Ongoing trials with matrix metalloproteinase inhibitors

Excessive or poorly regulated matrix metalloproteinase (MMP) activity has b een implicated as a pathogenic factor in a range of diseases where the extr acellular matrix is degraded or remodelled. Synthetic, potent, low molecula r weight MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with cancer, r heumatoid arthritis, osteoarthritis and acute macular degeneration. The pas t year has seen a number of disappointments with the halting of clinical tr ials 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 per haps the dearest indication of efficacy being seen in the results of a Phas e III trial of marimastat in patients with advanced gastric cancer. Clinica l trials are continuing with marimastat and other MMPIs, including prinomas tat, solimastat, EMS 275291, metastat and neovastat. Results from these tri als are expected in the next two years and it is likely that clinical trial s with MMPIs will begin in patients with other diseases where MMPs are beli eved to be involved, such as restenosis, cerebral haemorrhage and multiple sclerosis. Future research is likely to focus on the identification of spec ific MMP targets in different diseases, both in order to improve efficacy a nd to reduce the musculoskeletal side effect profile that has characterised several of the first generation oral MMPIs.