ABthrax(TM) Safe and Effective against Anthrax
Jul 25, 2005, 11:13, Reviewed by: Dr.
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"This report describes the first investigational agent against inhalational anthrax infection to be evaluated in a clinical study since the 2001 anthrax attacks in the United States. We have shown that ABthrax can be safely administered, is well tolerated, and is able to achieve levels of concentration in the blood that are comparable to levels that correlated with significant protection in relevant animal models of inhalational anthrax. Preclinical studies in relevant animal models have demonstrated the dose-related efficacy of ABthrax in both prevention and treatment of anthrax disease.
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By Human Genome Sciences,
Human Genome Sciences, Inc. (HGSI) announced today that results published in the current issue of Clinical Infectious Diseases demonstrate that the first investigational agent against anthrax infection to be evaluated in a clinical study since the 2001 anthrax attacks in the United States, is safe, well tolerated and achieves the blood levels predicted by relevant animal models as necessary to afford significant protection from the lethal effects of the anthrax toxin.(1, 2)
ABthrax(TM), a fully human monoclonal antibody to Bacillus anthracis protective antigen, was studied in a randomized, single-blind, placebo- controlled, dose-escalation Phase 1 clinical trial in 105 healthy adult volunteers. The trial was designed to evaluate the safety, pharmacokinetics and biological activity of ABthrax.(3)
The subjects received a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort) of either ABthrax or placebo. Three intramuscular (0.3, 1.0 and 3.0 mg/kg) and five intravenous (1.0, 3.0, 10.0, 20.0 and 40.0 mg/kg) dose levels were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated. The primary endpoints of the Phase 1 trial were safety and tolerability. Pharmacokinetics, immunogenicity and parameters of biological activity also were evaluated.
Results show that ABthrax was safe, well tolerated and bioavailable after a single intramuscular or intravenous dose, with no dose-limiting adverse events. Only transient, mild-to-moderate adverse events were observed, with no statistically significant difference in adverse event profiles between active and placebo arms of the study. Pharmacokinetic analysis demonstrated that the half-life of ABthrax ranged from 15 to 19 days. The biological activity of ABthrax correlated with serum concentrations. In the Phase 1 study, ABthrax concentrations were achieved that are comparable to, or in excess of, anti-protective antigen antibody levels that correlated with significant protection in relevant animal models of inhalational anthrax.
Mani Subramanian, M.D., lead author and Director of Clinical Research, Infectious Diseases, said, "This report describes the first investigational agent against inhalational anthrax infection to be evaluated in a clinical study since the 2001 anthrax attacks in the United States. We have shown that ABthrax can be safely administered, is well tolerated, and is able to achieve levels of concentration in the blood that are comparable to levels that correlated with significant protection in relevant animal models of inhalational anthrax. Preclinical studies in relevant animal models have demonstrated the dose-related efficacy of ABthrax in both prevention and treatment of anthrax disease.(4-10) The results of one such study showed that nonhuman primates that survived anthrax spore exposure following a single dose of ABthrax produced a robust immune response against the anthrax toxin that persisted at six months and nearly a year later.(6) Based on the results of the Phase 1 study, as well as the strongly supportive results of studies in relevant animal models of inhalational anthrax, we believe that further expanded safety studies with a larger number of subjects are warranted, as well as additional combination studies of ABthrax with antibiotic and vaccine agents."
James H. Davis, Ph.D., J.D., Executive Vice President and General Counsel, said, "We have advanced ABthrax to this point using our company's own resources and at our own risk, without receiving any financial assistance from the government. Guidelines were set forth in the Bioterrorism Act of 2002(11) for the development of treatments for disease organisms such as anthrax, which have high potential for use in bioterrorist attacks. The Bioterrorism Act recognizes that there is no practical way to conduct a clinical trial of the efficacy of a drug designed to treat a disease such as anthrax, which only rarely occurs in humans. The Bioterrorism Act states that successful studies in relevant animal models will be considered sufficient to establish efficacy for licensure and marketing approval, and states that a clinical trial in humans will be required to establish safety. In accordance with the Bioterrorism Act and consistent with current FDA guidance, we have shown in animals that ABthrax is effective against high doses of inhalation anthrax, and we have demonstrated initial safety in humans. In addition, we have developed the required assays and a scalable purification process that will enable Human Genome Sciences to manufacture the drug.(12)
"We have been ready to begin manufacturing of this product and to initiate additional human safety trials for over a year and a half, but the cost of the next phase of development is much too high for any biopharmaceutical company to undertake on a speculative basis. To move forward with further development of ABthrax, we need to bring to a favorable conclusion the lengthy procurement process now underway, and for the federal government to enter into a contract under the Project Bioshield Act of 2004 for the purchase of the drug for the Strategic National Stockpile. Once a contract is signed, and depending on the government's requirements, this key biodefense countermeasure could be available for emergency use in approximately one year from the date of a firm order."
The Need for New Means to Fight Anthrax Infections
Currently, two options are 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 first doses before immunity is detectable. The vaccine also requires multiple injections over a period of eighteen months, in addition to annual boosters, to maintain its protective effect. 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 do not provide the opportunity for development of protective immunity to future exposures. Antibiotics also may not be effective against antibiotic-resistant strains of anthrax.
In ABthrax, Human Genome Sciences discovered and developed 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 lethal toxins produced by anthrax bacteria. It may also prevent and treat infections by antibiotic-resistant strains of anthrax.
ABthrax is a human monoclonal antibody to Bacillus anthracis protective antigen that was discovered and developed by Human Genome Sciences. ABthrax was developed using technology that Human Genome Sciences has integrated into the Company as part of its collaboration with Cambridge Antibody Technology.(13) In 2003, ABthrax received a Fast Track Product designation from the FDA.(14)
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.(15) Research has shown that protective antigen is the key facilitator in the progression of anthrax infection at the cellular level.(15-17) After protective antigen and the anthrax toxins 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 the anthrax toxins to enter the cells. ABthrax blocks the binding of protective antigen to cell surfaces and prevents the anthrax toxins from entering and killing the cells. 
- The results are published in the current issue of Clinical Infectious Diseases
www.hgsi.com
For more information about ABthrax, see
http://www.hgsi.com/products/ABthrax.html.
For more information about anthrax, please visit the Centers for Disease Control and Prevention (CDC) web
site on bioterrorism and anthrax at
http://www.bt.cdc.gov/agent/anthrax/index.asp.
For more information about the FDA's Fast Track Drug Development Programs, see http://www.fda.gov.
Health professionals interested in more information about trials involving HGSI products are encouraged to inquire via the Contact Us section of the Human Genome Sciences web site, http://www.hgsi.com/products/request.html, or
by calling (240) 314-4400, extension 3550.
Human Genome Sciences is a company with the mission to discover, develop, manufacture and market innovative drugs that serve patients with unmet medical needs, with a primary focus on protein and antibody drugs.
ABthrax, HGS and Human Genome Sciences are trademarks of Human Genome Sciences, Inc.
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences' current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the Company's unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, the Company's ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with planned facilities, intense competition, the uncertainty of patent and intellectual property protection, the Company's dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today's date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
Footnotes:
1. Subramanian GM, et al. A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen in healthy volunteers. Clinical Infectious Diseases 2005: 41.
2. The article in Clinical Infectious Diseases is based on data previously presented at the American Society of Microbiology Biodefense Meeting in March 2004: Subramanian GM, et al. ABthrax (PAmAb) -- a novel fully human monoclonal antibody against protective antigen of B. anthracis: results of a Phase 1 dose-escalation study in
healthy human subjects. American Society of Microbiology Biodefense Meeting, 2004: Abstract 158D.
3. (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.
4. Cui X, Li Y, et al. Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis. Journal of Infectious Diseases February 1, 2005.
5. Beebe L, 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, 2004: Abstract 167G.
6. Zmuda JF, 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, 2004:
Abstract 65H.
7. 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, 2004: Abstract 168G.
8. Zhang X, Laird M, Choi G, 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.
9. Beebe L, Zhong J, 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.
10. (HGSI Press Release) Human Genome Sciences Describes Activity of ABthrax(TM) at 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. September 15, 2003.
11. Public Health Security And Bioterrorism Preparedness And Response Act Of 2002: Section 123.
http://www.fda.gov/oc/bioterrorism/PL107-188.html
12. Kahn D. Development and characterization of a scalable purification process for ABthrax. American Society of Microbiology Biodefense Meeting, 2004: Abstract 169G.
13. (HGSI Press Release) Human Genome Sciences Catapults to Leadership in Genomics-Based Human Antibody Product Development. February 29, 2000.
14. (HGSI Press Release) Human Genome Sciences Receives Fast Track Product Designation for ABthrax for Prevention and Treatment of Anthrax Infections. August 19, 2003.
15. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA May, 2002.
16. Wein LM, Craft DL, Kaplan EH. Emergency response to an anthrax attack. PNAS April 1, 2003.
17. Webb GF. A silent bomb: The risk of anthrax as a weapon of mass destruction (Commentary). PNAS April 15, 2003.
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