Human Genome Sciences, Inc. (HGSI) announced that the results of a Phase 1 clinical trial demonstrate that ABthrax (human monoclonal antibody to Bacillus anthracis protective antigen) is safe and well tolerated in healthy volunteers, and achieved the blood levels predicted by relevant animal models as necessary to afford significant protection from the lethal effects of the anthrax toxin. Company scientists presented the Phase 1 clinical trial data at the American Society of Microbiology (ASM) Biodefense Meeting, which is currently underway in Baltimore.
Human Genome Sciences also presented the results of recently completed preclinical studies in rabbit models of inhalation anthrax, which demonstrate that a single dose of ABthrax administered following anthrax spore challenge increases survival significantly. Results of preclinical studies presented in September 2003 demonstrate that a single dose of ABthrax administered prior to spore challenge increases survival significantly in both rabbit and nonhuman primate models of inhalational anthrax.
The Phase 1 placebo-controlled, dose-escalation clinical trial, which enrolled 105 subjects, was designed to evaluate the safety, tolerability and pharmacokinetics of ABthrax in healthy adults. The subjects received a single intramuscular (IM) injection (11 subjects/cohort) or intravenous (IV) infusion (10 subjects/cohort) of either ABthrax or placebo. Three IM (0.3, 1 and 3 mg/kg) and five IV (1, 3, 10, 20 and 40 mg/kg) doses were studied. Two separate IM 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 is safe and well tolerated, with only transient, mild-to-moderate adverse events observed, and with no statistically significant difference in adverse event profiles between active and placebo arms of the study. No dose-related increases in adverse events were observed. Pharmacokinetic analysis shows that the half-life of ABthrax is 15 to 20 days following IV administration and 15 to 22 days following IM administration. 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.
David C. Stump, M.D., executive vice president, Drug Development, said, "Results of the Phase 1 clinical trial in healthy adults demonstrate that ABthrax has an excellent safety and pharmacological profile. The doses and routes of administration evaluated achieved the blood levels of ABthrax predicted in animal studies to afford protection. Together with the mounting evidence of the efficacy of ABthrax in relevant animal models of inhalational anthrax, these results provide strong support for the potential of ABthrax to provide significant survival benefit with minimal side effects in the event of an anthrax attack. The next step would be to advance ABthrax into a larger, more definitive clinical safety trial in healthy volunteers."
Data were presented on two studies in rabbit models of inhalational anthrax, which were designed to evaluate the therapeutic potential of ABthrax.1 The studies evaluated the time course of intervention and the dose-response at a fixed time after an inhalation anthrax spore challenge, respectively. Results demonstrate that a single dose of ABthrax administered intravenously immediately after anthrax spore exposure or at 12 hours post-anthrax spore exposure provides complete protection. A single dose of ABthrax administered intravenously at 24 and 36 hours post-anthrax spore exposure showed an intervention time-related response in survival. Results of the second study show a significant dose-response relationship when ABthrax is administered at 24 hours post-anthrax spore exposure.
Another poster described the results of a study designed to evaluate the native immune response to anthrax Protective Antigen (PA) in nonhuman primates that survived a previous study in which they had been administered a single dose of ABthrax prior to exposure to anthrax. The presence of host-derived anti-PA antibodies and the presence of neutralizing antibodies against PA were evaluated at six months and at nearly one year following initial anthrax exposure. Results indicate that nonhuman primates that had been administered a single dose of ABthrax prior to anthrax spore exposure produce a robust immune response against PA that persists at six months and nearly a year later, with a majority developing antibodies that specifically neutralize PA activity. To evaluate the ability of the de novo immune response to protect animals against a second anthrax exposure, animals were re-challenged with lethal doses of anthrax spores. Results show that all of the nonhuman primates that were re-challenged were afforded complete protection by the immune response against PA. These results suggest that when a single dose of ABthrax is administered prior to anthrax exposure, not only does the drug provide a significant survival benefit, but it also does not interfere with the ability of an individual to recognize and mount a protective immune response against PA. The study's results demonstrate that such an immune response can continue to provide complete protection against anthrax for up to one year.
Additional posters were presented that described, respectively, the development of a relevant bioassay for determining the sustained biological activity of ABthrax during clinical trials, and the development of a process for large-scale manufacturing of ABthrax -- both of which are vital to the further development of ABthrax, and, ultimately, to the submission of a Biologics License application (BLA) to the FDA.
Craig A Rosen, Ph.D., president, Research and Development, said, "We have conducted multiple preclinical studies in relevant animal models, which demonstrate the dose-related efficacy of ABthrax in both prevention and treatment of anthrax infections. The results of a recently completed preclinical study in nonhuman primates demonstrate that, in addition to providing a significant survival benefit, ABthrax does not interfere with the ability of the native immune system to produce a robust and prolonged immune response against anthrax protective antigen. We have developed the required assays and a scalable purification process that will enable Human Genome Sciences to manufacture the drug. We have completed an initial Phase 1 clinical trial that demonstrates the safety and tolerability of ABthrax in healthy adults. We have achieved these goals using our Company's own resources. Further development, including a larger confirmatory clinical safety trial and completion of the manufacturing scale-up required for production of ABthrax, will require a much higher level of investment. Our ability to develop ABthrax further is now dependent on the government's willingness to commit to the purchase of ABthrax."
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 initially established. 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.
Under the Bioterrorism Act of 2002, the FDA specified the evidence required to demonstrate the efficacy of new drug and biological products used to counter biological agents, when traditional efficacy studies in humans are not feasible. According to the guidelines set forth in the Bioterrorism Act, successful studies in relevant animal models will be considered sufficient to establish efficacy for licensure and marketing approval. A clinical trial will be required to establish safety. In accordance with the current FDA guidance, Human Genome Sciences has demonstrated the preventive and therapeutic efficacy of ABthrax in multiple preclinical studies in relevant animal models of inhalational anthrax, and has demonstrated the safety and tolerability of ABthrax in a Phase 1 clinical trial in healthy adults.
William A. Haseltine, Ph.D., chairman and CEO, said, "I would like to commend everyone at Human Genome Sciences who has contributed to the rapid discovery and development of ABthrax. With our own resources, we developed a human monoclonal antibody drug that we have now demonstrated is safe and effective in preventing and treating anthrax infections. The scientific and clinical data to date clearly support the continued development of ABthrax, and demonstrate that it has significant potential to play an important prophylactic and therapeutic role in fighting anthrax infections. We were able to make such rapid progress because we have all of the relevant technology in house, including expertise in the creation of human monoclonal antibodies with desired medical properties, as well as antibody manufacturing capabilities.
"The next steps in the development of ABthrax require a much greater investment, one that we cannot undertake without the expectation that success will bring a suitable return. Our ability to move forward with large-scale development and manufacture of ABthrax is dependent on the government's willingness to commit to purchasing it, either under existing authority or under Project BioShield, which is pending passage in the U.S. Senate. Until such a commitment is made, we plan to focus on continuing the development of the other products in our clinical pipeline, including drugs to fight cancer, lupus, rheumatoid arthritis, and hepatitis C."
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 U.S. Food and Drug Administration (FDA). ABthrax used for preclinical and clinical studies was produced in the Company's manufacturing facilities in Rockville, Maryland.
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.