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.