Added Benefit of Raxibacumab to Antibiotic Treatment of Inhalational Anthrax

Abstract

bAlthough antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P ‫؍‬ 0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n ‫؍‬ 39) than for LVX alone (13 deaths; n ‫؍‬ 37), and the survival time was prolonged for the combination (P ‫؍‬ 0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course.

Efficacy of ETI-204 Monoclonal Antibody as an Adjunct Therapy in a New Zealand White Rabbit Partial Survival Model for Inhalational Anthrax

“…A high-affinity monoclonal antibody that targets anthrax toxins would be an important therapeutic addition in the treatment of anthrax. Six other monoclonal antibodies against PA are under investigation and are aimed at targeting PA to neutralize toxin production in anthrax infection (21,28,54,55).…”

Disaster Preparedness: Biological Threats and Treatment Options

“…This surrogate end point (concentrations of raxibacumab) was based on raxibacumab dose for humans translated from effective animal doses that were predictive of survival benefit . In combination with antibiotic therapy, raxibacumab plus levofloxacin had a higher rate of survival in rabbits than levofloxacin alone (82% vs 65%; p = 0.0874; respectively), concluding that the combination may have potential benefit over antibiotics alone …”

“…36 In combination with antibiotic therapy, raxibacumab plus levofloxacin had a higher rate of survival in rabbits than levofloxacin alone (82% vs 65%; p = 0.0874; respectively), concluding that the combination may have potential benefit over antibiotics alone. 37 The newest anthrax antitoxin agent is obiltoxaximab, a human immunoglobulin G1 monoclonal antibody with a similar mechanism of action as raxibacumab. It is given as a single IV dose (16 mg/kg if more than 40 kg).…”

An overview of investigational toxin-directed therapies for the adjunctive management ofBacillus anthracisinfection and sepsis

“…In rabbits and cynomolgus monkeys challenged with aerosolized B. anthracis (Ames strain), treatment with raxibacumab, either at initial detection of circulating PA or with an increase in body temperature, improved survival significantly [39]. Compared with antibiotic treatment alone in anthrax-challenged rabbits, post-exposure treatment with raxibacumab in combination with antibiotics increased survival in a trend approaching significance (p = 0.08) [40,41]. In LT-challenged canines, raxibacumab augmented the hemodynamic and survival benefits of standard hemodynamic support [42].…”