Mechanism Of Action
Raxibacumab is a monoclonal antibody that binds the PA of
B. anthracis [see Microbiology].
The PK of raxibacumab are linear over the dose range of 1
to 40 mg/kg following single IV dosing in humans; raxibacumab was not tested at
doses higher than 40 mg/kg in humans. Following single IV administration of
raxibacumab 40 mg/kg in healthy, male and female human subjects, the mean Cmax and
AUCinfwere 1,020.3 ± 140.6 mcg/mL and 15,845.8 ± 4,333.5 mcg•day/mL,
respectively. Mean raxibacumab 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 raxibacumab.
Because the effectiveness of raxibacumab cannot be tested
in humans, a comparison of raxibacumab 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 40
mg/kg IV as a single dose for the treatment of inhalational anthrax in humans.
Humans achieve similar or greater systemic exposure (Cmax and AUCinf) to
raxibacumab following a single 40 mg/kg IV dose compared with New Zealand White
rabbits and cynomolgus macaques receiving the same dosage regimen.
Effects of Gender, Age, and Race
Raxibacumab PK were evaluated via a population PK
analysis using serum samples from 322 healthy subjects who received a single 40
mg/kg IV dose across 3 clinical trials. Based on this analysis, gender (female
versus male), race (non-white versus white), or age (elderly versus young) had
no meaningful effects on the PK parameters for raxibacumab.
Raxibacumab PK have not been evaluated in children [see
DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Although raxibacumab is intended for single dose
administration, the PK of raxibacumab following a second administration of 40
mg/kg IV given 14 days after the first 40 mg/kg IV dose was assessed in 23
healthy subjects (Study 3). The mean raxibacumab concentration at 28 days after
the second dose was approximately twice the mean raxibacumab concentration at
14 days following the first dose. In the human trial assessing the
immunogenicity of raxibacumab (Study 2), 20 healthy subjects who had initially
received a single dose of raxibacumab 40 mg/kg IV received a second 40 mg/kg IV
dose at ≥ 4 months following their first dose. No statistically
significant differences in mean estimates of AUCinf, CL, or half-life of
raxibacumab between the 2 doses administered ≥ 4 months apart were
observed. The mean Cmax following the second dose was 15% lower than the Cmax following
the first dose.
Ciprofloxacin Interaction Trial
In an open-label trial evaluating the effect of
raxibacumab on ciprofloxacin PK in healthy adult male and female subjects
(Study 1), the administration of 40 mg/kg raxibacumab IV following
ciprofloxacin IV infusion or ciprofloxacin oral tablet ingestion did not alter
the PK of ciprofloxacin administered orally and/or intravenously. Likewise,
ciprofloxacin did not alter the PK of raxibacumab. [See DRUG INTERACTIONS]
Mechanism of Action
Raxibacumab is a monoclonal antibody that binds free PA
with an affinity equilibrium dissociation constant (Kd) of 2.78 ± 0.9 nM.
Raxibacumab 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
Raxibacumab binds in vitro to PA from the Ames, Vollum,
and Sterne strains of B. anthracis. Raxibacumab binds to an epitope on
PA that is conserved across reported strains of B. anthracis.
In vivo studies in rats suggest that raxibacumab
neutralizes the toxicity due to lethal toxin, as animals slowly infused with
lethal toxin (a combination of PA + lethal factor) survived 7 days following
administration. The median time to death in control rats was 16 hours. Similar
observations were noted in animal efficacy studies in rabbits and monkeys
challenged with B. anthracis spores by the inhalational route. PA was
detected in animals following exposure to B. anthracis spores. PA levels
rose and then fell to undetectable levels in animals that responded to
treatment and survived, whereas levels continued to rise in animals that failed
treatment and died or were euthanized because of poor clinical condition. [See
Healthy cynomolgus macaques administered 3 intravenous
doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a
single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects,
including no effects up to 120 days post-dosing.
Studies with raxibacumab in rabbit, cynomolgus macaque,
and human donor tissues showed no cross reactivity with brain.
Anthrax-infected rabbits and monkeys administered an
intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia
reproducibly showed greater severity of central nervous system (CNS) lesions
(bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals
compared to dead placebo control animals, with no difference in mean time to
death from spore challenge. The raxibacumab monoclonal antibody appears unable
to penetrate the CNS until compromise of the blood-brain barrier (BBB) during
the later stages of anthrax infection. The most severe brain lesions in rabbits
were associated with bacteria and raxibacumab tissue binding in a similar
pattern as endogenous IgG antibody that leaked across the compromised BBB. No
dose/exposure-response relationship for brain histopathology was identified.
Surviving rabbits and monkeys at the end of the 28-day studies showed no microscopic
evidence of CNS lesions. CNS toxicity was not observed in healthy monkeys
administered raxibacumab (40 mg/kg) or in GLP combination treatment studies
with antibacterials in rabbits (levofloxacin) or in monkeys (ciprofloxacin) at
Because it is not feasible or ethical to conduct
controlled clinical trials in humans with inhalational anthrax, the
effectiveness of raxibacumab for therapeutic treatment of inhalational anthrax
is based on efficacy studies in rabbits and monkeys. Raxibacumab effectiveness
has not been studied in humans. Because the animal efficacy studies are
conducted under widely varying conditions, the survival rates observed in the
animal studies cannot be directly compared between studies and may not reflect
the rates observed in clinical practice.
The efficacy of raxibacumab for treatment of inhalational
anthrax was studied in a monkey model (study 2) and a rabbit model (studies 3
and 4) of inhalational anthrax disease. These 3 studies tested raxibacumab
efficacy compared to placebo. Another study in a rabbit model (study 1)
evaluated the efficacy of raxibacumab in combination with an antibacterial drug
relative to the antibacterial drug alone. Studies were randomized and blinded.
The animals were challenged with aerosolized B.
anthracis spores (Ames strain) at 200xLD50 to achieve 100% mortality if
untreated. In rabbit study 1, treatment was delayed until 84 hours after spore
challenge. In monkey study 2, study treatment commenced at the time of a
positive serum electrochemiluminescence (ECL) assay for B. anthracis PA.
The mean time between spore challenge and initiation of study treatment was 42
hours. In rabbit studies 3 and 4, sustained elevation of body temperature above
baseline for 2 hours or a positive result on serum ECL assay for PA served as
the trigger for initiation of study treatment. The mean time between spore
challenge and initiation of study treatment was 28 hours post-exposure.
Efficacy in all therapeutic studies in animals was determined based on survival
at the end of the study. Most study animals (88% to 100%) were bacteremic and
had a positive ECL assay for PA prior to treatment in all 4 studies.
Treatment Of Inhalational Anthrax In Combination With Antibacterial
The efficacy of raxibacumab administered with
levofloxacin as treatment of animals with systemic anthrax disease (84 hours
after spore challenge) was evaluated in New Zealand White rabbits (study 1).
The dose of levofloxacin was chosen to yield a comparable exposure to that
achieved by the recommended doses in humans. Levofloxacin and raxibacumab PK in
this study were unaffected by product co-administration. Forty-two percent of
challenged animals survived to treatment. Treatment with antibacterial drug
plus raxibacumab resulted in 82% survival compared to 65% survival in rabbits
treated with antibacterial drug alone, P = 0.0874 (Table 4).
Table 4: Survival Rates in NZW Rabbits in Combination
Therapy Study, All Treated Animals
||NZW Rabbits (35 days)a Study 1
|Number (%) Survivors
||95% CIc Levofloxacin versus Levofloxacin + Raxibacumab
|Levofloxacin + Raxibacumab 40 mg/kg IV single dose
|a Survival assessed 28 days after last dose of
b P value based on a two-sided likelihood ratio chi-square test.
c 95% confidence interval based on normal approximation.
Treatment Of Inhalational Anthrax
Monkey study 2 and rabbit
studies 3 and 4 evaluated treatment with raxibacumab alone at an earlier time
point after exposure than rabbit study 1. Treatment with raxibacumab alone
resulted in a statistically significant dose-dependent improvement in survival
relative to placebo when administered at the time of initial manifestations of
anthrax disease in the rabbit and monkey infection models (Table 5). Raxibacumab
at 40 mg/kg IV single dose was superior to placebo in the rabbit and monkey
studies in the all treated and the bacteremic animal analysis populations. All
surviving animals developed toxin-neutralizing antibodies.
Table 5: Survival Rates in
Animals Treated with Raxibacumab, All Treated Animals
||Cynomolgus Macaques at 28 daysa Study 2
||NZW Rabbits at 14 daysb Study 3
||NZW Rabbits at 28 daysa Study 4
|Number (%) Survivors
||Number (%) Survivors
||Number (% ) Survivors
|20 mg/kg raxibacumab
|40 mg/kg raxibacumab
|a Survival measured at 28 days after spore
b Survival measured at 14 days after spore challenge.
c P value based on two-sided Fisher's exact test for comparisons
between raxibacumab and placebo.
d 95% CIs are exact confidence intervals for the difference between
raxibacumab and placebo.
In other animal studies evaluating antibacterial drug
alone and raxibacumab-antibacterial drug combination, the efficacy of an
antibacterial drug alone (levofloxacin in rabbits and ciprofloxacin in monkeys)
was very high (95-100%) when given at the initial manifestations of
inhalational anthrax disease. The timing of treatment was similar to that
reported for studies 2, 3, and 4 above.
In another study, rabbits were exposed to 100 times LD50 B.
anthracis spores and administered raxibacumab at a single dose of 40 mg/kg
at the time of exposure, 12 hours, 24 hours, or 36 hours after exposure.
Survival was 12/12 (100%) in animals treated at time of exposure or 12 hours,
but decreased to 6/12 (50%) and 5/12 (42%) at 24 hours and 36 hours,