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”
Species: general tox
Cynomolgus monkey only (4-week and 16-week weekly IV studies)
“The safety profile of odronextamab was evaluated in cynomolgus monkeys in 2 GLP-compliant repeat-dose toxicology studies following 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 and following once weekly IV infusions of 0.1 and 1 mg/kg for 16 weeks (total of 17 doses) with a 14-week recovery period.”
Species: DART
Fertility endpoints within repeat-dose monkey study (no findings up to 1 mg/kg/week); EFD not conducted (limited value in advanced cancer)
“There were no odronextamab-related findings in fertility endpoints or microscopic assessment of reproductive organs at doses of up to and including 1 mg/kg/week IV. 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.”
Species: carcinogenicity
Not conducted (ICH S9, advanced malignancies)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
Surrogate used in
No surrogate used; clinical molecule tested in cynomolgus monkey
“Cynomolgus monkey was considered the pharmacological relevant species further used in toxicology studies.”
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.”
Genotox: Ames
Not conducted (ICH S6/S2: 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.”
Genotox: in vitro mammalian
Not conducted (ICH S6/S2: 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.”
Genotox: in vivo
Not conducted (ICH S6/S2: 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 model
Not conducted (ICH S9, advanced malignancies)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
Carcinogenicity timing
Not required (ICH S9)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
hERG / QT
No hERG assay; no respiratory, neurological or cardiovascular changes in repeat-dose monkey studies
“There were no drug-related effects on vital signs (body temperature, blood pressure, and respiration and heart rate); or respiratory, neurological, or cardiovascular changes evident, nor infusion site reactions.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ordspono don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (EMA assessment report, p. 34)
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.”
Anti-drug antibodies: animals
Few ADA-positive monkeys; low impact on odronextamab concentrations
“In conclusion the presence of ADA can be regarded as having low impact on concentration of odronextamab both in regard to the low number of animals that had detectable levels of ADA, and also with respect to concentration levels of odronextamab.”
Anti-drug antibodies: patients
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.
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
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ordspono don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (EMA assessment report, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
16-week weekly IV cynomolgus monkey GLP study with 14-week recovery
“following 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”
DART package
Species: DART
Fertility endpoints within repeat-dose monkey study (no findings up to 1 mg/kg/week); EFD not conducted (limited value in advanced cancer)
“There were no odronextamab-related findings in fertility endpoints or microscopic assessment of reproductive organs at doses of up to and including 1 mg/kg/week IV. 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.”
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.”
PPND / ePPND: when
Not conducted: embryo-fetal studies expected to have limited value for patients with advanced cancer
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced malignancies)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
Carcinogenicity model
Not conducted (ICH S9, advanced malignancies)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
Carcinogenicity timing
Not required (ICH S9)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
Safety marginopen answer page →
Safety margin at NOAEL
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.
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Lymphoma tumour models in humanized (BRG) mice and immunodeficient NSG mice
“The applicant has submitted 3 in vivo studies utilising two in vivo mouse models, consisting of humanized (BRG) mice and immunodeficient NSG mice, to evaluate antitumour activities of odronextamab in a repeat-dose setting.”
Why that model
No binding to rat or mouse CD3 or CD20
“Odronextamab was not able to bind to rat or mouse CD3 or CD20.”
Reviewer's view of the efficacy data
EMA: antitumour activity satisfactorily demonstrated in vivo; first two studies were prevention models (dosing at tumour implantation)
“Overall, the antitumour activity of odronextamab was satisfactorily demonstrated in the conducted in vivo studies. It can be noted that the first two studies are to be considered models of prevention since treatment with odronextamab was administered at the same time as tumour cells.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development study; literature and nonclinical data risk assessment instead
Why: Consistent with previous CHMP conclusions for other bispecific antibodies of this class · Class precedent · Weight of evidence
“Embryo-fetal developmental toxicology studies were not conducted with odronextamab. A risk assessment based on available nonclinical data and literature was provided. This approach is agreed and is in line with previous CHMP conclusions on other members of this class of bispecific antibodies.”
SpeciesVerdict not stated
Monkey, the only relevant species, binds CD3 about 100-fold more weakly than human, possibly explaining lower cytokine responses than in humans
“Whereas the binding of CD20 was within the same concentration range for both human and monkey, there was approximately a 100-fold difference with respect to human and monkey CD3. This observed difference indicates a higher affinity for human CD3 which might be the cause of the observed discrepancy between cytokine levels observed in human and in cynomolgus, respectively.”
Similar precedents
ColumviMultispecifics · glofitamab · CD20 x CD3Monkey only · 4 wkElrexfioMultispecifics · elranatamab · BCMA x CD3Monkey only · 13 wkEpkinlyMultispecifics · epcoritamab · CD20 x CD3Monkey only · 5 wkLunsumioMultispecifics · mosunetuzumab · CD20 x CD3Monkey only · 26 wkLynozyficMultispecifics · linvoseltamab · BCMA x CD3Monkey only · 14 wkTalveyMultispecifics · talquetamab · GPRC5D x CD3Monkey only · 4 wk