British Biotech plc -- Results of marimastat Study 128 - pancreatic cancer monotherapy trial.

OXFORD, U.K.--(BUSINESS WIRE)--Feb. 15, 1999--British Biotech announces the first result from a program of 10 randomized controlled trials of marimastat in a range of solid tumors. As far as British Biotech is aware, the results of this trial with marimastat represent the first time the this new class of potential oral anti-cancer agents, known as matrix metalloproteinase inhibitors, have completed investigation in a pivotal clinical trial.

Key points:

-- The main analyses of a randomized controlled trial of marimastat in 400 patients with advanced pancreatic cancer have now been completed.

-- The trial was designed to detect a 16 per cent or greater reduction in mortality of patients receiving the 10mg or 25mg twice daily marimastat versus gemcitabine treatment.

-- Study 128 did not meet its primary end point.

-- In a secondary analysis which was able to adjust for baseline variables, the 25mg marimastat group and the gemcitabine group were not significantly different from each other with respect to survival. Both 25mg and gemcitabine appeared to be better than either the 10mg or the 5mg marimastat group.

-- Safety data revealed no marked difference between the treatment groups other than the expected side effect of musculoskeletal events with marimastat and haematological events with gemcitabine.

-- The results of further studies of marimastat will be needed before a complete assessment of the efficacy, tolerability and dose regimen of marimastat can be made.

Commenting on the results of Study 128, Dr. Alexander Rosemurgy, Tampa General Hospital, Florida, and the University of South Florida, and the lead United States Study investigator, said, "While the data have not shown marimastat offers benefit over gemcitabine, it provides evidence that marimastat at 25mg twice a day is as effective as gemcitabine in treating unresectable pancreatic cancer. However, further clinical data will be essential to provide definitive evidence of efficacy."

Dr. Peder Jensen, British Biotech's Development Director and Chief Medical Officer, added, "The results of this study will be discussed externally, including with regulatory authorities, and will contribute to the Company's ongoing assessment of the overall clinical program for marimastat. Although the primary end point was not met in this study, the data suggest that the highest marimastat dose could show benefit compared with the two lower doses in patients with advanced pancreatic cancer."

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February 15, 1999 NASDAQ: BBIOY

British Biotech plc -- Results of marimastat Study 128 - pancreatic cancer monotherapy trial

British Biotech plc announces the outcome of Study 128, a clinical trial of its investigational new drug, marimastat, when administered as a monotherapy in patients with advanced pancreatic cancer. This trial is the first to report of a series of randomized, controlled trials of marimastat being undertaken by British Biotech and co-operative cancer groups, in a range of solid tumors.

Study design and objectives

Study 128 was a randomized, controlled study of 400 patients with advanced pancreatic cancer, conducted in the USA and Europe. Its primary objective was to compare the effect of marimastat against gemcitabine as first line therapy on survival in patients with advanced pancreatic cancer. Gemcitabine is a licensed drug and the current "drug of choice" for the treatment of advanced pancreatic cancer.

Patients were randomly allocated to one of four treatment regimens and received either: 5mg of marimastat twice daily; 10mg of marimastat twice daily; 25mg of marimastat twice daily; or 1000mg/m2 of gemcitabine given by a standard schedule. Marimastat was administered orally and gemcitabine by intravenous injection.

The size of the study, 100 patients per treatment group, was based on the assumption that one of the two higher doses of marimastat (25mg twice a day or 10mg twice a day) would reduce mortality at the end of the study by 16 per cent or more compared to gemcitabine.

A total of 414 patients were recruited across 52 centers in Europe and the USA. Enrolment commenced in June 1996 and the study ended in October 1998, when 90 per cent of the patients receiving gemcitabine had died.

The analyses and results of Study 128 have been reviewed with an external expert statistician and oncologist.

Study results

As far as British Biotech is aware, the results of this trial with marimastat represent the first time that this new class of potential oral anti-cancer agents, known as matrix metalloproteinase inhibitors, have completed investigation in a pivotal clinical trial.

The primary end point of the study was survival i.e. time from entry into the study to death. Survival was analysed using Kaplan-Meier graphs applying the log rank test, with a significance level of 0.025, a conventional way to evaluate such data in clinical trials. The study did not meet its primary end point. Statistical analysis showed no significant difference between the survival curves for gemcitabine and the three doses of marimastat. In particular, individual comparisons between gemcitabine and the 25mg marimastat dose, and gemcitabine and the 10mg dose, showed no statistically significant differences.

In a secondary analysis of the data using the Cox Proportional Hazards model, a technique which is used to analyse clinical trial survival data adjusting for baseline variables, the 25mg marimastat group and the gemcitabine group were not significantly different from each other with respect to survival. Both 25mg and gemcitabine appeared to be better than either the 10mg or the 5mg group.

Overall, 31 patients withdrew from the study (7.5 per cent of all patients) due to adverse events of which 21 were receiving marimastat (6.7 per cent of all marimastat patients) and 10 receiving gemcitabine (9.7 per cent of gemcitabine patients). Of the marimastat patients, six (1.9 per cent) withdrew primarily due to musculoskeletal side effects, a further four (1.3 per cent) partly due to musculoskeletal side effects and the remaining 11 (3.5 per cent) due to other events. Comparison of safety data, between the four treatment regimens, revealed no marked difference between the treatment groups other than the expected side effects of musculoskeletal events with marimastat and haematological events with gemcitabine.

The study results have been submitted for presentation in full at an international medical meeting later this year.

Marimastat pivotal trial program

In addition to Study 128, nine further trials of marimastat are being conducted which are intended to provide information on the efficacy and safety of marimastat in a range of solid tumor types. The current estimate is that these data will be available progressively over the next three years. In the ongoing trials, doses of either 10mg or, in two studies, 20mg of marimastat administered twice a day are being compared either alone or in combination with cytotoxic drugs, to placebo. Of the nine ongoing trials, four studies, all using 10mg, have completed recruitment and are in the follow-up phase, and five are continuing to recruit patients. As none of these nine studies have reached their predefined end point, it is difficult to be precise about when further clinical results will be available. However, the Company believes that results of the pancreatic combination study will be available in the second half of 1999 and that results of one or more other marimastat studies may be available this calendar year.

Implications of Study 128 results for marimastat program British Biotech is currently assessing the full implications of the results of Study 128 for the overall marimastat development program.

The Company believes that the results of further studies of marimastat will be needed before a complete assessment of the efficacy, tolerability and dose regimen can be made.

Discussions will be held with external experts, including regulatory agencies. The Company will then consider whether or not a further clinical trial of marimastat should be undertaken in light of the results of Study 128 and the conclusions of the recent review of the marimastat pivotal trial program. The decision to undertake such a study would be prioritized against the overall ongoing development programs in order to focus resources where chances of success can be maximized.

This news release contains forward-looking statements which reflect the Company's current expectation regarding future events. Forward-looking statements involve risks and uncertainties. Actual events could differ materially from those projected herein and depend on a number of factors including the success of the Company's research strategy, the applicability of the discoveries made therein, the successful and timely completion of clinical studies and the uncertainties related to the regulatory process.