By Lisa Seachrist

Washington Editor

BETHESDA, Md. — An FDA advisory panel unanimously agreed that Genzyme Corp.'s recombinant thyroid stimulating hormone, Thyrogen, should be approved for use in screening for thyroid cancer metastases.

The panel concluded that while using Thyrogen as a scanning method is not as definitive as the current withdrawal scanning method, its lack of side effects make it a useful tool in the management of thyroid cancer.

"We are very, very pleased; it is actually more than we expected," said Henri Termeer, the Cambridge, Mass.-based company's chairman and CEO. "We consider the panel's vote to give us a very broad indication. The panel has decided to put it in the hands of the physicians."

Thyroid cancer strikes more than 17,000 people in the U.S. each year. The disease is two times more likely to strike women than men. There is an 85 to 90 percent cure rate for the disease; however, the recurrence rate is relatively high, requiring careful patient monitoring.

The standard treatment for thyroid cancer is the removal of the thyroid gland. Patients then take a synthetic thyroid hormone to replace the function of the gland. In order to test for metastatic recurrences, patients have annual or biannual full body radioactive iodine screens. That procedure requires that patients have elevated levels of thyroid stimulating hormone (TSH) in order force metastasis to take up the iodine. TSH also causes thyroid tissue to release a protein called thyroglobulin which is measured by a blood test.

The conventional method for elevating TSH is to take patients who have had their thyroid glands removed off the synthetic hormone supplement three weeks prior to testing. However, patients develop symptoms of hypothyroidism, including fatigue, weight gain, constipation, mental dullness, lethargy and depression.

Hypothyroidism Symptoms Keep Many From Scans

The symptoms of hypothyroidism are so severe many patients refuse to have the scan. Speaking in the public comment section of the FDA meeting, Robert Robbins, chief of endocrinology at Memorial Sloan-Kettering Cancer Center, in New York, noted that "thyroid cancer patients using the Internet thyroid cancer chat lines are saying they are waiting for the approval of Thyrogen before they are having their scans in the hopes of avoiding the symptoms associated with hypothyroidism."

Thyrogen, a recombinant TSH, provides a patient with elevated levels of TSH while they continue to take hormone supplements, thus avoiding the side effects associated with hypothyroidism.

Previously, patients could avoid these symptoms with TSH from human pituitary or bovine pituitary sources. However, the risks of contracting the prion-based Creutzfeldt-Jakob disease and the development of antibodies against the bovine product have prompted the removal of both products from the market.

The company presented data from two Phase III trials testing Thyrogen as a means for elevating TSH levels enough to provide adequate scans. The first trial tested 152 patients by scanning with Thyrogen followed by a withdrawal scan.

In 8 percent of the patients, the withdrawal scanning method was deemed superior and detected disease in 6 percent of the patients that the Thyrogen scan missed. However, the company noted the trial did prove Thyrogen does stimulate the uptake of iodine.

In the second Phase III study, the company tested 220 patients in the U.S. and Europe. The researchers performed a Thyrogen scan followed by a withdrawal scan. The scans were evaluated by a panel of three nuclear medicine specialists. In addition, the company collected blood samples to measure serum thyroglobulin and supplement the assessment of Thyrogen scans.

The study used two dosing regimens: arm I, 0.9 milligrams per day for two days; and arm II, 0.9 milligrams every 72 hours over a seven day period. The first group's scans were equivalent to hormone withdrawal in 92 percent of cases, the second in 93 percent.

Among the 113 patients in arm I, nine withdrawal scans were rated better than Thyrogen while three Thyrogen scans were rated better than withdrawal. In arm II, which contained 107 patients, eight withdrawal scans were rated better than Thyrogen and five Thyrogen scans were rated better than withdrawal. All patients had significantly higher quality of life measures in the Thyrogen phase of the study than in the withdrawal phase.

Patients on Thyrogen experienced nausea, headaches and vomiting; however, the side effects tended to be transient and mild to moderate in severity.

The FDA was concerned that patients with active disease would be missed by thyrogen scanning even in combination with thyroglobulin tests.

When thyroglobulin levels are above 10 nanograms per milliliter many physicians choose to treat patients even though their traditional withdrawal scans are negative. Because thyroglobulin levels were higher using the withdrawal method than the levels obtained with Thyrogen, the agency noted it was easier to miss microscopic disease.

Thyrogen Not Perfect But 'Good Alternative'

"When it comes down to the clinical status of your patients," said Jean Temeck, medical officer in the division of metabolic and endocrine drug products at FDA, "the best method is to withdraw your patients. It is the best measure that we have to date."

The FDA maintained that Thyrogen's place in follow-up exams for thyroid cancer is as a screening test in patients otherwise to be followed solely with measures of thyroglobulin or in patients who cannot undergo a withdrawal test.

The advisory panel, however, felt Thyrogen may also have an important role with patients who refuse to have the withdrawal test. And the panel felt that by making the thyroglobulin level cutoff at 2 nanograms per milliliter as the company suggests, physicians could adequately identify patients who need treatment.

"I see patients every day and when a patient goes through withdrawal, it's a lot of suffering," said Jaime Davidson, an endocrinologist in Dallas. "We clearly need a new source of TSH and now we have it. It's not 100 percent specific and it's not 100 percent accurate, but it is a good alternative." *

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