Phase III Clinical Trial of Prinomastat Halted

August 7, 2000 -- The pharmaceutical company Pfizer announced today (Aug 7, 2000) that it halted its Phase III clinical trials of the antiangiogenic drug Prinomastat (AG3340) for both advanced non-small cell lung cancer and prostate cancer, due to the drug's lack of effectiveness in patients with late-stage disease. According to Pfizer, patient safety was not a factor in this decision.

Several earlier stage clinical trials of Prinomastat are to continue, for glioblastoma, cancer of the esophagus, melanoma, and breast cancer. Prinomastat is an oral antiangiogenic drug that belongs to a new class of therapeutics known as matrix metalloproteinase inhibitors (MMPI). MMPIs interfere with enzymes that are involved in both angiogenesis and tumor invasion.

The decision to halt Prinomastat comes as the worldwide effort to develop safe and effective antiangiogenic drugs for cancer accelerates rapidly. There are presently 51 drug, including Prinomastat, in oncology clinical trials in human cancer patients. Prinomastat was one of 15 antiangiogenic agents in Phase III clinical trials. Presently, 12 antiangiogenic agents remain as strong contenders in the race.

The division of Pfizer responsible for antiangiogenic drug development, Agouron Pharmaceuticals, will continue to develop other experimental antiangiogenic agents for cancer.

Comment from Angiogenesis Foundation

Prinomastat is the third matrix metalloproteinase inhibitor (MMPI) to be halted in the final stages of development. Last year, two other drugs, Bay 12,9566, sponsored by Bayer Corporation, and MMI-270, sponsored by Novartis, were also stopped. All three drugs were being developed for non-small cell lung cancer, as well as several other tumor types. Only Prinomastat was halted solely for lack of effectiveness. Bay 12,9566 was stopped due to more rapid tumor growth in patients treated with the drug. MMI-270 was halted because of poorly tolerated joint and muscular pains.

According to Angiogenesis Foundation's experts, there are at least two possible explanations for Prinomastat's poor performance in its Phase III trials:

• Suboptimal clinical trial design - the Prinomastat Phase III trials enrolled patients with very advanced, late-stage disease. Inhibiting matrix metalloproteinases as a strategy to starve tumors may be more effective in earlier stages of disease, when tumors are smaller and may be more sensitive to these agents. Recent research from Dr. Roberto Nicosia's laboratory in Seattle, Washington has also shown that MMP inhibition may lead to slowing of angiogenesis early in the process of blood vessel growth, while in later stages of angiogenesis, MMP inhibition may lead to stabilization of the blood vessels, making them more permanent. The Angiogenesis Foundation is currently meeting with numerous biopharmaceutical companies to discuss techniques that may help fine tune clinical trial design in the angiogenesis field.
• Biological reasons - Prinomastat was designed to be highly selective for several specific matrix metalloproteinase enzymes (2,9, 21). There are at least 20 such enzymes in total, and Prinomastat's selectivity may not be sufficient enough to cause significant inhibition of cancer growth. Furthermore, suppressing several enzymes may also lead to increased production by cancer cells of the remaining enzymes, leading to continued tumor growth.

The precise reasons for Prinomastat's failure will remain unknown until further research on the drug is conducted.

Although 4 of the 51 antiangiogenic drugs in clinical trials for cancer have been stopped, there is strong optimism among experts in the angiogenesis field. Twelve agents are still in Phase III testing, and the Angiogenesis Foundation believes that the first of these will likely be submitted to the FDA for consideration of approval sometime in the next 36 months.

For more information about antiangiogenesis drugs in development for cancer, please contact the Angiogenesis Foundation at: [email protected], or telephone us at (617-576-5708).