Box 2. Bioterror-inspired approaches

Still other viruses are attracting attention, much of it involving conventional approaches to drug development, but some of it slightly offbeat. Perhaps some of those unconventional approaches can be attributed to lingering influence from the Defense Advanced Research Projects Agency (DARPA; Arlington, VA), which is no longer working on antivirals, according to a spokesperson. However, the Defense Threat Reduction Agency (DTRA; Ft. Belvoir and Alexandria, VA) continues to issue contracts supporting biotech companies that work on antiviral products. Moreover, the NIH supports antiviral product development in the private sector, particularly through the Small Business Innovation Research (SBIR) program.

For example, last August DTRA awarded Alnylam (Cambridge, MA, USA) a $38.6 million contract to develop broad-spectrum antiviral products based on its RNA interference (RNAi) approach, for diseases including viral hemorrhagic fever. NIH awarded the company a $23 million contract in 2006 to develop therapeutic products for the Ebola virus. Similarly, AVI BioPharma (Portland, OR, USA) has received a series of multimillion-dollar contracts from the Department of Defense, including some from DTRA, to develop morpholino antisense (NeuGene) therapeutics against such pathogens as Ebola and Marburg viruses. In preclinical testing, one candidate product protected nonhuman primates against Ebola virus infections.

Separately, Protiva Biotherapeutics (Burnaby, BC, Canada) is developing short interfering RNA (siRNA) technology aimed at several viruses of biodefense interest, such as Ebola, and other viruses such as influenza, HBV and HCV for general use, according to president and CEO Mark Murray. "Our particular angle is a very infective intracellular delivery vehicle for siRNA, whose efficacy critically depends on delivery," he says, referring to the company's stable nucleic acid lipid particle (SNALP) technology, which provides stability and extended serum half-lives for encapsulated siRNA molecules and was licensed by Merck in October. "In the Ebola case, this technology is extraordinarily effective," he says. "Animals survive otherwise lethal infections, and their serum is aviremic 14 days later."

Siga Technologies (New York, NY, USA) is developing several candidate small-molecule drugs targeting several viruses of biodefense interest, including smallpox and other orthopox viruses as well as Lassa fever virus. In September, the company reported that its ST-246, its leading small-molecule candidate against orthopox, protected 100% of cynomolgus monkeys against a lethal dose of monkeypox virus in tests conducted at the US Army Medical Research Institute of Infectious Diseases (USAMRIID; Frederick, MD) facilities. Monkeypox virus is closely related to variola, the virus that causes smallpox in humans. Earlier in March, under an emergency investigational new drug designation granted by the FDA, administration of ST246 to a child who had developed eczema vaccinatum after receiving live vaccinia vaccine, resulted in a complete resolution of the child's symptoms. In a separate study at USAMRIID that was reported last May, low doses of Siga's ST-193 antiviral candidate product protected 71% of guinea pigs against an otherwise lethal dose of Lassa fever virus.

Other companies, including MacroGenics (Rockville, MD, USA) and Symphogen (Lyngby, Denmark), are developing both mAbs and polyclonal antibodies for possible use in neutralizing smallpox or other orthopox viruses, including vaccinia, which is used to vaccinate active military and other individuals to protect them against smallpox. Although safe for most people, vaccinia sometimes causes a disseminated infection that now is treated with a mix of immunoglobulins. "Our mAb cocktail is much more potent when tested in mice," says Jeffrey Nordstrom, director of product development at MacroGenics. Meanwhile, Symphogen is evaluating recombinant polyclonal antibodies for several applications, including against disseminated vaccinia and smallpox infections and those caused by RSV, both of which are in preclinical development. "In our RSV program we have found that antibody mixtures are significantly more potent than when tested individually," says John Haurum, Chief Scientific Officer at Symphogen.