By Mary Welch

A new drug application (NDA) for Agenerase, an HIV protease inhibitor developed by Vertex Pharmaceuticals Inc., has been submitted to the FDA by Vertex's partner, Glaxo Wellcome plc. Since Agenerase (amprenavir) is a designated fast-track product, the FDA must rule on the drug by April 16, 1999. Applications to market Agenerase are expected be submitted in Europe and Canada within weeks.

"This is the first NDA filing for Vertex on a compound that was designed by Vertex scientists," said Lynne Brum, vice president of corporate communications for the Cambridge, Mass., company. "We look at it as potentially the first in a series of drug advances that will hit the clinic and marketplace from Vertex."

With the filing, Vertex received a $3 million payment from London-based Glaxo Wellcome. Vertex entered into a $42 million deal in 1993 with Wellcome plc of London (now Glaxo Wellcome), which included an upfront payment of $15 million as well as research support and milestones. So far, Vertex has received about $33 million from its partner. The deal called for $13 million to be awarded as developmental and regulatory milestones, with about $5 million paid to date. "The other $8 million will come for various regulatory and commercial activities in the U.S. and Europe," Brum said.

Clinical results to date show that Agenerase, a second-generation protease inhibitor, has significant antiviral activity and can be used in combination in a variety of two-, three-, and four-drug regimens. It has been clinically tested in combination with numerous approved antiretrovial therapies, including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and other protease inhibitors.

Phase III Combination Therapy Trials Succeed

Preliminary Phase III trials of more than 1,500 participants showed that the drug reduced viral load to below detectable limits in 88 percent of the patients using it in combination with a pair of reverse transcriptase inhibitors, as opposed to 19 percent given the latter therapy alone. Significant virus suppression was shown in patients who took Agenerase with Epivir (lamivudine), also known as 3TC, and Retrovir (zidovudine; or AZT). Epivir and Retrovir are marketed by Glaxo, along with Combivir, a combination of the two drugs in one tablet. (See BioWorld Today, Sept. 29, 1998, p. 1.)

Combination therapy has been the standard HIV treatment since protease inhibitors were introduced in 1995. Protease inhibitors intervene late in the viral life cycle and are the only class of drugs that block virus production in cells already infected with HIV. Reverse transcriptase inhibitors, also called nucleoside analogues, attack HIV early in the replication cycle.

The 48-week results from the Phase III trials should be available next year, Brum said. She added that further follow-up studies would continue even after the drug is marketed.

"Agenerase will be an important step forward for several reasons," she said. "First, the dosing regimen is twice a day as opposed to three times a day for the other approved treatments. Plus, those treatments tend to have some food requirements. Agenerase has no such restrictions. It's a very flexible regimen. The patient has a more convenient dosing schedule with no risk of lessening the potency. Any adverse effects are mild to moderate and transient, which we think is important."

Vertex currently has three other compounds in early Phase II trials. Last month the company started Phase II trials for VX-497 in patients with hepatitis C virus infection. VX-497 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), a human enzyme essential for production of nucleotides — the building blocks for RNA and DNA. Next year, it plans to start a Phase II trial for VX-497 in psoriasis, an autoimmune disease of the skin.

The company is conducting five Phase II trials with Incel (biricodar dicitrate) in patients with solid tumors. Incel, an intravenous compound, is designed to resensitize tumor cells to treatment with chemotherapeutic agents in patients with cancer complicated by multidrug resistance. In July, Intracel entered a Phase II trial for treatment of advanced hormone-refractory prostate cancer. The Phase II trials for liver cancer started in June 1996; breast and soft tissue sarcoma in April 1997; and in ovarian cancer in July 1997. Lung cancer trials are also planned by year-end.

In addition, VX-853 (timcodar dimesylate), an oral compound, is in Phase I/II studies for cancer multidrug resistance that were started in April 1996. Both Incel and VX-853 block two major multidrug resistance mechanisms, P-glycoprotein (MDR-1) and MRP.

Vertex's stock (NASDAQ:VRTX) closed Monday at $23.75, up $0.625. *

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