Anthim
obiltoxaximab
Species
MonkeyRat
Longest study
1 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“General toxicology studies were performed in rats and cynomolgus monkeys.”
Why that species
Exogenous bacterial target; similar tissue cross-reactivity in human, rat and monkey supported both species as relevant models
“The study and peer review pathologists stated that the data demonstrated that both the rat and cynomolgus monkey were appropriate and relevant models for toxicity testing of ETI-204.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats, cynomolgus monkeys and rabbits
“General toxicology studies were performed in rats and cynomolgus monkeys.”
Species: general tox
Rat and cynomolgus monkey
“General toxicology studies were performed in rats and cynomolgus monkeys.”
Species: DART
Rabbit (EFD, pilot and definitive); fertility not studied
“Two studies, a pilot study and a definitive study, were performed in rabbits.”
Species: carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Surrogate used in
No surrogate used; clinical antibody tested in rats, cynomolgus monkeys and rabbits
“General toxicology studies were performed in rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
1 (dosing on Days 1, 4 and 7 in rats)
“In the definitive study, 8 rats/sex/group were administered vehicle (saline), 3, 10, or 30 mg/kg by IV injection on Days 1, 4, and 7.”
Pivotal GLP studies
Definitive GLP rat study: 3, 10, 30 mg/kg IV on Days 1, 4, 7; plus monkey IV infusion safety pharmacology/toxicology study
“In the definitive study, 8 rats/sex/group were administered vehicle (saline), 3, 10, or 30 mg/kg by IV injection on Days 1, 4, and 7.”
Route in tox
IV (rats, monkeys); IM also tested in rats
“was performed in 10-13 week old male Fischer 344 rats at repeated IV and IM doses up to 2.91 mg/rat”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Reproductive & developmental
Rabbit EFD: maternal and developmental NOEL 32 mg/kg (highest dose); fertility not studied
“The No-Observed-Effect Level (NOEL) of ETI-204 for maternal and developmental toxicity was determined to be 32 mg/kg/dose, the highest dose tested”
Safety pharmacology
Monkey cardiovascular telemetry studies: definitive study at 10 or 30 mg/kg IV showed no BP or QT effects (earlier study showed BP rise)
“In the second study, following doses of 10 or 30 mg/kg IV, the changes in blood pressure were not seen; blood pressures were in the normal range for this species. No QT prolongation was reported.”
Genotox: Ames
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Genotox: in vitro mammalian
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Genotox: in vivo
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Carcinogenicity model
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Carcinogenicity timing
Not conducted: carcinogenicity studies not performed
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
hERG / QT
No hERG assay; monkey telemetry at 10 or 30 mg/kg IV showed no QT prolongation (earlier study showed apparent QT increase)
“In the second study, following doses of 10 or 30 mg/kg IV, the changes in blood pressure were not seen; blood pressures were in the normal range for this species. No QT prolongation was reported.”
First doseopen answer page →
First-in-human starting dose
Single-dose clinical escalation supported by monkey AUC margin: 10 mg/kg AUC ~50,000 µg·hr/mL vs human AUC 10,000 at 114 mg
“The 10 mg/kg dose to monkeys with an approximate AUC of 50,000 µg·hr/ml provides an appropriate margin of safety based upon the human AUC of 10,000 following a 114 mg dose of Anthim.”
NOAEL / key findings
NOAEL 30 mg/kg (highest dose) in definitive rat study; no test article-related toxicity; MTD not reached
“The NOAEL was the high dose, 30 mg/kg, for both the Lonza and Baxter material”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies in 8 of 12 monkeys (75%) after a single dose
“Anti-product antibodies were detected in samples from 2 monkeys on Day 13 and an additional 6 monkeys on Day 26, for a total of 8 out of 12 monkeys, or 75%.”
Biodistribution & persistence
TCR in human, rat and monkey tissues: cytoplasmic staining only (cytoskeletal elements), considered not relevant
“Staining was reported to be cytoplasmic and was specifically localized to cytoplasmic granules and/or filaments, often associated with cell borders, suggestive of intracellular cytoskeletal elements, and therefore not relevant.”
Modality-specific risk
CNS inflammation and hemorrhage in infected non-survivors attributed to anthrax bacteria, not obiltoxaximab
“Microscopic changes in the non-surviving animals that received obiltoxaximab were due to the presence of extravascular bacteria and not the effect of obiltoxaximab.”
Anti-drug antibodies: animals
Monkeys: ADA in 8 of 12 (75%) after a single dose
“Anti-product antibodies were detected in samples from 2 monkeys on Day 13 and an additional 6 monkeys on Day 26, for a total of 8 out of 12 monkeys, or 75%.”
Anti-drug antibodies: patients
Eight subjects (2.5%) developed treatment-emergent ADA
“Eight subjects (2.5%) who received at least one dose of IV ANTHIM were positive for a treatment-emergent anti-therapeutic antibody (ATA) response.”
Label warnings
Boxed warning: HYPERSENSITIVITY and ANAPHYLAXIS
- Hypersensitivity and Anaphylaxis
Hypersensitivity & infusion reactions
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Single-dose clinical escalation supported by monkey AUC margin: 10 mg/kg AUC ~50,000 µg·hr/mL vs human AUC 10,000 at 114 mg
“The 10 mg/kg dose to monkeys with an approximate AUC of 50,000 µg·hr/ml provides an appropriate margin of safety based upon the human AUC of 10,000 following a 114 mg dose of Anthim.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rat IV study with doses on Days 1, 4 and 7 (about 1 week, GLP definitive); recovery phase not stated
“In the definitive study, 8 rats/sex/group were administered vehicle (saline), 3, 10, or 30 mg/kg by IV injection on Days 1, 4, and 7.”
Pivotal GLP studies
Definitive GLP rat study: 3, 10, 30 mg/kg IV on Days 1, 4, 7; plus monkey IV infusion safety pharmacology/toxicology study
“In the definitive study, 8 rats/sex/group were administered vehicle (saline), 3, 10, or 30 mg/kg by IV injection on Days 1, 4, and 7.”
DART package
Species: DART
Rabbit (EFD, pilot and definitive); fertility not studied
“Two studies, a pilot study and a definitive study, were performed in rabbits.”
Reproductive & developmental
Rabbit EFD: maternal and developmental NOEL 32 mg/kg (highest dose); fertility not studied
“The No-Observed-Effect Level (NOEL) of ETI-204 for maternal and developmental toxicity was determined to be 32 mg/kg/dose, the highest dose tested”
PPND / ePPND: when
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Carcinogenicity model
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Carcinogenicity timing
Not conducted: carcinogenicity studies not performed
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD NOEL: AUC 0.62x and Cmax ~3x human exposure at 16 mg/kg
“mean maternal AUC inf (3220 mcg•day/mL) were approximately 3 times and 0.62 times the respective values for C max and AUC reported in clinical trial subjects at the maximum recommended adult dose of 16 mg/kg.”
NOAEL / key findings
NOAEL 30 mg/kg (highest dose) in definitive rat study; no test article-related toxicity; MTD not reached
“The NOAEL was the high dose, 30 mg/kg, for both the Lonza and Baxter material”
Efficacy evidenceopen answer page →
Efficacy evidence
Inhalational anthrax (aerosol B. anthracis spores) in NZW rabbits and cynomolgus macaques
“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.”
Why that model
Human efficacy trials not feasible or ethical; efficacy based on animal infection models (Animal Rule)
“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.”
Reviewer's view of the efficacy data
Most studies showed significantly improved survival over controls, but survival not always dose-dependent and control survival confounded some studies
“Survival varied and was not always dose-dependent. Survival in control animals in some studies confounded results, but most studies showed significant increase in survival in treated animals over controls.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Rabbit embryo-fetal NOEL (highest dose) gave AUC 0.62 times human exposure at the maximum recommended dose
“In those rabbits, mean maternal maximum plasma concentration (C max = 1180 mcg/mL) and mean maternal AUC inf (3220 mcg•day/mL) were approximately 3 times and 0.62 times the respective values for C max and AUC reported in clinical trial subjects at the maximum recommended adult dose of 16 mg/kg.”
SpeciesQuestioned
Rabbit used for embryo-fetal toxicity without tissue cross-reactivity data supporting its suitability
“It should be noted that tissue cross-reactivity (TCR) studies have not been performed in rabbit tissues to assess the suitability of that species for toxicity testing of ETI-204.”
DARTVerdict not stated
No fertility study conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”
Similar precedents
CyfendusVaccines · anthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)Rodent only · 4 wkBeyfortusAntibodies · nirsevimab · RSV F proteinMonkey only · 4 wkEbangaAntibodies · ansuvimab · Zaire ebolavirus glycoproteinMonkey only · 4 wkEnflonsiaAntibodies · clesrovimab · RSV F protein (site IV)Rodent only · 2 wkRaxibacumabAntibodies · raxibacumab · B. anthracis protective antigenMonkey only · 3 wkSynagisAntibodies · palivizumab · RSV F proteinNo relevant species · none