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Smallpox Antiviral Effective in Animal Trials

By Eric Toner, M.D. and Luciana Borio, M.D., October 23, 2006

On October 18, 2006, SIGA Technologies, Inc. announced that its antiviral drug candidate SIGA-246 demonstrated a high degree of protection against variola, the smallpox virus, in a primate trial conducted at the Centers for Disease Control and Prevention (CDC) [1]. The study challenged cynolmogus monkeys with high intravenous doses of variola virus, equivalent to the level present in late-stage disease in humans, according to Dr. Dennis Hruby, Chief Scientific Officer of SIGA. All animals that received the drug orally once a day were protected from developing clinical smallpox. The drug was effective whether administered at the same time as the virus challenge or 24 hours later, suggesting it may be useful for post exposure prophylaxis or treatment of smallpox. SIGA’s press release indicates that the drug “completely prevented lesion formation and reduced viral load to non-threatening levels in treated animals, with no obvious toxicity.”

SIGA-246 is a potent inhibitor of the core protein cysteine proteinase that is essential for assembly and maturation of multiple species of orthopoxviruses, including variola [2]. The proteinase is highly conserved in all orthopoxviruses, but not present in other viruses or bacteria [3]. In 2004 and 2005, SIGA-246 demonstrated complete protection from lethal doses of orthopoxviruses, including monkeypox, in several rodent models. In July 2006, the drug candidate was found to be safe and well tolerated in its first human trial; pharmacokinetic data supported oral, once a day dosing. Earlier this month, the National Institute of Allergy and Infectious Diseases (NIAID) awarded a $16.5 million dollar contract to SIGA Technologies, Inc., to support the advanced development of SIGA-246.

Although there are a number of smallpox vaccines in the Strategic National Stockpile available to be used in the event of a bioterrorist attack employing variola virus, there is no available antiviral drug treatment for the disease.  Antiviral drugs may be especially important because the expected mortality for smallpox infection is approximately 30%, even with supportive treatment. To our knowledge, the only other smallpox antiviral candidate in development is Chimerix’s CMX-001, a modified form of the licensed antiviral cidofovir [4]. Because the Department of Homeland Security has designated smallpox a “material threat” to national security, smallpox antiviral drugs in advanced stages of development (expected to be licensed within the next 8 years) could be eligible for contracts awarded under project BioShield.

References

  1. Press release: Siga announces smallpox treatment breakthrough. Available online at http://www.siga.com/press/101806.html. Accessed October 18, 2006.

  2. Byrd CM,  Bolken TC,  Hruby DE. The vaccinia virus I7L gene product is the core protein proteinase. J of Vir. 2002:76;8973-8976. Available at http://jvi.asm.org/cgi/content/full/76/17/8973. Accessed October 18, 2006.

  3. Siga Technologies, Inc. Product Profile: Smallpox Antiviral Drug. Available at http://www.siga.com/product_profile_smallpox_antiviral.html.  Accessed October 18, 2006.

  4. Chimerix acquires license for smallpox pills. Triangle Business Journal. September 12, 2003. Available at http://triangle.bizjournals.com/triangle/stories/2003/09/08/daily58.html.  Accessed 0ctober 18, 2006.