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FDA Panel Advises against Cold Drug, Citing Concerns over Drug Interactions

Members of the Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee recommended in March against approving what could have been the first antiviral drug to combat the common cold. In voting to reject pleconaril, whose trade name is Picovir, panel members concluded that its modest benefits are overshadowed by potentially harmful side effects. The drug is being developed by ViroPharma, Inc. of Exton, Pa., and Aventis Pharmaceuticals, a U.S. unit of the French company Aventis.

Advisory panel members expressed concerns for several problems associated with use of the drug during clinical trials, particularly its interactions with other drugs. For example, some women taking oral contraceptives who received the drug experienced breakthrough bleeding, and other volunteers who were receiving asthma medications experienced heart rhythm disturbances.

"The vote was the expected result under the circumstances," says Frederick G. Hayden of the University of Virginia School of Medicine in Charlottesville, one of several clinical investigators who is testing the drug. "The [FDA advisory panel members] were considering a novel antiviral drug—first in its class for common cold treatment—and they were asked to judge whether it was safe and effective. The questions were not fully answered with regard to drug interactions."

However, the panel's advice regarding pleconaril does not necessarily end its development. Company officials say they will address the concerns of the FDA panel members in the coming months with additional research, and hope to get the drug back on the track toward approval. "We continue to be optimistic about the ultimate approvability," says Bryan K. deCastro, a spokesman for ViroPharma.

Pleconaril is a first-of-a-kind, orally active small molecule, with broad activity against both enteroviruses and rhinoviruses, which are closely related members of a large, prevalent group of RNA viruses called picornaviruses. Such viruses are responsible for the vast majority of colds, as well as viral meningitis, myocarditis, pericarditis, encephalitis, chronic meningoencephalitis, otitis media, neonatal enteroviral disease, and acute viral exacerbations in asthma.

The drug acts by inhibiting capsid functions—in this case, integrating into a hydrophobic pocket within the virus and interrupting its replication cycle. "It has dual mechanisms of action," Hayden says. "When it binds into a pocket of the protein shell of the virus, it changes the receptor binding site of the virus and also inhibits the opening up of the protein shell during intracellular replication. It's an uncoating inhibitor. It makes the shell less flexible, so it doesn't open up to release the RNA and start the infection."

Pleconaril inhibited replication in vitro of 96% of the rhinoviruses and enteroviruses isolated from 332 human patients, according to the company. Moreover, orally administered pleconaril protected mice against lethal enteroviruses, even when the drug was administered after animals were infected. In clinical studies, the drug reduces the duration of illness by one day and significantly reduces the severity of symptoms within 24 hours of starting treatment, according to Hayden. "In contrast to over-the-counter medicines, which are so widely used and don't treat all the symptoms, six symptoms were significantly benefited," he says. These include stuffed nose, runny nose, cough, sore throat, malaise, and muscle aches. "There's real evidence of an early treatment benefit," he continues. "I would like to have this agent for myself."

The drug is also being studied as a cold preventive, and it was during this prophylaxis study that some women on oral contraceptives developed breakthrough bleeding, raising questions about interactions with other drugs. "It does modestly induce levels of CYP3A4," one of the isoenzymes in the liver important to drug metabolism, Hayden says. "It causes more activity, which means it may metabolize certain drugs faster, causing them to be less effective. The estrogen levels in oral contraceptives were reduced as a result of these dynamics, which is probably the explanation for the breakthrough bleeding," he adds. "The progestin component is not influenced, andthe belief is that it does not diminish the protective contraceptive effect." In studies involving nearly 2,100 people, the incidence of breakthrough bleeding was about 3.5% over levels in the placebo group.

In another instance of possible drug interaction, seven patients receiving pleconaril and also taking theophylline to treat bronchospasm experienced heart palpitations or tachycardia. "Overall, the [advisory] committee was concerned about the ability to generalize from the data to the population for whom it would be prescribed once marketed," says Jason Brodsky, an FDA official. "They also had safety concerns relative to the proven benefit and severity of the condition it treats."

"These are appropriate concerns," Hayden says. "We need to be certain there are no surprises." Nevertheless, he adds, "from a public health perspective, we spend from $2 to 5 billion on over-the-counter medications for cough and cold treatment—a lot of money for a modest benefit. And some of these have substantial side effects. There is also considerable inappropriate antibiotic use—about 15% of cold sufferers will seek out a physician, and up to 60% of them will walk out with an antibiotic prescription. In my view, it would be better to have a prescription for pleconaril."

Marlene Cimons
Marlene Cimons is a freelance writer in Bethesda, Md.