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Ongoing trials with matrix metalloproteinase inhibitors
1British Biotech Pharmaceuticals Ltd., Watlington Road, Oxford, OX4 6LY, UK. brownp@britbio.co.uk
Abstract:
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.
Insights
Matrix metalloproteinase inhibitors (MMPIs) show promise for treating diseases involving extracellular matrix degradation. While some trials faced setbacks, recent successes in gastric cancer trials indicate potential therapeutic benefits.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Matrix metalloproteinase (MMP) dysregulation contributes to diseases marked by extracellular matrix degradation.
- Matrix metalloproteinase inhibitors (MMPIs) are synthetic low molecular weight compounds designed to target MMP activity.
Purpose of the Study:
- To review the clinical development and therapeutic potential of matrix metalloproteinase inhibitors (MMPIs).
- To highlight recent successes and ongoing challenges in MMPI clinical trials across various diseases.
Main Methods:
- Review of clinical trial data for MMPIs in cancer, rheumatoid arthritis, osteoarthritis, and macular degeneration.
- Analysis of trial outcomes, including successes and halts, for specific MMPIs like marimastat, Ro 32-3555, and BAY 12-9566.
Main Results:
- Clinical trials of MMPIs have yielded mixed results, with some trials halted (e.g., Ro 32-3555, BAY 12-9566).
- Phase III trials of marimastat demonstrated efficacy in advanced gastric cancer, indicating therapeutic promise.
- Ongoing trials with marimastat and other MMPIs (prinomastat, solimastat, BMS 275291, metastat, neovastat) are expected to yield further results.
Conclusions:
- MMPIs represent a developing therapeutic class for diseases involving MMPs.
- Future research will focus on specific MMP targeting to enhance efficacy and mitigate side effects like musculoskeletal issues.