By Mary Welch

U.S. Bioscience Inc. submitted a supplemental new drug application (sNDA) to the FDA for the use of Ethyol (amifostine) to reduce the incidence and severity of radiation-induced dry mouth.

The drug, a cytoprotective agent, already is approved for use in reducing the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small-cell lung cancer.

"We have an indication to prevent side effects from chemotherapy, and now we're trying for an indication of reducing toxicity from radiation," said Robert Kriebel, chief financial officer.

In the dry-mouth indication, Ethyol has been given orphan drug status and, upon approval, would be marketed to radiation oncologists by Alza Corp., of Menlo Park, Calif., which sells it in the U.S, and co-promoted by U.S. Bioscience. Schering-Plough Corp., of Madison, N.J., markets the drug in Europe. A registration dossier was filed there in September, requesting marketing authorization to expand the indication to dry mouth in Europe.

Dry mouth caused by reduction of salivary function, or xerostomia, is a frequent and often permanent toxicity associated with radiation to the head and neck. Patients with xerostomia are at increased risk of oral infection, dental cavities and loss of teeth. Daily activities, such as chewing, swallowing, speaking and sleeping, are also often difficult. About 40,000 cases of head-and-neck cancer are diagnosed annually in the U.S. Radiation therapy, often in conjunction with surgery and/or chemotherapy, is the standard form of treatment.

To back up its sNDA, U.S. Bioscience conducted an open-label, multi-center randomized Phase III study that involved approximately 300 patients with head and neck cancer. At the end of the treatment, which is given intravenously 15 minutes before radiation, 78 percent of the patients treated with radiation only showed moderate or severe dry mouth, compared with 51 percent of the patients treated with Ethyol prior to radiation.

Ethyol Developed In The 1960s

A year after radiation therapy, 57 percent of the patients treated with radiation alone were still experiencing moderate or severe xerostomia, compared with 34 percent of the patients in the Ethyol arm, possibly because patients who received Ethyol also had a greater preservation of saliva production.

"Ethyol has been around awhile," Kriebel said. "Its origins go back to the 1960s, when the military was looking for something to help protect the soldiers from radiation fallout."

In 1992, an FDA advisory panel refused to recommend Ethyol to prevent or decrease toxicities caused by chemotherapeutic agents without further data. In 1994, an FDA advisory committee voted unanimously not to recommend agency approval of the drug for the protection against certain toxicities of chemotherapy in ovarian cancer patients. The panel said there was not conclusive proof of efficacy. However, several European companies, including the U.K., approved it. (See BioWorld Today, Dec. 13, 1994, p. 1.)

In early 1995, the company filed an amendment to its NDA, seeking a narrower approval focus and maintaining Ethyol protects against renal toxicity associated with cisplatin, as well as cumulative hematologic toxicities associated with cisplatin and cyclophosphamide. Five months latter, an FDA committee concurred, with the full FDA issuing an approvable letter in October. Final approval came in December. (See BioWorld Today, Feb. 3, 1995 p. 1, and Oct. 10, 1995 p. 1.)

Later in 1995, U.S. Bioscience inked a $35 million collaboration with Alza Corp., of Menlo Park, Calif., which subsequently acquired a $21 million stake - or 4.9 percent - of U.S. Bioscience. (See BioWorld Today, Dec. 14, 1995, p.1, and Feb. 5, 1997, p. 1.)

Third-quarter 1998 sales of Ethyol totaled $9.5 million, up 67 percent over the third quarter of 1997. For the first nine months of 1998, Ethyol sales were $23.4 million, up 63 percent over the corresponding period in 1997.

U.S. Bioscience's stock (AMEX:UBS) closed Thursday at $8, up $0.062. *

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