Discussion
anthrax, meningeal inflammation, Anthrax Vaccine, bacteremia, infection, hemorrhage, Meningeal lesions, toxemia
ANTHRAX, SYSTEMIC DISEASE, INFLAMMATION, DISEASE, INFECTION, HEMORRHAGE, TOXEMIA
ANTHRASIL is a purified human IgG product manufactured using plasma collected from healthy donors vaccinated with AVA (Anthrax Vaccine Absorbed) and consists of polyclonal neutralizing antibodies against the PA antigen of When given after the onset of systemic disease based on the detection of PA toxin in circulation, ANTHRASIL demonstrated a statistically significant survival benefit compared to placebo control groups. The mean The treatment dose of 15 U/kg ANTHRASIL in rabbits was based on a previous dose-time range study in which animals were administered ANTHRASIL prophylactically at fixed time points (20 h or 30 h) post-exposure (The therapeutic intervention study in rabbits described here involved challenging animals with a lethal aerosol dose of This study was randomized and blinded as per Animal Rule guidance and demonstrated that ANTHRASIL-treatment significantly enhances survival compared to IGIV controls in a therapeutic setting. Treatment with ANTHRASIL significantly decreased levels of circulating PA, and the proportion of rabbits found to be toxemic post-infusion (p < 0.0001), consistent with the mechanism of action of polyclonal anti-sera directed against PA. Interestingly, two ANTHRASIL-treated rabbits that survived were positive for toxemia at the end of the study. As neither of these animals were bacteremic after treatment, it is unclear if the low levels of PA detected (> LOD of 1 ng/mL but < LLOQ of 5 ng/mL) at the end of the study were false positives.While not as quick as antimicrobials that eliminate bacteremia within 24 hours of treatment [As in the rabbit study, nonhuman primates also were individually treated with ANTHRASIL following the detection of PA in real-time. Since no dose-ranging study was conducted previously in NHPs, three doses of ANTHRASIL were evaluated in this study. Henning et al. [Consistent with observations in rabbits, treatment with ANTHRASIL after the onset of toxemia in nonhuman primates resulted in significantly enhanced survival and reduced levels of toxemia, incidence of bacteremia and clinical signs of infection. This contrasts with monoclonal antibody treatment, in which monoclonals enhanced survival but did not significantly reduce toxemia [While the gross lesions were similar between rabbits and NHPs, histopathological findings in the brain were different in NHPs, wherein a trend towards the development of meningeal inflammation was observed in the higher dose groups. Meningeal lesions in IGIV-treated control NHPs were largely confined to minimal to mild hemorrhage with no evidence of inflammation. In addition, more numerous and widespread bacteria were observed in the brains of ANTHRASIL-treated NHPs that succumbed to disease, while bacteria in the brains of IGIV-treated control NHPs were often confined to blood vessels or the immediate perivascular space. These findings are consistent with those by Migone [The lack of similar brain lesions in rabbits has been suggested by Zaucha et al. [Exposure to ANTHRASIL was confirmed in a formal PK analysis in rabbits and non-GLP post hoc PK analysis in NHPs (Overall, an improvement in survival rates was observed following a single administration of ANTHRASIL after the detection of toxemia compared to placebo in both rabbit and cynomolgus macaque models of inhalational anthrax. The improved survival in both models was associated with an immediate and efficient reduction in toxemia. This is consistent with the use of ANTHRASIL for the treatment of toxemia associated with inhalational anthrax, and modeling by Rubinson [One drawback of the NHP study is that it was not powered to detect the significant differences between different doses; however, the goal was to evaluate if a dose of ANTHRASIL that mimics the exposure in humans with the estimated clinical dose would confer significant protection over the control group. Further, determining differences between treatment groups would require a very high number of nonhuman primates which is prohibitive for ethical reasons. Further, since these studies were conducted with a focus on meeting the regulatory requirements for drug approval, no detailed pathophysiological mechanisms were explored for the observed differences in brain lesions between rabbits and NHPs.It should also be noted that the studies described in this report involved a very high challenge dose and relied on a single dose of ANTHRASIL for efficacy, representing the most stringent model for product evaluation and yet significantly improved survival was observed after treatment with ANTHRASIL. In a clinical scenario, where patients receive a multitude of therapies, even better treatment outcome could be expected.Based on the work presented here, ANTHRASIL was approved by FDA in 2015 [