As governments around the world stockpile Tamiflu in preparation for a possible pandemic of bird flu, scientists are feverishly working to develop entirely new ways to combat the deadly H5N1 avian virus.
Why work on novel prevention and treatment approaches when there are already antiviral drugs like Tamiflu available and vaccines in advanced testing? Because many experts say the drugs and vaccines relied upon in the current World Health Organization plan, as well as in the pandemic preparedness plan recently released by the Department of Health and Human Services, may actually be of little or no use whatsoever.
An article in the October issue of the journal Nature, for example, reported on a Vietnamese girl who contracted avian flu and, while successfully treated, had one strain of the virus in her body that was resistant to Tamiflu, an oral drug that is one of two products in a class of drugs called neuraminidase inhibitors that are now being stockpiled around the world.
So far, there has been no evidence of resistance to Relenza, the second drug in government warehouses, but it has its problems, too. The current version of the drug must be inhaled, which limits its use to people old enough and well enough to use the inhaler. A new approach to delivering the drug — intravenously — could be useful, but it would require equipment and a healthcare worker, and could slow down the treatment process. And the most effective doses for the drugs are still being studied, according to Stephen Morse, director of the Center for Public Health Preparedness at Columbia University in New York City. If very high doses are required, the stockpiled amounts won’t treat as many people as had been hoped.
'Dangerous' to rely on one drug class
Many experts say what’s needed is a totally new approach, not a reliance on older drugs.
"In terms of treatment, we need to put money into basic research,’’ says Dr. Anne Moscona, a professor of pediatrics, microbiology and immunology at the Weill Medical College of Cornell University in New York.
"At this point, we are just relying on neuraminidase inhibitors. This is dangerous,’’ says Moscona, because viruses will always be able to escape if attacked with just one class of drugs. As with AIDS, which is now a chronic and treatable disease, it's important to attack viruses at several points in their life cycle simultaneously, with more than one drug, which will make it harder for resistant influenza to emerge, she says.
And while the U.S. government has signed contracts for over $160 million dollars worth of two vaccines that target particular strains of the avian flu and are both still in clinical trials, Dr. Paul Offit, chief of the division of infectious diseases at the Children's Hospital of Philadelphia, says if a different strain emerges to infect humans, the two vaccines may be largely useless.
What’s more, production of any vaccine is limited by the current vaccine technology, which grows the vaccine in eggs. A new approach, cell culture technology, still takes about six months to produce a vaccine supply from the time the culprit strain is identified, but the amount you could produce would be far greater, says Offit, who estimates that the technology is at least three years away from being able to be used commercially. The vaccine supply could also be compromised if an avian flu is the culprit in a pandemic and the chicken flocks relied on by vaccine firms become infected, though firms say they have multiple sites where chickens are kept and they also have many safeguards in place.
Although the government’s avian flu vaccine contracts are for egg-based vaccines, the two companies awarded the business, Chiron, which is expected to merge with Novartis, and Sanofi Pasteur, both have cell technology avian flu vaccines in development.
Government health officials seem well aware of the need to provide new approaches to stem a potential pandemic. "Moving forward with research conducted by the world’s top scientists and openly disseminating their research results remains our best defense against H5N1 avian influenza virus and other dangerous pathogens that may emerge,’’ said Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, and Dr. Julie Gerberding, head of the Centers for Disease Control and Prevention, in a statement issued last month.
Speeding up the process will be Food and Drug Administration guidelines for drugs intended to be for emergency use, such as many likely to be added to the government pandemic stockpile. While companies would normally have to show safety and effectiveness in humans, the emergency use rules allow firms to show effectiveness in animals and safety in humans. Drug testing typically takes three years or more, but under the emergency regulations, the testing time could be shortened to three to six months, says John McCamant, editor of the Medical Technology Stock Letter, who is following some of the new avian flu products.
In the pipeline
Two NIAID-funded projects that Cornell’s Moscona finds exciting include Fludase, a new inhaled antiviral drug in development from San Diego firm NexBio that may be able to protect against any influenza virus entering a person’s respiratory system, and a new neuraminidase inhibitor from Biota, an Australian firm whose researchers developed Relenza. Patients would take the Biota drug just once or twice a week, instead of the daily doses that are needed for the current drugs in that class. NexBio says their drug could be ready for FDA submission by June of 2006; Biota’s product, isn’t expected before Fall of 2007.
Several other companies are moving along on research aimed at preventing and treating avian flu. Some products are already available, some are expected by Spring, and everyone is working at breakneck speed.
- Genaco Biomedical Products of Huntsville, Ala., has created a diagnostic test that can, using DNA, identify the avian flu within just four hours, instead of the several days it currently takes. That would allow health department labs to identify avian flu if it strikes, and put emergency plans into place. It would also allow the labs to do frequent tests on virus samples; if the virus changes, the types and doses of drugs can be adjusted. The test is in current use internally by the CDC, and Genaco expects to be selling the test equipment and materials shortly to both private and public laboratories.
- Research by Hemispherx Biopharma of Philadelphia is exploring whether its drug Ampligen can increase the immune response of Tamiflu, Relenza or avian flu vaccines. The company will be able to use data from human safety studies conducted to see if the drug is safe in patients for the treatment of chronic fatigue syndrome, and they have already started animal studies. Hemispherx CEO William A. Carter says the company could be ready to apply to the FDA for approval for treating avian flu by next January.
- Peramivir, a drug from BioCryst of Birmingham, Ala., is a neuraminidase inhibitor that may be able to be given as a one-time injection rather than in daily doses. According to McCamant, of the Medical Technology Stock Letter, approval and drug production could happen by early to mid-2006.
- AVI BioPharma, Inc., of Portland, Ore., has a novel drug in development called AVI-5706 that targets the part of the genetic code of the virus that allows it to replicate. The compound "acts like a staple across the zipper to keep it in place,’’ says Michael Hubbard, a company spokesman. By keeping the virus from reproducing, the company is able to reduce the amount of virus in the body, which would allow the body’s own immune response to kick in. The company expects to file for FDA approval as early as mid-2006.
- Medimmune of Gaithersburg, Md., is working with NIAID researchers on an avian flu vaccine that uses the company’s nasal spray technology, which is already available as a standard flu vaccine, FluMist. However, the company says it could take years before the they know if the vaccine is effective.
- Powdermed, based in Oxford, England, has a novel vaccine technology that uses recombinant bacteria rather than eggs to grow the vaccine. The vaccine is embedded in gold particles and delivered via a high-pressured system applied to the skin, and people may be able to give the vaccine to themselves. Although the company is heavily engaged in clinical trials, and could ramp up a vaccine in three months once the strain is identified — that’s half the time needed for egg culture vaccines — they recently announced that they won’t have the manufacturing facility for the device needed to deliver the vaccine completed before April 2007.
With all this fast-paced development, the FDA has promised to step on the gas once the applications reach their offices, and has formed a "rapid response team" to help with the approval and availability of vaccines and drugs for avian flu.
While approval times for drugs generally take months or years, Dr. Andrew von Eschenbach, acting FDA commissioner, is far more optimistic about avian flu products.
"We believe,’’ says the commissioner, "[that] we could review a complete drug application [for these products] in six to eight weeks.’’