Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

Brent J Yamamoto,Gregory V Stark,Natalya V Serbina,Leslie S Casey,Lisa N Henning,Daniel Sanford,Edward O'Connor,Alan C Fisher,Annette M Shadiack,Jonathan French,John Mondick,Sarah Carpenter,Nestor Gonzales

doi:10.1128/aac.00972-16

Abstract

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.

Highlights

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are recommended as an adjunct to standard antimicrobial regimens
Treatment was triggered by PAECL in 35.3 to 66.7% and 14.3 to 35.7% of rabbits in studies R1 and R2, respectively, with the rest of the animals triggering by significant increase in body temperature (SIBT) (Table 1)
Efficacy of a toxin-neutralizing monoclonal antibody, obiltoxaximab, was investigated in a series of studies conducted in two well-characterized animal models of inhalational anthrax, New Zealand White (NZW) rabbit and cynomolgus macaque models [22, 23], which have been accepted as a basis of approval under the Food and Drug Administration (FDA’s) Animal Rule [20]

Summary

Introduction

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P ‫ ؍‬0.0085, P ‫ ؍‬0.0053, P ‫ ؍‬0.0068). Inhalational anthrax is often fatal, despite treatment with antibiotics, because of rapid progression to bacteremia and toxemia [8, 9]. Obiltoxaximab efficacy was evaluated in two well-characterized animal models for inhalational anthrax, New Zealand White (NZW) rabbit [22] and cynomolgus macaque [23], in studies designed to mimic human clinical trials. Survival data were integrated with a modeling approach to understand the impact of disease progression on obiltoxaximab-mediated survival and to predict the monotherapy window of effectiveness

Methods

Results

Conclusion