ABthrax is a human monoclonal antibody drug that HGS discovered and developed for the treatment and prevention of anthrax disease.[1-2] It specifically recognizes and neutralizes Bacillus anthracis protective antigen, which is the key facilitator of anthrax infection at the cellular level. The results of clinical and preclinical studies to date provide strong support for the potential of ABthrax to provide significant survival benefit with minimal side effects in the event of an anthrax attack.[3-13] ABthrax is being developed under a contract with the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services (HHS).[14-15]

How ABthrax Works

Anthrax infection is caused by a spore-forming bacterium, Bacillus anthracis, which multiplies in the body and produces lethal toxins. Most anthrax fatalities are caused by the irreversible effects of the anthrax toxins.

Research has shown that Bacillus anthracis protective antigen is the key facilitator in the progression of anthrax infection at the cellular level.[16] The other two anthrax toxin components are lethal factor and edema factor. After the three anthrax toxin components are produced by the bacteria, protective antigen binds to the anthrax toxin receptor on cell surfaces and forms a protein-receptor complex that makes it possible for lethal factor and edema factor to enter the cells, where they are toxic.

ABthrax blocks the binding of protective antigen to cell surfaces and prevents the anthrax toxins from entering and killing the cells (see Figure 1).

ABthrax Prevents Anthrax Toxin-Mediated Cell Death

Figure 1.  ABthrax specifically recognizes and neutralizes protective antigen (PA). By neutralizing PA, ABthrax effectively blocks the binding of PA to cell surfaces and prevents the anthrax toxins from entering and killing the cells.

U.S. Government Contract to Supply ABthrax to the Strategic National

ABthrax is being developed under a $165 million contract with the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services (HHS).[14] HGS has reached agreement with the FDA on the regulatory pathway for ABthrax and plans to submit the final data package to BARDA and FDA by mid-2008 to support authorization of delivery to the Strategic National Stockpile. The Company is currently manufacturing ABthrax on schedule to begin delivery of 20,000 doses to the Stockpile by fall 2008. HGS expects to receive approximately $100-120 million in revenues from this award in late 2008, after delivery to the Stockpile begins.

Potential Treatment Setting

Two options are currently available for the prevention or treatment of anthrax infections – a vaccine and antibiotics. Both are essential to dealing with anthrax, but both have limitations. The anthrax vaccine takes several weeks following the initial doses before immunity is detectable, and requires multiple injections over a period of eighteen months, in addition to annual booster vaccination, to maintain protective immunity. Antibiotics are effective in killing anthrax bacteria, but are not effective against the anthrax toxins once those toxins have been released into the blood. Antibiotics also may not be effective against antibiotic-resistant strains of anthrax.

 In ABthrax, HGS has discovered a third mechanism of defense against anthrax infections. In contrast to the anthrax vaccine, the protection afforded by a single dose of ABthrax would be immediate following the rapid achievement of appropriate blood levels of the antibody. In contrast to antibiotics, ABthrax acts against the deadly toxins produced by anthrax bacteria. It may also prevent and treat infections by antibiotic-resistant strains of anthrax.

  Survival Analysis
Rabbit Model of Inhalation Anthrax

Figure 2.  In an experimental model of inhalation anthrax in rabbits, a single injection of ABthrax administered at five different dose levels 48 hours prior to spore challenge or within one hour after spore challenge, significantly improved 14-day survival compared to the control group (p< 0.0001). In addition, a single injection of ABthrax at the highest dose administered within one hour after spore challenge provided 100% protection against lethality.[12]

Efficacy and Safety Data 

In December 2007, HGS announced that the results of two animal studies demonstrated the life-saving potential of ABthrax for the treatment of inhalation anthrax disease.[3} The results showed that a single dose of ABthrax, administered without the use of antibiotics, improved survival rates by up to 64 percent – even when administered after animals were already showing clinical symptoms as a result of inhalation exposure to massively lethal doses of anthrax spores. These dramatic and statistically significant findings demonstrated a survival benefit in two animal species, which is the requirement for establishing the efficacy of new drugs used to counter bioterrorism. 

In one of the animal studies, three groups of monkeys were exposed by inhalation to massively lethal amounts of anthrax spores and treated with either ABthrax or placebo after they showed clinical signs of anthrax disease.[3} After 28 days, the study found that:

• 64.3 percent of monkeys that received a single high dose of ABthrax survived (p=0.0007 vs. placebo).
• 50 percent of those that received a low dose survived (p=0.0064 vs. placebo).
• None of the monkeys in the placebo control group survived. 

A separate study that measured 14-day survival in rabbits also demonstrated a statistically significant survival benefit versus placebo.[3] All ABthrax-treated animals that survived in both studies were rapidly cleared of anthrax toxin and bacteria following intravenous administration of a single dose of ABthrax as a single agent. In contrast, all placebo-treated animals remained bacteremic or toxemic and died.

The results of these two studies provide the scientific evidence required to establish the efficacy of ABthrax in the treatment of inhalation anthrax. Because the design of the studies required that the animals not be treated until after showing clinical symptoms resulting from exposure to massively lethal doses of anthrax spores, HGS believes that the results closely simulate what might take place in the event of an actual inhalation anthrax attack. In addition, the new data are consistent with the results of previous studies in multiple animal models, which demonstrated that a single dose of ABthrax given prophylactically provided up to 100% protection against death.[12]

HGS also reported in December 2007 that it has completed the second safety study of ABthrax in human volunteers, bringing the total number of people who have participated in human safety trials to more than 180. The clinical results to date suggest that ABthrax was generally safe and well tolerated. In addition, the new study demonstrated that co-administration of ABthrax with the antibiotic Cipro (ciprofloxacin) did not affect the pharmacokinetics of either Cipro or ABthrax, and suggested that ABthrax can be administered in combination with antibiotics. This is a key finding given the important role that antibiotics are expected to continue to play in the treatment of anthrax disease.[3]

Pharmokinetics After a Single IV Infusion

Figure 2.  Pharmacokinetic analysis of data from a Phase 1 clinical trial in healthy adults shows that the half-life of ABthrax is 15 to 20 days following IV administration and 15 to 22 days following IM administration. ABthrax exhibited an excellent safety profile, and achieved the blood levels predicted in animal studies as necessary to afford significant protection.[5]

How ABthrax Was Discovered

ABthrax is a human monoclonal antibody to Bacillus anthracis protective antigen that was discovered and developed by HGS. ABthrax was developed using technology that HGS has integrated into the Company as part of its collaboration with Cambridge Antibody Technology. ABthrax is produced in Human Genome Sciences’ manufacturing facilities in Rockville, Maryland. .

Footnotes

1. (HGSI Press Release) Human Genome Sciences Develops New Means to Prevent and Treat Anthrax Infections. March 18, 2003.
2. (HGSI Press Release) Human Genome Sciences Describes Activity of ABthrax at 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. September 15, 2003.
3. (HGSI Press Release) New Approach to Treating Anthrax Significantly Improves Survival Rates in Pivotal Efficacy Studies. December 18, 2007.
4. (HGSI Press Release) Human Genome Sciences Publishes Results of Phase 1 Clinical Trial of ABthrax for Use in Prevention and Treatment of Anthrax Disease. July 18, 2005.
5. Subramanian GM, et al. A Phase 1 study of PA mAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen in healthy volunteers. Clinical Infectious Diseases 2005: 41.
6. Subramanian M, Cronin P, Poley G, et al. ABthrax (PA mAb) – a novel fully human monoclonal antibody against protective antigen of B. anthracis: results of a Phase 1 single dose-escalation study in healthy human subjects. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 158D
7. (HGSI Press Release) Human Genome Science Reports Results of Phase 1 Clinical Trial of ABthrax for Use in Prevention and Treatment of Anthrax Infection. March 9, 2004.
8. 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.
9. 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.
10. Zmuda, JF, 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.
11. Kahn D. Development and characterization of a scalable purification process for ABthrax. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 169G.
12. 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.
13. Zhang X, Askins J, Fleming R, et al. Selection of potent neutralizing human monoclonal antibodies to protective antigen of Bacillus anthracis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy: Abstract # 3976.
14. (HGSI Press Release) U.S. Government Agrees to Purchase ABthrax from Human Genome Sciences for the Strategic National Stockpile. June 20, 2006.
15. (HGSI Press Release) Human Genome Sciences Awarded Two-Phase Contract to Supply ABthrax for the Treatment of Inhalational Anthrax Disease to the U.S. Government. October 3, 2005.
16. Inglesby TV, O’Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA May, 2002. 287(17): 2236-2252.
17. Project BioShield Act of 2004 (P.L. 108-276): http://www.hhs.gov/ophep/bioshield/3prngdprgrm.html.
18. (HGSI Press Release) Human Genome Sciences Receives Fast Track Product Designation for ABthrax for Prevention and Treatment of Anthrax Infections. August 19, 2003.
19. (HGSI Press Release) Human Genome Sciences Receives FDA Clearance to Initiate Human Trial of Novel Drug to Prevent or Treat Anthrax Infections. June 25, 2003.
20. Public Health Security and Bioterrorism Preparedness and Response Act of 2002: Section 123. http://www.fda.gov/oc/bioterrorism/PL107-188.html.
    

Bibliography

Casadevall A. Passive antibody administration (immediate immunity) as a specific defense against biological weapons. Emerging Infectious Diseases Aug 2002. 8(8): 833-841.

Friedlander A, et al. Postexposure prophylaxis against experimental inhalation anthrax. Journal of Infectious Diseases May 1993. 167(5): 1239-43.

Hart CA, Beeching NJ. Spotlight on anthrax. Clinics in Dermatology 2002. 20: 365-375.

Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA May, 2002. 287(17): 2236-2252.

Ivins BE, Pitt MLM, et al. Comparative efficacy of experimental anthrax vaccine candidates in rhesus macaques. Vaccine 1998. 16(11/12): 1141-1148.

Kobiler D, Gozes Y, et al. Efficiency of protection of guinea pigs against infection with Bacillus anthracis spores by passive immunization. Infection and Immunity Feb 2002. 70(2): 544-550.

Little SF, Ivins BE, et al. Passive protection by polyclonal antibodies against Bacillus anthracis infection in guinea pigs. Infection and Immunity Dec 1997. 65(12): 5171-5175.

Swartz MN. Recognition and management of anthrax: an update. New England Journal of Medicine Nov 2001. 345(22): 1621-1626.

Turnbull PC, Broster MG, et al. Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Infection and Immunity May 1986. 52(2): 356-363.

 

To view announcements on ABthrax, click on the following:

U.S. Government Agrees to Purchase ABthrax from Human Genome Sciences for the Strategic National Stockpile - June 20, 2006 

Human Genome Sciences Awarded Two-Phase Contract to Supply ABthrax for the Treatment of Inhalational Anthrax Disease to the U.S. Government - October 3, 2005 

Human Genome Sciences Publishes Results of Phase 1 Clinical Trial of ABthrax for Use in Prevention and Treatment of Anthrax Disease -  July 18, 2005  

Human Genome Science Reports Results of Phase 1 Clinical Trial of ABthrax for Use in Prevention and Treatment of Anthrax Infection - March 9, 2004

Human Genome Sciences Describes Activity of ABthrax at 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy - September 15, 2003 

Human Genome Sciences Receives Fast Track Product Designation for ABthrax for Prevention and Treatment of Anthrax Infections - August 19, 2003

Human Genome Sciences Receives FDA Clearance to Initiate Human Trial of Novel Drug to Prevent or Treat Anthrax Infections - June 25, 2003

Human Genome Sciences Develops New Means to Prevent and Treat Anthrax Infections - March 18, 2003