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New Anthrax Countermeasure to be Acquired by HHS

By Clarence Lam and Luciana Borio, M.D., July 20, 2006

On June 20, 2006, the U.S. Department of Health and Human Services (HHS) announced [1] a plan to purchase 20,000 treatment courses of ABthrax™ (raxibacumab), an anthrax therapeutic, at a price of $165 million with delivery to the Strategic National Stockpile set to begin in 2009.

ABthrax™ is a human monoclonal antibody that neutralizes the function of Bacillus anthracis protective antigen (PA). It binds to anthrax toxin receptors on cell surfaces and serves as an essential component to facilitate the entrance of anthrax toxins into cells and, eventually, the death of cells. [2]

Supporting Data

The preventative and therapeutic efficacy of ABthrax™ has been shown in multiple preclinical studies in relevant animal models. Its safety and tolerability has been demonstrated in a Phase 1 clinical trial in healthy adults.  

Based on results of a Phase 1 trial [3], Human Genome Sciences, Inc. (HGS), the manufacturer of ABthrax™, concluded that the drug was safe and well-tolerated. In the randomized, single-blind, placebo controlled study, 105 healthy volunteers received a single dose of ABthrax™ or placebo, intramuscularly or intravenously. Adverse events, including headache, arthralgia, nausea, cough, and rhinorrhea, were considered transient and mild-to-moderate in severity after tests with intravenous infusion (dose levels 0.3, 1.0, and 3.0 mg/kg) and intramuscular injection (1.0, 3.0, 10, 20, 40 mg/kg). No dose-limiting adverse events were observed. Pharmacokinetic data demonstrated that the mean terminal elimination half-life of ABthrax™ ranged from 15 to 19 days.

Several earlier animal studies demonstrated the efficacy of ABthrax™ as a preventative and therapeutic measure against inhalational anthrax. In a study [4] of rabbits and cynomolgus monkeys, a single subcutaneous, prophylactic dose of ABthrax™ administered two days prior to challenge significantly improved survival of the animals. Results were dose-dependent: at the highest doses, 83% of rabbits and 90% of monkeys survived. Other studies displayed a significant dose-response relationship in rabbits, with 100%, 50%, and 40% surviving after receiving a single 40 mg/kg intravenous dose of ABthrax™ at 12, 24, and 36 hours post-exposure, respectively [5, 6].  An additional study [7] found that primates that were rechallenged via the aerosol route with a lethal dose of anthrax spores six and twelve months after initial therapeutic administration all survived.

Conclusion

A human monoclonal antibody to anthrax PA has several potential advantages that make it an attractive addition to the Strategic National Stockpile, along with anthrax vaccine and antibiotics. ABthrax™ provides immediate protection with a single dose and may improve the outcome of anthrax disease, which was associated with 45% mortality in the U.S. 2001 bioterrorist events [8]. Its major value rests in its potential efficacy against infection with anthrax spores engineered to be resistant to antibiotics. Major drawbacks of the therapeutic are the associated expense and the need for parenteral administration, which would be logistically difficult in large scale emergencies.

References

  1. HHS To Acquire New Anthrax Therapeutic Treatment For Stockpile. Available at http://www.hhs.gov/news/press/2006pres/20060620.html. Accessed on July 17, 2006. 

  2. Human Genome Sciences.  ABthrax™ (Human Monoclonal Antibody to Bacillus anthracis Protective Antigen). Available at http://www.hgsi.com/products/ABthrax.html. Accessed July 17, 2006.

  3. Subramanian GM, Cronin PW, Poley G, et al. A Phase 1 study of PA mAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen in healthy volunteers. Clin Infect Dis 2005;41(1):12-20.

  4. Beebe L, Zhong J, Clagett M, et al. Protection against inhalation anthrax-induced lethality by a human monoclonal antibody to protective antigen in rabbits and cynomolgus monkeys. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy: Abstract # 3836.

  5. Zmuda JF, Zhang L, Sosnovtseva S, et al. Detection of biologically active PA mAb (monoclonal antibody against anthrax protective antigen) by edema factor-mediated camp-induction bioassay during Phase 1 dose escalation studies: comparison to traditional pharmacokinetic analysis. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 168G.

  6. Beebe L, Babin M, Barnewall R, et al. Post-exposure therapeutic potential of PA mAb in an inhalation model of anthrax in New Zealand white rabbits. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 167G.

  7. Zmuda JF, Zhang L, Sosnovtseva S, et al. Detection of host-derived neutralizing antibodies against anthrax protective antigen (PA) in PA mAb-treated monkeys surviving lethal spore challenge: relationship to secondary exposure immunity. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 65H.

  8. Jernigan DB, et al. Investigation of Bioterrorism-Related Anthrax, United States, 2001: Epidemiological Findings. Emerg Infect Dis 2002;8(10):1019-28.