Ongoing trials with matrix metalloproteinase inhibitors

Excessive or poorly regulated matrix metalloproteinase (MMP) activity has been implicated as a pathogenic factor in a range of diseases where the extracellular matrix is degraded or remodelled. Synthetic, potent, low molecular weight MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with cancer, rheumatoid arthritis, osteoarthritis and acute macular degeneration. The past year has seen a number of disappointments with the halting of clinical trials of Ro 32-3555 in patients with rheumatoid arthritis and of BAY 12-9566 in patients with cancer. There have, however, been some successes with perhaps the clearest indication of efficacy being seen in the results of a Phase III trial of marimastat in patients with advanced gastric cancer. Clinical trials are continuing with marimastat and other MMPIs, including prinomastat, solimastat, BMS 275291, metastat and neovastat. Results from these trials are expected in the next two years and it is likely that clinical trials with MMPIs will begin in patients with other diseases where MMPs are believed to be involved, such as restenosis, cerebral haemorrhage and multiple sclerosis. Future research is likely to focus on the identification of specific MMP targets in different diseases, both in order to improve efficacy and to reduce the musculoskeletal side effect profile that has characterised several of the first generation oral MMPIs.