Korjuny
catumaxomab
Sources:EMA assessment report ↗
Species
no relevantMonkeyRatMouse
Longest study
none
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
No relevant species; limited single-dose mouse, rat, one cynomolgus; BiLu mouse surrogate
“None of the animal species analysed is suitable for assessing the safety of catumaxomab.”
Why that species
No binding to cells from rodents, rabbit, dog or NHPs; CD3/EpCAM binding human-specific
“None of the studies demonstrated binding of catumaxomab to cells from non-clinical species.”
Surrogate molecule
Yes: BiLu (anti-human EpCAM x anti-mouse CD3) in mice; only partially reflects catumaxomab
“Since BiLu recognises only murine CD3 but not murine EpCAM, the surrogate mAb only partially reflects the functionality of catumaxomab.”
Species: general tox
No suitable species; limited single-dose catumaxomab studies in mouse, rat and cynomolgus monkey
“Therefore, a limited toxicology programme was performed, i.e. single dose toxicity studies with catumaxomab in mice, rats and cynomolgus.”
Species: DART
Not conducted (no appropriate species; late-stage malignancy)
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Species: carcinogenicity
Not conducted (ICH S6)
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
Surrogate used in
Yes: surrogate mAb BiLu in mice (single escalating-dose study)
“In addition, a single escalating dose study was performed with the surrogate mAb BiLu in mice.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”
Pivotal GLP studies
GLP single-dose IV: mouse, rat, one cyno (escalating 1-300 µg/kg); BiLu 4-dose escalating mouse; rabbit local tolerance
“Therefore, a limited toxicology programme was performed, i.e. single dose toxicity studies with catumaxomab in mice, rats and cynomolgus.”
Route in tox
IV (maximal systemic exposure) and i.p. (clinical route); rabbit local tolerance multiple routes
“The intraperitoneal (i.p.) route of administration corresponds to the intended therapeutic use in humans.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been performed according to ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6); no proliferation of EpCAM+ or CD3+ cells in vitro
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
Reproductive & developmental
Not conducted (no relevant species; late-stage malignancy)
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Safety pharmacology
No dedicated studies; inferred from BiLu studies, human tissue cross-reactivity and in vitro hepatocytes
“Due to the restricted specificity of catumaxomab for human target antigens, safety aspects were assessed in vivo using the surrogate antibody BiLu in a secondary PD study and as part of a toxicology study (see Toxicology section).”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies have not been performed according to ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies have not been performed according to ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies have not been performed according to ICH S6(R1).”
Carcinogenicity model
Not conducted (ICH S6); no proliferation of EpCAM+ or CD3+ tumour cells in vitro
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6. Catumaxomab does not have the potential to induce proliferation of EpCAM-positive or CD3-positive tumour cells (as demonstrated in 2° PD studies in vitro).”
Carcinogenicity timing
Not required (inappropriate for biotechnology-derived products per ICH S6)
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
hERG / QT
Not conducted; no dedicated safety pharmacology endpoints; cardiovascular effects not expected (no heart tissue binding)
“Dedicated safety pharmacology endpoints were not included in these studies. However, catumaxomab is unlikely to affect the central nervous system as it is not expected to cross the blood-brain-barrier. Cardiovascular effects are not expected considering the lack of catumaxomab to human heart tissue in the tissue cross-reactivity study.”
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 Korjuny 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: BiLu NOAEL 0.2-3.0 µg/kg (~clinical dose); liver, mammary, spleen, marrow, lymphocyte findings; catumaxomab tolerated 1.5 mg/kg mouse, 0.5 mg/kg rat (EMA assessment report, p. 38)
NOAEL / key findings
BiLu NOAEL 0.2-3.0 µg/kg (~clinical dose); liver, mammary, spleen, marrow, lymphocyte findings; catumaxomab tolerated 1.5 mg/kg mouse, 0.5 mg/kg rat
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg).”
Risksopen answer page →
Immune & cytokine safety
In vitro TNF-α/IL-6/IL-2 release with EpCAM+ cells; transient lymphopenia (BiLu); neutralising HAMA/HARA
“In vitro data show that catumaxomab can induce the production of pro-inflammatory cytokines (e.g. TNF-α, IL-6 and IL-2) in the presence of EpCAM-expressing tumour cells.”
Biodistribution & persistence
123I-catumaxomab SCID xenograft: tumour peak 15.7% ID/g at 48 h; i.p. bioavailability 82%; mouse t1/2 128 h
“Tumour uptake of catumaxomab increased over the first 48 h and peaked at 15.7% ID/g; it then declined to 6.6% ID/g on Day 4.”
Modality-specific risk
Cytokine release and transient lymphopenia; liver (BiLu); on-target normal EpCAM tissue untestable; murine ADA
“Potential risks associated with the use of catumaxomab were identified in secondary PD studies, i.e. cytokine release that is enhanced in the presence of EpCAM-positive tumour cells and transient lymphopenia.”
Anti-drug antibodies: animals
Single cynomolgus monkey developed antibodies against mouse and rat Ig one week after last dose; TK not evaluated
“TK was not evaluated as part of the study, although the development of ADA was assessed. One week after the last dose, antibodies against mouse Ig and rat Ig were detected.”
Anti-drug antibodies: patients
90-100% of patients ADA-positive 28-30 days after the last infusion
“At 28 to 30 days after the last infusion, 90-100% of patients were ADA positive across the studies.”
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 Korjuny 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: BiLu NOAEL 0.2-3.0 µg/kg (~clinical dose); liver, mammary, spleen, marrow, lymphocyte findings; catumaxomab tolerated 1.5 mg/kg mouse, 0.5 mg/kg rat (EMA assessment report, p. 38)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose toxicity study (no appropriate animal species); single/escalating-dose studies only
“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”
Pivotal GLP studies
GLP single-dose IV: mouse, rat, one cyno (escalating 1-300 µg/kg); BiLu 4-dose escalating mouse; rabbit local tolerance
“Therefore, a limited toxicology programme was performed, i.e. single dose toxicity studies with catumaxomab in mice, rats and cynomolgus.”
DART package
Species: DART
Not conducted (no appropriate species; late-stage malignancy)
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Reproductive & developmental
Not conducted (no relevant species; late-stage malignancy)
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
PPND / ePPND: when
No PPND or other DART studies: no appropriate species, late-stage malignancy population
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6)
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
Carcinogenicity model
Not conducted (ICH S6); no proliferation of EpCAM+ or CD3+ tumour cells in vitro
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6. Catumaxomab does not have the potential to induce proliferation of EpCAM-positive or CD3-positive tumour cells (as demonstrated in 2° PD studies in vitro).”
Carcinogenicity timing
Not required (inappropriate for biotechnology-derived products per ICH S6)
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: surrogate BiLu mouse NOAEL (0.2-3.0 µg/kg) equivalent to the clinical catumaxomab dose (1.43 µg/kg)
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg). This mouse dose is equivalent to the catumaxomab dose used in the clinical regimen; the maximum human dose is 100 µg (i.e. 1.43 µg/kg in a 70 kg person).”
NOAEL / key findings
BiLu NOAEL 0.2-3.0 µg/kg (~clinical dose); liver, mammary, spleen, marrow, lymphocyte findings; catumaxomab tolerated 1.5 mg/kg mouse, 0.5 mg/kg rat
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg).”
Efficacy evidenceopen answer page →
Efficacy evidence
SCID mouse i.p. human ovarian carcinoma ascites xenograft treated with human PBMCs plus catumaxomab
“In vivo pharmacology of catumaxomab was investigated in a xenograft model of malignant ascites in immuno-deficient SCID mice. Mice received a human ovarian carcinoma xenograft i.p. and were treated one day later with human PBMCs (i.p.) together with a single i.p. injection of catumaxomab.”
Why that model
Catumaxomab does not react with murine CD3, so surrogate BiLu was used for syngeneic proof of concept
“Due to the lack of catumaxomab reactivity with murine CD3, the variant antibody BiLu (anti-human EpCAM & anti-mouse CD3) was used to demonstrate proof of concept in syngeneic mouse tumour models expressing human EpCAM.”
Reviewer's view of the efficacy data
EMA accepted a programme based on in vitro studies plus tailored in vivo work with catumaxomab and partially active surrogate BiLu
“Therefore, the nonclinical programme is based on in vitro studies and a tailored in vivo programme with catumaxomab and a surrogate mAb BiLu, that is cross-reactive with CD3 and therefore partially active in mice. This is accepted.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No pharmacologically relevant species; limited single-dose studies plus partially active murine surrogate BiLu
Why: No cross-reactivity with CD3 or EpCAM in any routine species, including NHPs · No relevant species
“None of the animal species analysed is suitable for assessing the safety of catumaxomab. Any in vivo study with catumaxomab provides results on safety of catumaxomab with limited information for humans.”
“Therefore, the non-clinical programme is based on in vitro studies and a tailored in vivo programme with catumaxomab and a surrogate mAb BiLu, that is cross-reactive with CD3 and therefore partially active in mice. This is accepted.”
Study lengthVerdict not stated
No repeat-dose toxicity studies with catumaxomab
Why: No appropriate animal species · No relevant species
“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: No appropriate animal species; patients with late-stage malignant disease · No relevant species · Within the guideline
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Safety marginVerdict not stated
Surrogate BiLu mouse NOAEL equivalent to the clinical catumaxomab dose (no margin)
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg). This mouse dose is equivalent to the catumaxomab dose used in the clinical regimen; the maximum human dose is 100 µg (i.e. 1.43 µg/kg in a 70 kg person).”
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