Human Genome Sciences has announced 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.
ABthrax, 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. 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.
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. 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 200211 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, w e 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.
“ 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. In 2003, ABthrax received a Fast Track Product designation from the FDA.
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 protective antigen is the key facilitator in the progression of anthrax infection at the cellular level. 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.