By Mary Welch
Agouron Pharmaceuticals Inc. started Phase II/III trials with AG3340, a matrix metalloprotease (MMP) inhibitor, in patients with advanced lung or prostate cancer.
The La Jolla, Calif.-based company expects to file a new drug application with the FDA before the end of 2000, said Donna Nichols, Agouron's vice president.
"The MMPs are responsible for certain functions, both good and bad," Nichols said. "We're looking at AG3340 to determine whether this distinctive selectivity [of a specific inhibitor] results in safety and efficacy."
One trial will evaluate AG3340 tablets in combination with the anticancer drugs Taxol (paclitaxel) and Paraplatin (carboplatin) to ascertain if AG3340 inhibits the growth, invasion and metastasis of advanced, non-small-cell lung cancer. A second trial is testing AG3340 tablets in conjunction with Novantrone (mitoxantrone) and prednisone, with an intent to evaluate time to symptomatic progression in patients with advanced, hormone-refractory prostate cancer.
Secondary endpoints in both trials include response rates, survival and quality of life measurements.
MMPs are believed to play a key role in tumor growth and the spread of tumor cells to secondary sites within the body as well as the growth of new blood vessels through which tumor cells obtain nutrients to survive.
Agouron also is conducting preclinical evaluations of second-generation MMP inhibitors with selectivity profiles distinct from that of AG3340. Phase I trials showed AG3340 potently arrested angiogenesis and tumor growth while strengthening the anti-tumor activity of other chemotherapy agents. The same trials indicated that AG3340 was well tolerated at the administered doses.
The company is entering a Phase II/III trial at the urging of the FDA, Nichols said.
"It's impossible to do a Phase II trial without looking at a large number of patients over a long period of time because we're looking at time and the progression of the disease," she said. "We'll be looking at different doses for each trial and, one year down the road, we'll take a safety look and see if one dose is too high and carries toxicity problems, and then we'll change the dosage. But you can't look at the efficacy until way out in the progression of the trial."
Agouron has a preclinical program exploring the value of MMP inhibitors in the field of ophthalmology. In addition, the company plans to file an investigational new drug application with the FDA late this summer to initiate Phase I trials of AG3340 in patients with acute macular degeneration.
Last year, Agouron discontinued development of another enzyme inhibitor, Thymitaq, which works on the enzyme thymidylate synthase. Although the drug seemed to work as a single agent in head, neck and liver cancers, it was not sufficiently better than existing therapies, according to the company. Agouron agreed to end its collaboration with Basel, Switzerland-based F. Hoffman-La Roche Ltd., after an informal analysis of Phase II/III trials. (See BioWorld Today, Dec. 3, 1997, p. 1.)
Agouron's stock (NASDAQ:AGPH) closed Tuesday at $36.875, up $2.50 *