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New Drugs, New Drug Targets Make Prospects Brighter for Flu Drug Pipeline

Posted on: Tuesday, 19 June 2007, 18:00 CDT

By HELEN BRANSWELL

TORONTO (CP) - Potential flu drugs in development and newly identified targets for flu drugs suggest the era of dependence on merely two classes of influenza drugs could end in the next few years, experts at a major influenza conference here suggested Tuesday.

"The potential for development of other drugs is quite significant at the present time," Dr. Alan Hay of the National Institute for Medical Research in London said in a presentation to the Options for the Control of Influenza Conference.

With concerns about a possible flu pandemic, public health officials have worried that the reliance on only four flu drugs from two drug classes leaves the world in a vulnerable position.

But work presented at the conference points to progress in lessening that vulnerability, said Dr. Frederick Hayden, an antiviral expert with the World Health Organization.

"The pipeline is not full, but it's certainly more robust than it was some years ago," Hayden said.

One of the promising things about the work is that the drugs and drug targets that are in the pipeline would diversify the number of classes of flu drugs if they are successfully brought to market. That, in turn, would lower the risk posed by drug resistance.

Flu viruses mutate constantly and some of those mutations can render viruses resistant to a drug. When this resistance develops, it can be to an individual drug or to the entire class of drugs, as drugs within a class generally attack the same target or work to inhibit the same mechanism of the virus.

Later this week, scientists will present an update on work to bring to market a new drug, provisionally called T705, which targets the polymerase protein. Hayden said Phase 2 clinical trials will begin in Japan later this year.

Typically drugs are tested in people in three phases to determine safety and then efficacy; results from those clinical trials are used when drug makers seek regulatory approval to bring a drug to market.

Dr. Robert Krug, of the Institute for Cellular and Molecular Biology at the University of Texas at Austin, reported on finding a drug target on the non-structural protein of the virus. A drug target is a site on a protein created by the virus that could be neutralized by the right chemical molecule.

Krug reported that his lab had screened molecules that might be used against the target, and have come up with a good "hit." But he cautioned that even if the work goes well, it could be five years before a drug could be developed, tested and marketed.

The non-structural or NS1 protein of influenza makes an attractive target for a drug because it does not change from virus to virus, unlike other parts of flu viruses.

That "conserved" state suggests the protein plays a pivotal role, and that the virus might be crippled if it were to undergo the type of mutation that could lead to drug resistance, Krug said.

"This, by evolution, has gotten to the point where it's absolutely needed and it's conserved. So to get an escape from that is not going to be easy," he said.

That is not the case for one of the current classes of flu drugs, the M2 inhibitor drugs called amantadine and rimantadine. Circulating human flu viruses, particularly of the H3N2 subtype, show high rates of M2 inhibitor resistance. As a result, public health officials in Canada and the United States have advised against using these drugs at present.

The only other current class of flu drugs, the neuraminidase inhibitors, works against the neuraminidase protein. The function of neuraminidase is to help replicated viruses to break out of newly infected respiratory tract cells, a process needed to spread infection.

There are two neuraminidase inhibitors on the market, oseltamivir (Tamiflu) and zanamivir (Relenza). A third, peramivir, is in clinical trials.

To date surveillance has turned up very low levels of resistance to these drugs globally, but experts insist it is unwise to rely too heavily on one class of drugs.

Source: Canadian Press

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