By Mary Welch
British Biotech plc shares gained 32 percent Tuesday on the London Stock Exchange following release of Phase III data on marimastat in gastric cancer, one of 10 randomized, controlled trials of the drug.
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 International. "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 company's stock (LSE:BBG) gained #7.25 after the news was released Tuesday to close at #29.75. The share price has been volatile, ranging over the past 52 weeks from #1.72 to #47.
The Phase III randomized, placebo-controlled study in the UK 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 had no 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 after 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 reaching 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 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 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 (p=.033) in favor of marimastat - 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?" Goldstein said. "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.
Marimastat failed a Phase III trial in pancreatic cancer and trials involving ovarian cancer previously were stopped. (See BioWorld International, Feb. 17, 1999, p. 1; and Dec. 23, 1998, p. 1.)
Trials are still progressing for other indications, including small-cell lung cancer, non-smal-cell lung cancer, breast cancer and brain cancer.