Mixed Review on Bristol Drug

A FDA staff report says entecavir is effective in treating hepatitis B but may also pose risks.
By Robert Steyer ,

Updated from 10:12 a.m.

A Food and Drug Administration staff report on Thursday gave a mixed review to an experimental drug for treating the dangerous chronic hepatitis B virus, setting the stage for regulators to weigh the risks vs. the benefits of this compound from

Bristol-Myers Squibb

(BMY) - Get Report

The staff report, issued a day before an FDA advisory committee reviews the drug entecavir, said the drug "achieves reliable drug exposure in patients

and has few significant drug-drug interactions." The report concluded that, on the basis of test results and supporting documents submitted by the company, entecavir "effectively reduces" the impact of the hepatitis B virus and improves liver function.

The staff report, however, told advisory committee members that they must assess these benefits in light of tests that show certain doses of the drug can cause cancer in rodents. The staff noted that similar tests for one competing drug already on the market showed no cancer risk for rats even at high doses. Cancer tests for another drug on the market were hampered because high doses of this drug were highly toxic to rats' kidneys.

"It is always difficult to extrapolate animal carcinogencity data to human risk, and so we are unable to determine the magnitude of the risks to humans from currently available data," the staff report said. "To our knowledge, there has not been a public discussion of an acceptable level of carcinogencity risk in relationship to chronic hepatitis B virus treatment."

In its application, the company conceded that the drug causes cancer in rodents, adding that "investigative data do not definitively eliminate a risk to humans." The company has proposed conducting a post-marketing survey of the drug involving 12,500 patients to determine if long-term use causes cancer, serious liver disease and leads to liver transplants.

The FDA staff said the proposal represents "a good faith effort" to assess a five-to-eight-year cancer risk, but it said "there are inherent limitations in a study of this type," including the uncertainty of identifying a slow developing cancer and the inability for targeting a specific tumor other than liver cancer.

Although financial analysts haven't counted on entecavir to be a gigantic revenue producer, Bristol-Myers Squibb has cited the drug as one of the

keys to its making a comeback. At a research-and-development conference in November, Peter R. Dolan, the chairman and CEO, cited entecavir and experimental drugs for treating diabetes and rheumatoid arthritis as examples of the company's efforts to focus "on areas of serious unmet medical need."

Hepatitis B is caused by a virus that attacks the liver and can cause cirrhosis, liver cancer and organ failure. It is often spread through unprotected sex, the sharing of needles among drug abusers and from an infected mother to her baby at birth.

Over the years, the number of annual cases of hepatitis B virus, or HBV, has been reduced in the U.S. The Centers for Disease Control and Prevention says the number of new, annual cases dropped from an estimated 260,000 in the 1980s to 73,000 in 2003. There are an estimated 1.25 million chronically infected Americans. The number of annual cases has dropped due to the development of new drugs and the efforts to vaccinate infants and young children against HBV.

The prevalence of HBV is low in most of the developed countries and is most severe in large portions of Africa, Asia and sections of South America.

According to the World Health Organization, an estimated 2 billion people worldwide have some form of HBV. About 350 million have the chronic version; about 1 million people die annually. But because chronic HBV drugs are so expensive, they will "never be available to most patients in developing countries," the health group says.

Existing Drug Choices

For those who get chronic HBV and can afford treatment, three companies provide drugs that won't cure HBV but can ameliorate its effects. The drugs are Intron-A from

Schering-Plough

(SGP)

, Epivir from

GlaxoSmithKline

(GSK) - Get Report

and Hepsera from

Gilead Sciences

(GILD) - Get Report

. Intron-A and Epivir also are approved for treating other diseases. Intron-A is injected; the other drugs are pills.

Each has plusses and minuses. For example, people who take Epivir can develop a resistance to the drug. The American Association for the Study of Liver Diseases cites one Asian study in which 14% of patients developed resistance within one year of treatment; after five years, the rate was 69%.

The association says a "major advantage" for Hepsera, which is prescribed only for adults, "is the lack of resistance after the first year of therapy." Intron-A doesn't provoke resistance; its drawbacks are "the costs and side effects." Hepsera costs more than Epivir. For Hepsera," the durability of response and its long-term safety and risk of drug resistance remain to be determined," the association says.

Questions of potential drug resistance were raised by the FDA staff about entecavir, even though Bristol-Myers Squibb's application included tests in which its drug performed better than Epivir. The FDA staff cautioned that just because the experimental drug hadn't provoked resistance among patients during a 48-week trial, patients with prior resistance to Epivir "appear to be at risk for reduced susceptibility" to the Bristol-Myers Squibb drug. "This may have a significant impact on long-term dosing as the clinical trials continue," the FDA said.

Bristol-Myers Squibb's stock rose 18 cents to $24.90.

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