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.

Disaster Preparedness: Biological Threats and Treatment Options

“…It is given as a single IV dose (16 mg/kg if more than 40 kg) . Multiple animal treatment studies of rabbits and monkeys demonstrate significant improvement in survival with obiltoxaximab alone relative to placebo . In rabbits receiving 16 mg/kg, survival in two studies were 61.5% and 92.9%, which was significantly improved compared with no survivors in those given placebo (p = 0.0013 and p = 0.001, respectively).…”

“…In the macaque studies, survival with obiltoxaximab treatment (doses 4–32 mg/kg) ranged from 6.3–78.6%. The authors of the study concluded that varying survival rates were associated with infection severity and time to treatment administration . Also survival was higher when obiltoxaximab was given in combination with antibiotics as compared with antibiotic therapy alone for treatment of inhalational anthrax…”

“…The authors of the study concluded that varying survival rates were associated with infection severity and time to treatment administration. 39 Also survival was higher when obiltoxaximab was given in combination with antibiotics as compared with antibiotic therapy alone for treatment of inhalational anthrax. 33 The CDC recommends the addition of an antitoxin in combination with antibiotic treatment for any patient with high suspicion of systemic anthrax.…”

Safety, Pharmacokinetics, and Immunogenicity of Obiltoxaximab After Intramuscular Administration to Healthy Humans

“…Obiltoxaximab was developed under the US Food and Drug Administration's Animal Rule regulation (21 CFR 601.90), which is specifically intended for agents for which the conduct of definitive human efficacy studies is not ethical or feasible, as in the case of agents for the treatment of anthrax . The obiltoxaximab intravenous dose of 16 mg/kg was selected and justified based on efficacy data in animals and pharmacokinetic (PK) data in animals and healthy human volunteers, as well as population modeling of PK and efficacy data …”

“…9 The obiltoxaximab intravenous dose of 16 mg/kg was selected and justified based on efficacy data in animals and pharmacokinetic (PK) data in animals and healthy human volunteers, as well as population modeling of PK and efficacy data. [10][11][12] Efficacy following intramuscular administration of obiltoxaximab for pre-and postexposure prophylaxis of inhalational anthrax has previously been demonstrated in animals. 13 In this study we investigated the safety, PK, and immunogenicity of obiltoxaximab following intramuscular administration to healthy adult subjects.…”