title: Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.
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.
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Yamamoto
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Shadiack
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Carpenter
authors.affiliation: Battelle, West Jefferson, Ohio, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sanford
authors.affiliation: Battelle, West Jefferson, Ohio, USA.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Henning
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: O'Connor
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Nestor
authors.initials: N
authors.lastname: Gonzales
authors.affiliation: Metrum Research Group LLC, Tarrifville, Connecticut, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mondick
authors.affiliation: Metrum Research Group LLC, Tarrifville, Connecticut, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: French
authors.affiliation: Battelle, West Jefferson, Ohio, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Stark
authors.affiliation: BDM Consulting, Inc., Somerset, New Jersey, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Fisher
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Casey
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey, USA nserbina@elusys.com.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Serbina
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000992:Antitoxins / Q000494:pharmacology*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000992:Antitoxins; C000611266:obiltoxaximab