Mechanism Of Action
Obiltoxaximab is a monoclonal antibody that binds the PA
of B. anthracis [see Microbiology].
The PK of obiltoxaximab are linear over the dose range of
4 mg/kg (0.25 times the lowest recommended dose) to 16 mg/kg following single
IV administration in healthy subjects. Following single IV administration of ANTHIM
16 mg/kg in healthy, male and female human subjects, the mean Cmax and AUCinf were
400 ± 91.2 mcg/mL and 5170 ± 1360 mcg•day/mL, respectively.
Although ANTHIM is intended for single dose
administration, the PK of obiltoxaximab following a second dose administration
of 16 mg/kg IV given 2 weeks or ≥ 4 months after the first 16 mg/kg IV
dose was assessed in 65 healthy subjects (study 2). The obiltoxaximab AUCinf following
two 16 mg/kg doses 2 weeks apart was approximately twice that after a single 16
mg/kg dose on Day 1 or Day 120. No significant differences in mean estimates of
Cmax, AUCinf, CL, or half-life of obiltoxaximab between the 2 doses
administered ≥ 4 months apart were observed.
Mean obiltoxaximab steady-state volume of distribution
was greater than plasma volume, suggesting some tissue distribution.
Clearance values were much smaller than the glomerular
filtration rate, indicating that there is virtually no renal clearance of
Because the effectiveness of ANTHIM cannot be evaluated
in humans, a comparison of ANTHIM exposures achieved in healthy human subjects
to those observed in animal models of inhalational anthrax in therapeutic efficacy
studies is necessary to support the dosage regimen of 16 mg/kg IV as a single
dose for the treatment of inhalational anthrax in humans. Based on observed and
simulated data, humans achieve similar obiltoxaximab Cmax and greater AUCinf following
a single 16 mg/kg IV dose compared to exposures achieved in NZW rabbits and
Gender, Age, and Race
ANTHIM PK were evaluated via a population PK analysis
using serum samples from 303 healthy adult subjects who received a single IV
dose across 3 clinical trials. Based on this analysis, gender (female versus
male), race (non-Caucasian versus Caucasian), or age (elderly versus young) had
no meaningful effects on the PK parameters for ANTHIM.
ANTHIM PK have not been evaluated in children [see DOSAGE
AND ADMINISTRATION and Use In Specific Populations].
Drug Interaction Studies
In an open-label study evaluating the effect of
ciprofloxacin on obiltoxaximab PK in healthy adult male and female subjects
(study 3), the administration of 16 mg/kg ANTHIM IV infusion prior to
ciprofloxacin IV infusion or ciprofloxacin oral tablets twice daily did not
alter the PK of obiltoxaximab. Likewise, obiltoxaximab did not alter the PK of
ciprofloxacin administered orally and/or intravenously [see DRUG
Mechanism Of Action
Obiltoxaximab is a monoclonal antibody that binds free PA
with an affinity equilibrium dissociation constant (Kd) of 0.33 nM. Obiltoxaximab
inhibits the binding of PA to its cellular receptors, preventing the
intracellular entry of the anthrax lethal factor and edema factor, the
enzymatic toxin components responsible for the pathogenic effects of anthrax
Activity In Vitro And In Vivo
Obiltoxaximab binds in vitro to PA from the Ames, Vollum,
and Sterne strains of B. anthracis. Obiltoxaximab binds to an epitope on
PA that is conserved across reported strains of B. anthracis.
In vitro studies in a cell-based assay, using murine macrophages,
suggest that obiltoxaximab neutralizes the toxic effects of lethal toxin, a
combination of PA + lethal factor.
In vivo efficacy studies in NZW rabbits and cynomolgus
macaques challenged with the spores of the Ames strain of B. anthracis by
the inhalational route, showed a dose-dependent increase in survival following treatment
with ANTHIM. Exposure to B. anthracis spores resulted in increasing
concentrations of PA in the serum of NZW rabbits and cynomolgus macaques. After
treatment with ANTHIM there was a decrease in PA concentrations in a majority
of surviving animals. PA concentrations in placebo animals increased until they
died [see Clinical Studies].
Animal Toxicology And/Or Pharmacology
Central nervous system (CNS) lesions (bacteria,
inflammation, hemorrhage and occasionally necrosis) were seen in
anthrax-infected non-surviving NZW rabbits and cynomolgus macaques administered
IV obiltoxaximab ( ≥ 4 mg/kg) or control at the time of disease
confirmation. Microscopic changes in the non-surviving animals that received
obiltoxaximab were due to the presence of extravascular bacteria and not the
effect of obiltoxaximab. No dose response relationship for brain histopathology
was identified. No treatment-related brain lesions were shown in
anthrax-infected surviving NZW rabbits (at day 28) or cynomolgus macaques (up to
day 56) after a single administration of obiltoxaximab at doses up to 16 mg/kg
and up to 32 mg/kg/dose, respectively. No obiltoxaximab-related neurobehavioral
effects were observed in surviving anthrax-infected cynomolgus macaques
following treatment with obiltoxaximab.
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.
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.
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
Table 4: Survival Proportions in Monotherapy Treatment
Studies of 16 mg/kg IV, All Randomized Animals Positive for Bacteremia Prior to
||Proportion of Survival at Day 281 (# survived/n)
||ANTHIM 16 mg/kg IV
||31% (5/16) 35% (6/17)
||(0.08, 0.59) (0.11, 0.62)
|IV: intravenous, CI: Confidence Interval
1Survival assessed 28 days after spore challenge
2p-value is from 1-sided Boschloo Test (with Berger-Boos
modification of gamma=0.001) compared to placebo
3Exact 95% confidence interval of difference in survival rates
4ANTHIM products manufactured at two different facilities were
tested in two separate treatment arms
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).