Ordspono
odronextamab
Sources:EMA assessment report ↗
Species
Monkey
Longest study
16 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Binding to human and cynomolgus CD20 and CD3 was confirmed in in vitro studies. Cynomolgus monkey was considered the pharmacological relevant species further used in toxicology studies.”
Why that species
Binds CD20 and CD3 on human and monkey cells (CD3 affinity ~100-fold weaker in monkey); no binding to mouse/rat cells
“An additional binding study showed that odronextamab did not bind to either B-cells or T-cells isolated from mouse and rat.”
Surrogate molecule
No surrogate; clinical molecule (REGN1979) tested in cynomolgus monkey
“The safety profile of odronextamab was evaluated in cynomolgus monkeys in 2 GLP-compliant repeat”
Study lengthopen answer page →
Longest pivotal study
16 weeks
“once weekly IV infusions of 0.1 and 1 mg/kg for 16 weeks (total of 17 doses) with a 14-week recovery period.”
Pivotal GLP studies
GLP cynomolgus single-dose, 4-week (0.01/0.1/1 mg/kg) and 16-week (0.1/1 mg/kg) weekly IV studies with recovery
“once weekly IV infusions of 0.01, 0.1, and 1 mg/kg for 4 weeks (total of 5 doses) with a 12-week recovery period”
Route in tox
IV infusion (repeat-dose); IV and SC (single-dose)
“following a single dose of 0.1 or 1 mg/kg SC or 1 mg/kg IV (Phase I) or escalating doses of 1/25/100 mg/kg (IV and SC; Phase II) with an 8-week recovery period.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (antibody not expected to interact with DNA)
“Antibodies, such as odronextamab, are not expected to interact directly with DNA or other chromosomal material. Therefore, no genotoxicity studies were conducted with odronextamab.”
Carcinogenicity
Not conducted (ICH S9, advanced malignancy)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab”
Reproductive & developmental
No EFD study; fertility endpoints in 16-week monkey study unaffected; risk assessment in lieu (fetal B-cell lymphocytopenia, CRS)
“Embryo-fetal developmental toxicology studies with odronextamab were not conducted as such studies are expected to have limited value in further understanding and communicating risks to patients with advanced cancer.”
Safety pharmacology
Integrated into 4- and 16-week GLP monkey studies up to 1 mg/kg; no changes
“No changes on safety pharmacology endpoints were detected.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Up to 1 mg/kg weekly tolerated; no formal NOAEL/HNSTD stated; B-cell depletion, inflammation, presumed opportunistic infections requiring early euthanasia
“In the repeat-dose toxicology studies, once weekly IV infusion of up to 1 mg/kg odronextamab for up to 4 weeks was tolerated.”
Risksopen answer page →
Immune & cytokine safety
Transient T-cell activation and plasma cytokine rise after first dose only; limited translatability of in vitro cytokine data to CRS
“Overall, based on the in vitro data on cytokine release there is a limited value in translating these results to a clinical setting for assessment of CRS.”
Biodistribution & persistence
No distribution studies; GLP tissue cross-reactivity showed only expected CD20/CD3 leukocyte staining
“As expected, based on the known expression of CD20 by B cells and CD3 by T cells, REGN1979-Bio stained the membrane and/or cytoplasm of mononuclear leukocytes in both lymphoid”
Modality-specific risk
CRS/T-cell activation and B-cell depletion with opportunistic infections (early euthanasia of monkeys)
“increased CRP and neutrophils, and multiorgan inflammation, including of the gastrointestinal tract, were consistent with acute inflammation and attributed to presumed opportunistic infections due to sustained B-cell depletion.”