan. (See BioWorld Today, Nov. 15, 1996, p. 1.)

The gastric cancer trial is one of 10 involving marimastat. It failed a Phase III trial in pancreatic cancer and trials in ovarian cancer previously were stopped. Trials are still progressing for other indications, including small-cell lung cancer, non-small-cell lung cancer, breast cancer and brain cancer.