Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: SFL Pharmaceuticals Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany
Pharmacotherapeutic group: Immune sera and immunoglobulins, specific immunoglobulins
ATC code: J06BB22
Obiltoxaximab is a monoclonal antibody that binds the protective antigen (PA) of B. anthracis. Obiltoxaximab inhibits the binding of PA to its cellular receptors, preventing the intracellular entry of the anthrax lethal factor and oedema factor, the enzymatic toxin components responsible for the pathogenic effects of anthrax toxin.
Obiltoxaximab binds free PA with an affinity equilibrium dissociation constant (Kd) of 0.33 nM. In vitro, obiltoxaximab binds to PA from the Ames, Vollum, and Sterne strains of B. anthracis. The epitope on PA to which obiltoxaximab binds is conserved across reported strains of B. anthracis.
In vitro studies in a cell-based assay, using murine macrophages, suggest that obiltoxaximab neutralises the toxic effects of lethal toxin, a combination of PA + lethal factor.
In vivo efficacy studies in New Zealand White (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 obiltoxaximab. Exposure to B. anthracis spores resulted in increasing concentrations of PA in the serum of NZW rabbits and cynomolgus macaques. After treatment with obiltoxaximab there was a decrease in PA concentrations in a majority of surviving animals. PA concentrations in placebo animals increased until they died.
Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the efficacy of obiltoxaximab administered as monotherapy compared with placebo for the treatment of inhalational anthrax is based on efficacy studies in NZW rabbits and cynomolgus macaques.
In these studies, the animals were challenged with aerosolised B. anthracis spores (Ames strain) at approximately 200xLD50 and thereafter treated with obiltoxaximab at different time points. In treatment studies of inhalational anthrax, animals were administered treatment after exhibiting clinical signs or symptoms of systemic anthrax. In post-exposure prophylaxis studies, animals were treated following exposure to B. anthracis but prior to the development of symptoms. 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. Survival was assessed at 28 days post-challenge with B. anthracis in studies described below.
The efficacy of a single intravenous dose of obiltoxaximab as monotherapy for the treatment of inhalational anthrax was evaluated in one study in NZW rabbit studies and three studies in cynomolgus macaques (AP202, AP204 and AP301); all studies were placebo-controlled, randomized, and GLP-compliant. Studies AR033, AP202 and AP301 were blinded; study AP204 was blinded to group.
Table 5. Survival rates in monotherapy efficacy studies with obiltoxaximab (16 mg/kg):
| Proportion of survival at end of study (% [survived/n]) | p-value2 | 95% CI3 | |||
|---|---|---|---|---|---|
| Placebo | Obiltoxaximab 16 mg/kg | ||||
| Treatment – NZW rabbits | |||||
| Study AR0331 | 0 (0/13) | 61.5% (8/13) | 0.0013* | (0.290, 0.861) | |
| Treatment – Cynomolgus macaques | |||||
| Study AP2041 | 6% (1/16) | 46.7% (7/15) | 0.0068* | (0.089, 0.681) | |
| Study AP2021 | 0 (0/17) | 31.3% (5/16) | 0.0085* | (0.079, 0.587) | |
| Post-exposure prophylaxis – Cynomolgus macaques | |||||
| Study AP3014 | 18 h after exposure | 0 (0/6) | 100% (6/6) | 0.0012* | (0.471, 1.000) |
| 24 h after exposure | -- | 83% (5/6) | 0.0042* | (0.230, 0.996) | |
| 36 h after exposure | -- | 50% (3/6) | 0.0345 | (-0.037, 0.882) | |
CI: Confidence Interval
1 Survival assessed 28 days after spore challenge, all randomised animals positive for bacteraemia prior to treatment, treatment triggered by a significant increase in body temperature (study AR033) or by a positive result in the protective antigen-electrochemiluminescence assay (studies AP204 and AP202).
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 Survival assessed 28 days after spore challenge
* Denotes statistical significance at the 0.025 level
The European Medicines Agency has deferred the obligation to submit the results of studies with NYXTHRACIS in one or more subsets of the paediatric population in the treatment of bacillary infection (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease and for ethical reasons it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The pharmacokinetics 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 intravenous administration in healthy subjects. Following single intravenous administration of obiltoxaximab 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. The half-life of obiltoxaximab was approximately 20 days (mean).
Mean obiltoxaximab steady-state volume of distribution was 79.7 ± 19.2 mL/kg and greater than plasma volume, suggesting some tissue distribution.
No formal metabolism studies have been conducted with obiltoxaximab. However, the disposition of monoclonal antibodies generally involves distribution beyond the vascular space with potential uptake into tissues, and catabolism by proteases to small peptides and amino acids which are subsequently incorporated into the endogenous pool or excreted.
Mean obiltoxaximab clearance values were 3.35 ± 0.932 mL/d/kg and much smaller than the glomerular filtration rate, indicating that there is virtually no renal clearance of obiltoxaximab.
Obiltoxaximab PK were evaluated via a population PK analysis using serum samples from 370 healthy subjects who received a single intravenous dose across 4 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 obiltoxaximab. However, clinical studies of obiltoxaximab did not include sufficient numbers of subjects aged 65 years and over to determine whether their PK differs from younger subjects. Of the 320 subjects in clinical studies of obiltoxaximab, 9.4% (30/320) were 65 years and over, while 2% (6/320) were 75 years and over.
Clearance at a high body weight (109 kg) was approximately 38% higher than in a reference population. Following weight-based dosing (16 mg/kg) this results in an increase in AUCinf of 12%, which is not clinically meaningful.
Obiltoxaximab pharmacokinetics have not been evaluated in children. The dosing recommendations in Table 2 (section 4.2) are derived from simulations using a population PK approach designed to match the observed adult exposure to obiltoxaximab at a 16 mg/kg dose.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity to reproduction and development.
Central nervous system (CNS) lesions (bacteria, inflammation, haemorrhage and occasionally necrosis) were seen in anthrax-infected non-surviving NZW rabbits and cynomolgus macaques administered intravenously 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 anthraxinfected 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 neurobehavioural effects were observed in surviving anthrax-infected cynomolgus macaques following treatment with obiltoxaximab.
A single embryonic-fetal development study was conducted in pregnant, healthy NZW rabbits administered 4 intravenous doses of obiltoxaximab up to 32 mg/kg (2 times the human dose on a mg/kg basis) on gestation days 6, 10, 13, and 17. No evidence of harm to the pregnant dam or the foetuses due to obiltoxaximab was observed. Cumulative exposures in NZW rabbits (10,000 mcg•day/mL) at the NOAEL of 32 mg/kg/dose (n=4 doses) based on AUC0-15days were approximately two-fold the human male and female combined mean AUC at the clinical intravenous dose of 16 mg/kg. Cmax values following a 32 mg/kg/dose were 1180 mcg•day/mL.
Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.
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