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.”
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.”
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.”
Similar precedents
Raxibacumabraxibacumab · B. anthracis protective antigenMonkey only · 3 wkBeyfortusnirsevimab · RSV F proteinMonkey only · 4 wkEbangaansuvimab · Zaire ebolavirus glycoproteinMonkey only · 4 wkEnflonsiaclesrovimab · RSV F protein (site IV)Rodent only · 2 wkSynagispalivizumab · RSV F proteinNo relevant species · noneTrogarzoibalizumab · CD4Monkey only · 39 wk