Raxibacumab is a human monoclonal antibody drug that HGS discovered and developed for the treatment of inhalation anthrax.[1-4] Raxibacumab represents a new way to address the anthrax threat. While antibiotics can kill the anthrax bacteria, they are not effective against the deadly toxins that the bacteria produce. Raxibacumab is a first-in-class treatment that targets anthrax toxins after they are released by the bacteria into the blood and tissues. These toxins are the real culprits in most anthrax-related deaths.[5] In an inhalation anthrax attack, people may not know they are infected with anthrax until the toxins already are circulating in their blood, and it may be too late for antibiotics alone to be effective.

In July 2009, The New England Journal of Medicine published the results of two pivotal animal efficacy studies, which showed that a single dose of raxibacumab, 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.[6-9] 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.[10] The results of these and other clinical and preclinical studies to date provide strong support for the potential of raxibacumab to provide significant survival benefit with minimal side effects in the event of an anthrax attack.[7-18]

In April 2009, HGS completed the delivery of 20,000 doses of raxibacumab to the U.S. Strategic National Stockpile.[19] In July 2009, HGS received a second order for 45,000 doses to be delivered over a period of three years, beginning near the end of 2009.[20] Raxibacumab is being developed under a contract with the Biomedical Advanced Research and Development Authority (BARDA) of the Office of the Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services (HHS).[21-22]

How Raxibacumab 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.[3] 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 (see Figure 1).

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

Raxibacumab Prevents Anthrax Toxin-Mediated Cell Death

Figure 1.  Raxibacumab specifically recognizes and neutralizes protective antigen (PA). By neutralizing PA, raxibacumab 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 Raxibacumab to the Strategic National Stockpile

Raxibacumab is being developed under a contract with the Biomedical Advanced Research and Development Authority (BARDA) of the Office of the Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services (HHS).[18-19] In April 2009, HGS fulfilled its commitment under this contract to deliver 20,000 doses of raxibacumab to the U.S. Strategic National Stockpile for emergency use in the treatment of inhalational anthrax.[16] In July 2009, HGS received a second order for 45,000 doses to be delivered over a period of three years, beginning near the end of 2009.[17] Both purchase awards were made under the Project BioShield Act of 2004, which is designed to accelerate the development, purchase and availability of medical countermeasures for the Strategic National Stockpile.[20] HGS recognized $162.7 million in raxibacumab revenue in the first half of 2009.[21] The Company also filed a Biologics License Application (BLA) with the FDA in May 2009[22-23], and will receive an additional $10 million under the contract upon licensure.

Potential Treatment Setting

Two options have been available up until now 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.

Raxibacumab is a first-in-class treatment that targets anthrax toxins after they are released by the bacteria into the blood and tissues. In contrast to the anthrax vaccine, the protection afforded by a single dose of raxibacumab would be immediate following the rapid achievement of appropriate blood levels of the antibody. In contrast to antibiotics, raxibacumab 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 raxibacumab 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 raxibacumab at the highest dose administered within one hour after spore challenge provided 100% protection against lethality.[17]

Efficacy and Safety Data 

In December 2007, HGS announced that the results of two animal studies demonstrated the life-saving potential of raxibacumab for the treatment of inhalation anthrax disease.[9] The results, which were published in July 2009 along with data from other studies of raxibacumab in the New England Journal of Medicine, showed that a single dose of raxibacumab, 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.[6-9] 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 raxibacumab or placebo after they showed clinical signs of anthrax disease.[6-9] After 28 days, the study found that:

• 64.3 percent of monkeys that received a single high dose of raxibacumab 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.[6-9] All raxibacumab-treated animals that survived in both studies were rapidly cleared of anthrax toxin and bacteria following intravenous administration of a single dose of raxibacumab 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 raxibacumab 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 raxibacumab given prophylactically provided up to 100% protection against death.[17]

HGS has also completed safety studies of raxibacumab in more than 400 human volunteers. The clinical results to date suggest that raxibacumab was generally safe and well tolerated. In addition, clinical data have demonstrated that co-administration of raxibacumab with the antibiotic Cipro (ciprofloxacin) did not affect the pharmacokinetics of either Cipro or raxibacumab, and suggested that raxibacumab 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.[5]

Pharmokinetics After a Single IV Infusion

Figure 3. Pharmacokinetic analysis of data from a Phase 1 clinical trial in healthy adults shows that the half-life of raxibacumab is 15 to 20 days following IV administration and 15 to 22 days following IM administration. Raxibacumab exhibited a positive safety profile, and achieved the blood levels predicted in animal studies as necessary to afford significant protection.[10]

How Raxibacumab Was Discovered

Raxibacumab is a human monoclonal antibody to Bacillus anthracis protective antigen that was discovered and developed by HGS. Raxibacumab was developed using technology that HGS has integrated into the Company as part of its collaboration with Cambridge Antibody Technology. Raxibacumab 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 Receives FDA Clearance to Initiate Human Trial of Novel Drug to Prevent or Treat Anthrax Infections. June 25, 2003. 
3. (HGSI Press Release) Human Genome Sciences Receives Fast Track Product Designation for ABthrax for Prevention and Treatment of Anthrax Infections. August 19, 2003. 
4. (HGSI Press Release) Human Genome Sciences Describes Activity of ABthrax at 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. September 15, 2003. 
5. 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. 
6. Migone T, Subramanian GM, Bolmer SD, et al. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med 361;2. July 9, 2009. 
7. (HGSI Press Release) Data Published in the New England Journal of Medicine Support Use of Raxibacumab (ABthrax) for the Treatment of Inhalation Anthrax. July 9, 2009. 
8. Nabel GJ. Protecting against future shock – inhalational anthrax. N Engl J Med 361;2. July 9, 2009. 
9. (HGSI Press Release) New Approach to Treating Anthrax Significantly Improves Survival Rates in Pivotal Efficacy Studies. December 18, 2007. 
10. Public Health Security and Bioterrorism Preparedness and Response Act of 2002: Section 123. http://www.fda.gov/oc/bioterrorism/PL107-188.html. 
11. 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. 
12. (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. 
13. 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. 
14. 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. 
15. 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. 
16. Kahn D. Development and characterization of a scalable purification process for ABthrax. American Society of Microbiology Biodefense Meeting, March 2004: Abstract 169G. 
17. 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. 
18. 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. 
19. (HGSI Press Release) Human Genome Sciences Begins Delivery of First-in-Class Anthrax Treatment to U.S. Strategic National Stockpile. February 2, 2009.
20. (HGSI Press Release) Human Genome Sciences Announces New Order for Raxibacumab (ABthrax) from U.S. Government. July 22, 2009. 
21. (HGSI Press Release) U.S. Government Agrees to Purchase Raxibacumab from Human Genome Sciences for the Strategic National Stockpile. June 20, 2006. 
22. (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. 
23. Project BioShield Act of 2004 (P.L. 108-276): http://www.hhs.gov/ophep/bioshield/3prngdprgrm.html. 
24. (HGSI Press Release) Human Genome Sciences Announces Second Quarter 2009 Financial Results and Key Developments. July 22, 2009. 
25. (HGSI Press Release) Human Genome Sciences Submits Biologics License Application to FDA for ABthrax. May 21, 2009. 
26. (HGSI Press Release) Human Genome Sciences Receives Complete Response Letter from FDA for Raxibacumab Biologics License Application. November 16, 2009.
    

Bibliography

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. 

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.

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.

Healey LM, Zimmerman J, Farmer F, Subramanian GM, et al. Safety and pharmacokinetics of raxibacumab: a novel agent for the treatment of inhalational anthrax. Abstract. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, October 2008.

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.

Migone T, Subramanian GM, Bolmer SD, et al. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med 361;2. July 9, 2009.

Migone TS, Devalaraja M, Corey A, Bolmer S, et al. Efficacy of raxibacumab in the treatment of inhalational anthrax infection in rabbits and on-human primates. Abstract. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, October 2008.

Nabel GJ. Protecting against future shock – inhalational anthrax. N Engl J Med 361;2. July 9, 2009.

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.

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 Raxibacumab, click on the following:

Human Genome Sciences Receives Complete Response Letter from FDA for Raxibacumab Biologics License Application - November 16, 2009

Human Genome Sciences Announces New Order For Raxibacumab (ABthrax™) From U.S. Government - July 22, 2009

Data Published in the New England Journal of Medicine Support Use of Raxibacumab (ABthrax) for the Treatment of Inhalation Anthrax - July 9, 2009

Human Genome Sciences Submits Biologics License Application to FDA for ABthrax™ - May 21, 2009

Human Genome Sciences Begins Delivery of First-In-Class Anthrax Treatment to U.S. Strategic National Stockpile - February 2, 2009

New Approach to Treating Anthrax Significantly Improves Survival Rates in Pivotal Efficacy Studies - December 18, 2007

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