Biotech Innovations Aim To Conquer Influenza Virus

Few who have suffered from influenza need to be reminded of the misery it can inflict. Recent outbreaks in Hong Kong serve as a strong reminder that influenza is a costly and often fatal disease. In December, an outbreak of a deadly strain of avian influenza in Hong Kong caused the government there to mandate the slaughter of more than 1.5 million chickens. As of January, Centers for Disease Control and Prevention (CDC) researchers have identified 16 confirmed cases of the avian flu in humans. Five of the 16 patients have died. Building on years of research and development, small biotechnology companies are leading the drive against influenza as they improve old and create new weapons for the treatment and prevention of the disease. Some companies have developed novel compounds that prevent the virus from uncoating and infecting host cells, while others have developed adjuvants and delivery systems that greatly improve the efficacy of traditional vaccines. As these companies enter partnerships with giant pharmaceutical firms, they report strong job growth for scientists in this area. As many as 50 million Americans get the flu each year, and direct costs for the treatment of the disease are as high as $5 billion per year, according to statistics from CDC. Symptoms of infection include the rapid onset of fever, dry coughing, muscle aches, and fatigue. Acute symptoms last from two to four days, and fatigue may last as long as two weeks. During nine of the 20 influenza seasons from 1972 to 1992, more than 20,000 deaths were associated with complications from the disease in the United States, CDC reports. In four of those years, more than 40,000 deaths were blamed on influenza. Vaccines provide physicians with the first line of defense; they are from 70 percent to 90 percent effective in preventing influenza, according to CDC. But the vaccines sometimes fail because researchers have not correctly predicted which strains of viruses will be circulating during a season. Moreover, patients receiving vaccines may not be immune to a strain of influenza because of antigenic drift in the virus. When faced with patients suffering from influenza, physicians traditionally have been able to treat only the symptoms of the disease. Newer treatments like the Symmetrel (amantadine), made by Wilmington, Del.-based Dupont Merck Pharmaceutical Co., are effective only against influenza A, which becomes resistant to the drug in just three days. ACTING ON INHIBITION: Gilead's GS 4104 treats and prevents influenza by inhibiting an enzyme essential for viral replication. Two companies, Gilead Sciences Inc., based in Foster City, Calif., and Biota Ltd., based in Melbourne, Australia, are independently testing the efficacy of the newest weapon against influenza-neuraminidase inhibitors. Unlike treatments now on the market, neuraminidase inhibitors are effective against both influenza A and B viruses-the two most common but antigenically dissimilar causes of influenza. The inhibitors block the activity of neuraminidase, an enzyme playing a pivotal role in the replication of the virus. The enzyme serves to break the chemical bond between sugar molecules on the surface of cells and hemagglutinin proteins on the surface of the virus. Mimicking sugar molecules, the inhibitors bind to neuraminidase enzymes and prevent the virus from infecting host cells. Gilead, in partnership with Basel, Switzerland-based Hoffmann-La Roche Ltd., began clinical trials in the U.S., Canada, Europe, and Hong Kong in December to test the efficacy and safety of its anti-flu compound GS 4101. In animal models, GS 4104 proved highly effective, preventing the death of mice exposed to lethal doses of influenza virus and eliminated symptoms of the disease within a day of treatment, according to Robert Sidwell, a virologist at Utah State University. Four clinical trials are evaluating the efficacy of the compound in treating and preventing influenza, reports Norbert Bischofberger, senior vice president for research at Gilead. While researchers at Gilead have been able to produce GS 4104-resistant viruses, the mutations have compromised the fitness and infectiousness of the virus. In 1993, Biota developed the first neuraminidase inhibitor, known as GG167, or zanamavir. Unlike GS 4104, zanamavir is inhaled in powder form. Glaxo Wellcome Inc., based in Research Triangle Park, N.C., has licensed the product from Biota and is conducting Phase III clinical trials worldwide, including more than 80 sites throughout the U.S. Early trials have shown that the treatment reduces by 20 percent the duration of flu symptoms from both A and B virus strains. Glaxo officials expects to file for U.S. Food and Drug Administration (FDA) approval soon after the end of the flu season in April or May. Gilead decided on developing an orally available compound in part because consumers show a preference for taking pills, according to Bischofberger. He also notes that patients with respiratory problems are especially vulnerable to flu and would have difficulty using inhalers if infected by the disease. Additionally, scientists at Gilead believe influenza is a systemic disease and question if an inhaled neuraminidase inhibitor can reach all sites of replication by the virus. To be sure, Glaxo researchers argue that influenza is really a localized disease and that a localized inhaled compound reduces the potential for side effects. "In principle, Glaxo may be correct or [Gilead] may be correct," Bischofberger says. "This is really a question only clinical trials will resolve." While neuraminidase inhibitors appear to be effective for treatment of influenza, researchers do not expect the compounds to make vaccines obsolete. "Our first line of defense against influenza still will be vaccines," predicts Frederick G. Hayden, a professor of internal medicine and pathology at the University of Virginia School of Medicine who has conducted clinical trials for both zanamavir and GS 4104. "But often vaccines don't offer protection against the newest strains of flu or patients with compromised immune systems don't benefit from vaccines. These new compounds could provide health-care workers with an effective way for coping with these situations." If they eventually win FDA approval, neuraminidase inhibitors could be blockbuster products for companies like Glaxo and Roche, according to Richard van den Broek, a senior analyst at the investment firm of Hambrecht and Quist in New York. He estimates that the potential market for treatments for influenza is as high as $5 billion annually in the U.S. "As you can see, there is a substantial market for flu treatments," he notes. "Neuraminidase inhibitors could provide the most benefit to people who don't respond well to vaccines. While it is uncertain how the products will fare against vaccines, the market is really large enough to accommodate both approaches to the disease." ViroPharma, based in Malvern, Pa., also has hopes of offering a treatment for influenza. It is developing an anti-flu drug that inhibits replication by targeting the virus' RNA transcriptase complex, according to Claude H. Nash, CEO of ViroPharma. As do neuraminidase inhibitors, ViroPharma's drug targets highly genetically conserved areas of the virus that cannot mutate without dramatically effecting its overall fitness. Pleconaril, ViroPharma's most advanced product candidate, has driven recent company growth. It is an orally active inhibitor of the picornavirus group, including the enterovirus and the rhinovirus, which is estimated to cause about half of all common colds. Enteroviruses are responsible for several diseases, such as viral meningitis, "summer flu," and hand-foot-and-mouth disease in infants. PIERCING CHANGE: Aviron hopes its new intranasal flu vaccine will appeal to the "needlephobic." Aviron Co., based in Mountain View, Calif., is another biotechnology company that has made advances against influenza. The company's lead product, an intranasal flu vaccine, could reach the marketplace in time for the 1999 flu season, according to Martin L. Bryant, vice president for research at Aviron. In clinical trials completed in 1997, the intranasal spray showed a 93 percent protection rate for children against influenza. In order to stimulate an optimal immune system response at the site of infection, Aviron developed a live, cold adapted virus that could be administered in the nasal passages. It was first discovered in 1967 by Hunein F. Maassab, a professor of epidemiology at the University of Michigan. The cold adapted virus, unlike wild-type influenza, can be grown at temperatures below human body temperature and therefore replicates efficiently in relatively cooler nasal passages but not in the lungs. Bryant says a major advantage of the intranasal vaccine is the ease of delivery. "Many people are not inoculated because they're 'needle-phobic,'" he notes. "This product avoids inadvertent needle sticks and the need for needle disposal. It is also possible that the intranasal vaccine could be self-administered." In hopes of enhancing the performance of a wide variety of vaccines, the Virus Research Institute Inc. (VRI), a biotechnology company based in Cambridge, Mass., is testing the efficacy of a promising new adjuvant, polydicarboxlatophenoxyphosphazene (PCPP). Preclinical trials of PCPP show that the compound boosts antibody response tenfold in animals receiving a commercial trivalent influenza vaccine (L.G. Payne et al., Vaccine, 16[1]: 92-8, 1998). Alum, an aluminum salt preparation, is the only FDA-approved vaccine adjuvant in use in the U.S. In a collaboration with Chiron Corp., based in Emeryville, Calif., VRI researchers also showed that PCPP outperformed alum and could be used in vaccine for herpes simplex, tetanus toxoid, and hepatitis B. VACCINE BOOSTER: J. Barrie Ward of the Virus Research Institute says the company's new adjuvant could improve the efficacy of vaccines. VRI, in partnership with the Lyon, France-based Pasteur M}rieux Connaught SA (PMC), is testing the adjuvant in clinical trials. Phase I clinical trials of an adjuvanted vaccine conducted in France show that the adjuvant is well-tolerated, safe, and effective. However, Phase II trials completed in November in Peru contradict those earlier trials in certain respects, according to J. Barrie Ward, CEO of VRI. "The differences between the two trials were surprising to us," Ward says. "VRI and PMC are currently conducting further studies to determine the reasons underlying the differences." Later this year, the companies will begin clinical trials for an adjuvanted vaccine for lyme disease developed by PMC laboratories in Swiftwater, Pa. Aviron Co. 297 N. Bernardo Ave. Mountain View, Calif. 94043 (650) 919-6500 - Fax:(650) 919-6610 http://www.aviron.com/ Gilead Sciences Inc. 333 Lakeside Dr. Foster City, Calif. 94404 1-800-GILEAD-5 - Fax:(650) 573-4853 http://www.gilead.com/ Hambrecht and Quist 230 Park Ave. New York, N.Y. 10169 (212) 207-1412 - Fax:(212) 207-1541 rbroek@hamquist.com Protein Sciences Corp. 1000 Research Parkway Meriden, Conn. 06450-7159 (203) 686-0800 - Fax:(203) 686-0268 http://www.proteinsciences.com/ ViroPharma Inc. 76 Great Valley Parkway Malvern, Pa. 19355 (610) 651-0200 - Fax:(610) 651-0588 http://www.viropharma.com/ Virus Research Institute Inc. 61 Moulton St. Cambridge, Mass. 02138 (617) 864-6232 - Fax:(617) 864-6334 jbward@vrii.com Fearing the potential for a pandemic, researchers are turning their technology against the so-called Hong Kong strain of the avian influenza A. Although avian influenza typically requires an intermediate host to be transmitted to humans, CDC researchers believe the virus may be transmitted directly from chickens in an as-yet-unknown way. Health officials in the U.S. have called on several biotechnology companies to produce a vaccine for the deadly flu. In January, Aviron joined in a collaboration with the National Institutes of Health and the California Veterinary Diagnostic Laboratory at the University of California, Davis, to prepare two candidate vaccines for use in health-care workers, researchers, and others at high risk for exposure to avian influenza. Aviron will make the two candidates using its "genetic reassortment" manufacturing process, according to Bryant. Researchers prepare the vaccines by modifying hemaggluttin and neuraminidase surface proteins from the avian influenza virus and genetically inserting them into cold adapted, attenuated human virus strains already used. "With this approach, we remove a lot of the uncertainty and hazards associated with the development of new vaccines because we never really handle the live virus," Bryant says. Protein Sciences Corp., a Meriden, Conn.-based company that also is collaborating with NIH, produced more than 1,700 doses of its experimental avian flu vaccine by February 5. The company produced the vaccine in just over a month, according to Daniel D. Adams, CEO of Protein Sciences. "As soon as NIH and CDC isolated and mapped the Hong Kong strain, we had everything we needed to make a safe vaccine," Adams says. To produce a candidate vaccine, Protein Sciences manufactured a purified, genetically engineered influenza hemagglutinin protein derived from genetic material supplied by CDC. Carried by an insect virus vector, the protein is injected into insect cells genetically programmed to replicate high amounts of the protein. In addition to genetically engineering the emerging strain of influenza, the company utilizes insect cells instead of hen eggs to manufacture the vaccine. The use of insect cells provides several advantages over hen eggs, traditionally used by the industry to grow vaccines. Eggs often are not very sterile, are in limited supply, and take longer to produce the vaccine, according to Adams. "[This process] enables us manufacture a vaccine when researchers and epidemiologists are more certain which strain of influenza will strike," he says. All of the company officials interviewed for this article report growing job opportunities for scientists, especially for researchers in biochemistry and virology. Protein Sciences, for example, nearly doubled its work force from 22 to 39 in the last year and a half. Gilead, which has attempted to be conservative in its growth, saw employment jump from 30 in 1990 to 300 in 1998, according to Bischofberger. Because the company uses in-house staff for all research and development activity, employment opportunity exists for chemists, virologist, biostatisticians, and other scientists involved in the discovery and development of clinical compounds. ViroPharma also nearly doubled its staff in the last year to 100. While ViroPharma offers many opportunities for researchers, Nash says scientists can find opportunity in alternative careers within the company. "With products like Pleconaril getting closer to market, our strongest job growth has been in our sales and marketing departments," he says. "Scientists may not consider these fields or think they're unqualified, but their expertise in science is always asset and marketable throughout the company."

Biotech Innovations Aim To Conquer Influenza Virus

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