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.