By Lisa Seachrist

Washington Editor

GAITHERSBURG, Md. - An FDA panel declined to endorse Glaxo Wellcome plc's inhaled antiviral drug Relenza (zanamivir) as a treatment for all types of influenza.

The Antiviral Drugs Advisory Committee voted 13-4 against recommending approval, citing the North American pivotal trial that failed to show statistically significant benefit to patients suffering from the flu.

"We were a little surprised by the vote," said Michael Elliot, international project leader for influenza at Glaxo. "We are obviously confident that zanamivir is an effective therapy, and those who voted no said they did so with some hesitation. We just have to work with the agency to keep the drug moving."

Zanamivir was developed with Biota Holdings Ltd., of Melbourne, Australia. It is a rationally designed drug that inhibits the neuraminidase enzyme on the surface of the virus. Neuraminidase facilitates the influenza virus' ability to spread from cell to cell in the respiratory tract.

The FDA brought the drug to the panel because it represents a departure from many of the drugs it has reviewed. Because influenza is largely a self-limited disease, a drug to treat the flu is quite different than a drug to treat a progressive, fatal illness such as AIDS.

"It's not common for us to see treatment for an acute, self-limiting disease," said Barbara Styrt, an FDA medical officer. "Nor is it common for us to see a treatment for which the purpose is the reduction of self-reported symptoms."

The company acknowledged that the drug was different. Marc Rubin, vice president and worldwide director of therapeutic development for infectious diseases and hepatitis for Glaxo's Research Triangle Park, N.C.-based U.S. subsidiary, told the panel, "This is different from many of the drugs that we bring to the committee. This is a disease that routinely affects over 30 million people annually and has a tremendous economic impact on society."

Influenza typically lasts seven to 10 days. It is caused by two versions of influenza virus, A and B. Currently approved drug treatments for flu (rimantadine and amantadine) are effective only for influenza A. Zanamivir offers a potential improvement over those two therapies because it works on both influenza A and B.

Because those viruses mutate their exteriors every year, they have a continually changing antigenicity, which leaves people susceptible to influenza year after year. Frederick Hayden, professor of medicine at the University of Virginia in Charlottesville, said, "Influenza really is the paradigm of the re-emerging infectious threat."

Glaxo Presented Data From Three Phase IIIs

Glaxo presented data from three Phase III clinical trials - North American, European and Southern Hemisphere studies. Patients received two daily inhalations of 10 milligrams of zanamivir or placebo within the first two days of symptoms. Patients kept a daily diary of their flu symptoms for 14 days. The endpoint for the study was resolution of the following symptoms: feverishness, headache, sore throat, cough, muscle aches and temperature.

Patients in the zanamivir arm saw their symptoms end 1.5 to 2.0 days sooner than patients taking placebo. The European and Southern Hemisphere studies had statistically significant results, while the North American study failed to reach statistical significance.

The drug isn't metabolized and is excreted rapidly so there were few side effects reported, and the company expects that drug interactions are unlikely. In addition, Glaxo reported only one case of drug resistance, in a severely immunocompromised infant.

The agency, however, had a different take on the data Glaxo presented. The agency's analysis looked at the "mean symptom scores." Patients who were considered "alleviated" could have a panoply of mild symptoms that FDA statistical reviewer Michael Elashoff pointed out could result in a patient feeling unwell.

"Taken together, these patients may not describe how they are feeling as mild even though their symptoms are mild," Elashoff said.

Elashoff looked at the combined symptoms and found that in both the placebo and treatment arms of the studies, patients experienced a gradual improvement in symptoms, with a small difference in the symptoms they were experiencing. In addition, Elashoff described a number of cases when people would get better, then rebound with headaches. He called into question the drug's efficacy.

In addition, patients in the North American study took more relief medications such as acetaminophen, cough syrup and decongestants, which makes that study harder to evaluate.

Safety Clear, But Efficacy Questioned

Glaxo responded that the analyses didn't provide a clear picture of the benefit of the drug and noted that while the North American trial failed to reach statistical significance, it did show a trend, and additional analysis that removed patients who didn't complete their diaries showed the drug had benefit. The company also objected to referring to headaches five to seven days after the onset of flu symptoms as "a rebound."

All the members of the panel agreed the drug was clearly safe. However, the majority of the panel felt the North American study called into question the drug's efficacy.

"The safety is pretty clear," said Sharilyn Stanley, a physician with the Texas Department of Health in Austin. "I just don't think we are seeing much of an effect."

However, panel chairman Scott Hammer, associate professor of medicine at Beth Israel Deaconess Medical Center in Boston, considered the company's data package complete and said that it answered all questions.

"Are we going to toss out two studies on the basis of geography?" Hammer asked his colleagues. "I have trouble with that. We need to recognize that the first drug in a class isn't likely to be the best but it still has a place."