ANTHIM Solution for injection Ref.[10346] Active ingredients: Obiltoxaximab

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 C_max and AUC_inf were 400 ± 91.2 mcg/mL and 5170 ± 1360 mcg•day/mL, respectively.

Repeat Dosing

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 AUC_inf 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 C_max, AUC_inf, CL, or half-life of obiltoxaximab between the 2 doses administered ≥4 months apart were observed.

Distribution

Mean obiltoxaximab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution.

Elimination

Clearance values were much smaller than the glomerular filtration rate, indicating that there is virtually no renal clearance of obiltoxaximab.

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 C_max and greater AUC_inf following a single 16 mg/kg IV dose compared to exposures achieved in NZW rabbits and cynomolgus macaques.

Specific Populations

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.

Pediatric Population

ANTHIM PK have not been evaluated in children [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].

Drug Interaction Studies

Ciprofloxacin

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 Interactions (7.1)].

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 toxin.

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 (14)].

Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.

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.

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).

Table 4. Survival Proportions in Monotherapy Treatment Studies of 16 mg/kg IV, All Randomized Animals Positive for Bacteremia Prior to Treatment:

IV: intravenous, CI: Confidence Interval
¹ Survival assessed 28 days after spore challenge
² p-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma=0.001) compared to placebo
³ Exact 95% confidence interval of difference in survival rates
⁴ ANTHIM 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).