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Medarex Inc. and the FDA have agreed on a special protocol assessment for the pivotal Phase III trial with the fully human antibody MDX-010 plus MDX-1379, a gp100 melanoma peptide vaccine, against patients with unresectable metastatic disease who can't tolerate first-line therapy.

Investors were informed earlier about the SPA filing with the agency and about the plan to start the trial, which will begin enrolling in September.

Medarex's stock (NASDAQ:MEDX) closed Monday at $5.19, up 3 cents, an increase that proved less than investors may have hoped.

"Me, too," said Donald Drakeman, president and CEO of Princeton, N.J.-based Medarex. "We had told people that during the second quarter we had filed the SPA, and we talked generally about what the trial was likely to look like," but confirming the pact with the agency was expected to have more impact, he said.

"The whole sector's been in the doldrums for a while," he added.

Medarex's MDX-1379 vaccine consists of two gp100 melanoma peptides, in-licensed by the company from the National Cancer Institute. The peptides are part of a protein normally found on melanocytes, or pigmented skin cells. They also are present on melanoma cells and are recognized by cytotoxic T cells in melanoma patients who are positive for HLA-A2, an immune system compatibility antigen expressed in about half of the melanoma population.

MDX-01, the other part of the equation, is a fully human antibody against human CTLA-4, a molecule on T cells believed responsible for suppressing the immune response. The drug gained orphan drug designation in June from the FDA for high-risk Stage II, III and IV melanoma. It's also in multiple Phase II trials in other oncology indications, including prostate, breast and renal cancer.

In the Phase III trial, about 750 patients with previously treated Stage III or Stage IV metastatic melanoma are expected to be enrolled, randomized for one of three regimens: MDX-010 in combination with MDX-1379, MDX-010 alone or MDX-1379 alone. The randomization will be done on a 3:1:1 basis, with 60 percent, or about 450 patients, getting the combination. All patients given MDX-010 will receive a dose of 3 mg/kg every three weeks for up to four doses.

Medarex aims to use best objective response rate (including complete and partial responses) as the basis for an initial biologics license application, under an FDA rule that provides for early approval based on a surrogate endpoint in life-threatening or severely debilitating illnesses, although the company will continue to gather disease progression and survival results, with treatment assignment blinded and oversight provided by an independent data monitoring committee.

The trial is expected to finish in the first half of 2006, Drakeman told BioWorld Today. For melanoma, the need is large and forecast to grow, he said. Dermatologists long have cited sun exposure as a main contributor, but "as with all cancers, there's still some work that needs to be done to sort out the causes," Drakeman said.

In any case, once the disease has spread, the options are not many.

"Most recent data show that very few patients with front-line metastatic melanoma respond to anything, and those patients relapse," he said. "We've been extremely impressed with the durability of response we've seen [in research so far]. Patients with dozens of tumor sites have gone into complete remission and stayed in remission for two years or more."

Although various companies are targeting malignant melanoma, "we're one of the very few in pivotal trials," Drakeman said. "We're also, if not unique, one of an even smaller number [of firms] addressing patients who have measurable disease. A number of the trials in the cancer vaccine area are treating patients whose disease has been surgically eradicated, and [scientists] are trying to keep people from relapsing."

Among those with drugs in the pipeline, "CancerVax is always out there," Drakeman said. The Carlsbad, Calif.-based firm has Canvaxin in Phase III studies for advanced-stage melanoma, expecting to complete enrollment of Stage III melanoma patients by the end of this year, followed about a year later by Stage IV patients.

San Diego-based Maxim Pharmaceuticals Inc. has Ceplene (histamine dihydrochloride) for advanced malignant melanoma. A new drug application is pending with the FDA. First filed in 2000, the NDA was held up because the agency asked for a second Phase III trial in patients with liver metastasis. The company completed enrollment in September, having filed for approval in Europe last fall. (See BioWorld Today, May 13, 2004.)

The company said it expects to complete the liver metastasis trial this summer and amend the NDA with the results late this year. Recently, the FDA allowed Maxim to provide the drug, pending approval, as a combination therapy for the most critically ill malignant melanoma patients. Ceplene has orphan drug status in the U.S. in that indication.

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