Marimastat [BB 2516, TA 2516] is a second-generation anticancer drug originally 
developed with British Biotech in Europe and North America. It is an orally 
active metalloprotease inhibitor of the same class as batimastat, and is the 
first compound in this class to have completed a pivotal clinical trial. 
Marimastat also has collagenase- and angiogenesis-inhibiting properties. British 
Biotech and Schering-Plough have signed an agreement enabling the latter to 
develop and market marimastat in North America and Europe. Under the terms of 
the agreement, British Biotech will receive an up-front license fee of 4 million 
US dollars and a 4 million US dollars equity investment in British Biotech by 
Schering-Plough. Schering-Plough holds rights to marimastat in all countries 
other than the Far East and Japan. The two companies are considering asking the 
FDA for accelerated approval in gastric cancer based on the secondary endpoint 
of progression-free survival. Marimastat is licensed to Tanabe Seiyaku in Japan, 
where phase II clinical trials are underway for the treatment of advanced 
gastric cancer and lung cancer. Further phase II trials in other tumour types 
are planned. The commencement of phase II trials in Japan resulted in a 
milestone payment of 5 million US dollars to British Biotech from Tanabe 
Seiyaku. Tanabe Seiyaku also holds rights to marimastat in the Far East. 
Marimastat has been in pivotal phase III trials in glioblastoma, breast, ovarian 
and small and non-small cell lung cancer, but these trials have all been 
discontinued because marimastat failed to show superior efficacy over either 
standard chemotherapy or placebo. Results from the marimastat 131 trial in 
patients with glioblastoma, for example, indicated that marimastat was no better 
than placebo at prolonging survival in these cancer patients. In June 2000, when 
the results of this study were released, shares in British Biotech fell 21.6% to 
just 19 pence per share. The phase III trial in small cell lung cancer was 
discontinued when the results of study 140 were released in February 2001 
showing that marimastat was not significantly more effective than placebo in 
prolonging the survival of small cell lung cancer patients. The results of this 
study were consistent with those reported in study 117. British Biotech has also 
conducted a phase III placebo-controlled study of marimastat as monotherapy in 
patients with inoperable gastric cancer at 37 centres throughout Europe. Results 
from this trial indicated that it did not achieve its primary endpoint of a 
statistically significant survival benefit over placebo. However, data collected 
during the follow-up period have shown increases in survival benefit in the 
treatment group in addition to a significant improvement in disease-free 
progression, the secondary endpoint of the trial. Development of marimastat for 
this indication is ongoing. In May 2001, British Biotech reported data from an 
interim analysis of results from the remaining phase III study in pancreatic 
cancer (study 183) that showed no patient benefit for marimastat recipients 
compared with gemcitabine. However, these results did not meet stopping criteria 
and the study continues under the guidance of Schering-Plough. The multicentre 
trials are being conducted in the US, Canada and the European Union. The phase 
III trial of marimastat in combination with carboplatin that was being conducted 
in patients with ovarian cancer was discontinued because British Biotech 
realised that the design of the trial was insufficient for registration in the 
US or Europe. Altogether, seven phase III studies have failed to meet their 
primary end-points, but the company has stated that the effectiveness of 
marimastat is more likely to be seen in patients with less advanced disease. 
Phase II trials in prostate and head and neck cancer are still underway in the 
US.