Overview   
Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the efficacy of ANTHIM for the treatment of inhalational anthrax is based on efficacy studies in NZW rabbits and cynomolgus macaques. The animal efficacy studies are conducted under widely varying conditions, such that the survival rates observed in the animal studies cannot be directly compared between studies and may not reflect the rates observed in clinical practice.

Types of Studies   
The efficacy of ANTHIM for treatment and prophylaxis of inhalational anthrax was studied in multiple studies in the cynomolgus macaque and NZW rabbit models of inhalational anthrax. These studies tested the efficacy of ANTHIM compared to placebo and the efficacy of ANTHIM in combination with antibacterial drugs relative to the antibacterial drugs alone.

Study Design   
The animals were challenged with aerosolized B. anthracis spores (Ames strain) at approximately 200xLD50 to achieve 100% mortality if untreated. In prophylaxis studies of inhalational anthrax, animals were treated prior to the development of symptoms. In treatment studies, animals were administered treatment after exhibiting clinical signs or symptoms of systemic anthrax. Cynomolgus macaques were treated at the time of a positive serum electrochemiluminescence (ECL) assay for B. anthracis PA at a mean time of approximately 40 hours post-challenge with B. anthracis. In NZW rabbit treatment studies, animals were treated after a positive ECL assay for PA or sustained elevation of body temperature above baseline, at a mean time of approximately 30 hours post-challenge; the majority of animals triggered by temperature. In some of the treatment studies assessing the effect of ANTHIM in combination with antibacterial drugs, treatment was delayed to 72 to 96 hours post-challenge. Most study animals were bacteremic and had a positive ECL assay for PA prior to treatment. Survival was assessed at 28 days post-challenge with B. anthracis in most studies.

Results   
NZW rabbit studies 1 and 2 and cynomolgus macaque studies 3 and 4 evaluated treatment with ANTHIM 16 mg/kg IV single dose compared to placebo in animals with systemic anthrax. Treatment with ANTHIM alone resulted in statistically significant improvement in survival relative to placebo (Table 4).

ANTHIM administered in combination with antibacterial drugs (levofloxacin, ciprofloxacin and doxycycline) for the treatment of systemic inhalational anthrax disease resulted in higher survival outcomes than antibacterial therapy alone in multiple studies where ANTHIM and antibacterial therapy was given at various doses and treatment times.

ANTHIM administered as prophylaxis resulted in higher survival outcomes compared to placebo in multiple studies where treatment was given at various doses and treatment times. In one study, cynomolgus macaques were administered ANTHIM 16 mg/kg at 18 hours, 24 hours or 36 hours after exposure. Survival was 6/6 (100%) at 18 hours, 5/6 (83%) at 24 hours, and 3/6 (50%) at 36 hours. Another cynomolgus macaque study evaluated ANTHIM 16 mg/kg administered 72, 48 or 24 hours prior to exposure. Survival was 100% at all three time points (14/14, 14/14, 15/15, respectively) at day 56 (end of study).