LONDON — Shares in the U.K.'s largest biotechnology company, British Biotech plc, fell from £1.33 to 92 pence last week after the European Medicines Evaluation Agency (EMEA) deferred a decision on whether to approve Zacutex for acute pancreatitis.

The regulator told the company the 290-patient trial submitted as the basis for approval did not provide definitive proof of clinical efficacy. The EMEA said it wants to see the results of a second, 1,500-patient Phase III study, which will not reach its enrollment target until the end of 1998. This placebo-controlled trial was designed to gain U.S. approval for the drug.

British Biotech, of Oxford, said that assuming this second trial confirms the benefits shown by the U.K. Phase III trial, the new data would be submitted during the first quarter of 1999. It made the initial submission in February 1997. The company said the EMEA did not identify any issues in the preclinical sections of the submission that would prevent a recommendation for approval.

Although Zacutex is far from being a potential blockbuster, the delay means the network of European marketing subsidiaries developed to sell the drug will be left treading water.

British Biotech aims to be a fully integrated pharmaceutical company, and was expecting that Zacutex would enable it to shape up the marketing arm before the launch of its oral cancer treatment, marimastat. This is also due to go for approval in 1999.

Commenting on the decision, Keith McCullagh, CEO, said, "Deferral of the decision on the European Zacutex application will obviously be a disappointment to the shareholders. However, as a result of helpful discussions with the EMEA rapporteurs, we agree that it makes good sense to wait for the outcome of the ongoing Phase III trial."

Efficacy In US Trial Encouraging

In July 1997, British Biotech was forced to extend the U.S. Phase III trial of Zacutex from 450 to 1,500 patients. The trial recruited its initial target of 450 patients by June 1997. However, the company was alerted to anecdotal evidence that there was a lower incidence of death in the U.S. trial than would have been expected on the basis of the U.K. Phase III trial.

"With the approval of the FDA, an independent data monitoring committee was set up to review the trial data in the blinded state. This showed the overall incidence of death and serious organ failure to be half that of the U.K. trial," said Katie Arber, head of corporate communications for British Biotech.

The committee said there were no safety concerns, and recommended that to achieve statistically significant results more patients should be recruited. When the U.S. trial was designed the U.K. trial was still in progress.

Arber said that in light of the U.K. trial results, British Biotech also decided to make mortality the endpoint, whereas the previous endpoint was a composite of mortality, medical intervention and organ failure.

In the U.K. Phase III study there were fewer deaths in the Zacutex group. This was statistically significant in those patients treated within 48 hours of the onset of disease. There was also a statistically significant reduction in organ failure scores three days after beginning treatment in the drug-treated group.

British Biotech expects to file a new drug application for Zacutex with the FDA in the first half of 1999. It believes the drug will qualify for priority review on the basis of unmet medical need.

The company will not run out of money as a result of the European delay. Although expenditures in the last full year to April 1997 were £32 million, British Biotech has more than £180 million in cash.

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