Removab
catumaxomab
Sources:EMA assessment report ↗
Species
no relevantMonkeyMouse
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; in vitro human cells plus mouse surrogate (BiLu); limited single-dose rodent/monkey
“A number of common laboratory animal species, including the three monkeys marmoset (Callitrix sp.), cynomolgus (Macaca fascicularis) and rhesus (Macaca mulatta) were tested histologically for catumaxomab binding, but none showed a binding pattern similar to that of human tissues, and were consequently considered non-relevant.”
Why that species
Binding essentially human-specific; no animal species showed human-like tissue binding
“The non-clinical programme was adapted to the fact that catumaxomab is a protein, and its binding properties are essentially specific for humans.”
Surrogate molecule
Yes: BiLu (anti-human EpCAM x anti-mouse CD3) used for pharmacology, PK and toxicology in mice
“A surrogate antibody (BiLu), which is of equivalent structure to catumaxomab and has the same principal target specificity but binds to mouse CD3 instead of human CD3, was used for pharmacology, pharmacokinetic and toxicology studies in mouse models.”
Species: general tox
None: no relevant species, so no repeat-dose toxicology studies
“The most notable consequence of the inability to find a relevant species is that the present application does not contain repeated dose toxicology studies of catumaxomab.”
Species: DART
Not conducted (not submitted)
“Reproductive and developmental toxicity studies have not been submitted.”
Species: carcinogenicity
Not conducted (not submitted)
“Carcinogenicity studies have not been submitted.”
Surrogate used in
Yes: BiLu (anti-human EpCAM x anti-mouse CD3) surrogate for pharmacology, PK and toxicology in mice
“A surrogate antibody (BiLu), which is of equivalent structure to catumaxomab and has the same principal target specificity but binds to mouse CD3 instead of human CD3, was used for pharmacology, pharmacokinetic and toxicology studies in mouse models.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“Repeat-dose toxicity studies have not been submitted.”
Pivotal GLP studies
No repeat-dose studies; single-dose catumaxomab in mice, rats, one cynomolgus; BiLu single-dose mouse; rabbit local tolerance
“In the few studies performed in rats, mice and one cynomolgus monkey, no acute toxicity was seen even at very high doses of catumaxomab.”
Route in tox
IV (single-dose, escalating monkey infusion); i.p. and other routes in rabbit local tolerance
“Administration of 150 µg i.p. catumaxomab showed an histopathological moderate subchronic inflammation of skin and abdominal muscle after administration of the test item in one animal.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not submitted; biologic, no relevant model)
“Genotoxicity studies have not been submitted.”
Carcinogenicity
Not conducted (not submitted)
“Carcinogenicity studies have not been submitted.”
Reproductive & developmental
Not conducted (not submitted)
“Reproductive and developmental toxicity studies have not been submitted.”
Safety pharmacology
No in vivo studies; human tissue cross-reactivity and in vitro hepatocyte studies
“The safety pharmacology programme was defined by the accessibility of intact monoclonal antibodies in vivo to EpCAM positive tissue.”
Genotox: Ames
Not conducted (not submitted)
“Genotoxicity studies have not been submitted.”
Genotox: in vitro mammalian
Not conducted (not submitted)
“Genotoxicity studies have not been submitted.”
Genotox: in vivo
Not conducted (not submitted)
“Genotoxicity studies have not been submitted.”
Carcinogenicity model
Not conducted (not submitted)
“Carcinogenicity studies have not been submitted.”
Carcinogenicity timing
Not required: absence of studies accepted given no suitable animal models
“The absence of many nonclinical studies is considered acceptable for an antibody, given the absence of suitable animal models.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Removab 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: No NOAEL for catumaxomab; no acute toxicity at high single doses; surrogate BiLu suggested liver toxicity (EMA assessment report, p. 16)
NOAEL / key findings
No NOAEL for catumaxomab; no acute toxicity at high single doses; surrogate BiLu suggested liver toxicity
“The single-dose toxicity studies with BiLu indicate that catumaxomab may cause liver toxicity.”
Risksopen answer page →
Immune & cytokine safety
In vitro TNF-α, IL-6, IL-2 release (needs EpCAM+ cells); no cytokine change in monkey; anti-mouse/rat ADA
“The greatest stimulatory effect of catumaxomab was seen for TNF-α and IL-6, and a smaller stimulatory effect was seen for IL-2.”
Biodistribution & persistence
123I-catumaxomab localised to EpCAM+ xenograft; non-target organ kinetics like control antibody; complete i.p. bioavailability (BiLu)
“Catumaxomab localised to the tumour. The time-activity course for both catumaxomab and a control antibody without tumour specificity in non-target organs was similar.”
Modality-specific risk
No relevant model: T-cell engager cytokine release, hepatotoxicity and murine-protein immunogenicity left to clinic
“As argued by the applicant, the toxicity findings obtained with the surrogate antibody BiLu were considered of limited value. Due to the lack of a relevant animal model, safety assessment of catumaxomab mainly depend on the clinical safety assessment.”
Anti-drug antibodies: animals
Anti-mouse and anti-rat antibodies in the cynomolgus monkey after the last dose; impact on exposure not stated
“The development of anti-mouse and anti-rat antibodies was detected in serum samples after the last dose.”
Anti-drug antibodies: patients
HAMA in the majority of treated patients, within days or weeks after treatment
“Across studies the development of HAMA was observed within days or weeks after the treatment period in the majority of treated patients.”
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 Removab 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: No NOAEL for catumaxomab; no acute toxicity at high single doses; surrogate BiLu suggested liver toxicity (EMA assessment report, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose toxicology study (no relevant species)
“The most notable consequence of the inability to find a relevant species is that the present application does not contain repeated dose toxicology studies of catumaxomab.”
Pivotal GLP studies
No repeat-dose studies; single-dose catumaxomab in mice, rats, one cynomolgus; BiLu single-dose mouse; rabbit local tolerance
“In the few studies performed in rats, mice and one cynomolgus monkey, no acute toxicity was seen even at very high doses of catumaxomab.”
DART package
Species: DART
Not conducted (not submitted)
“Reproductive and developmental toxicity studies have not been submitted.”
Reproductive & developmental
Not conducted (not submitted)
“Reproductive and developmental toxicity studies have not been submitted.”
PPND / ePPND: when
Not conducted: reproductive and developmental toxicity studies not submitted
“Reproductive and developmental toxicity studies have not been submitted.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not submitted)
“Carcinogenicity studies have not been submitted.”
Carcinogenicity model
Not conducted (not submitted)
“Carcinogenicity studies have not been submitted.”
Carcinogenicity timing
Not required: absence of studies accepted given no suitable animal models
“The absence of many nonclinical studies is considered acceptable for an antibody, given the absence of suitable animal models.”
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
No NOAEL for catumaxomab; no acute toxicity at high single doses; surrogate BiLu suggested liver toxicity
“The single-dose toxicity studies with BiLu indicate that catumaxomab may cause liver toxicity.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human ovarian carcinoma xenograft (catumaxomab); syngeneic human-EpCAM mouse tumour model with surrogate BiLu
“The variant antibody BiLu (anti-human EpCAM & anti-mouse CD3) was used to demonstrate proof of concept in a syngeneic mouse tumour model expressing human EpCAM. Anti-tumour activity of catumaxomab was observed in a human ovarian carcinoma xenograft study.”
Why that model
Binding properties essentially specific for humans
“The non-clinical programme was adapted to the fact that catumaxomab is a protein, and its binding properties are essentially specific for humans.”
Reviewer's view of the efficacy data
CHMP: in vivo anti-tumour activity confirmed in an immunocompromised ovarian carcinoma mouse model with human PBMC (added to the SmPC)
“The in vivo anti-tumour activity of catumaxomab was confirmed in an immunologically compromised mouse model of ovarian carcinoma, where tumour development was delayed by an intraperitoneal treatment with catumaxomab and human peripheral blood mononuclear cells.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No relevant species: no repeat-dose, genotoxicity, carcinogenicity or reproductive toxicity studies submitted
Why: Absence of suitable animal models · No relevant species · Within the guideline
“Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity studies have not been performed.”
“The absence of many non-clinical studies is considered acceptable for an antibody, given the absence of suitable animal models.”
OtherCriticised but acceptedBeyond the letter
Toxicity assessed only with the mouse-CD3 surrogate antibody BiLu, considered of limited value; safety assessment relies on clinical data
Why: Lack of a relevant animal model; safety assessment depends on clinical data · No relevant species · Human data
“BiLu may thus not have similar toxicological and dynamic effects in the mouse as catumaxomab has in the human leaving the safety assessment of catumaxomab largely to the clinical studies.”
“Due to the lack of a relevant animal model, safety assessment of catumaxomab mainly depend on the clinical safety assessment.”
Impurity or metaboliteVerdict not stated
No toxicity studies with trace impurities
Why: No animal model permits testing of the full pharmacological activity · No relevant species
“"Since no animal model is available which permits toxicological testing of the full pharmacological activity of catumaxomab, toxicity studies with trace impurities were not performed."”
GLPVerdict not stated
Most pharmacokinetic studies not fully GLP-compliant
Why: Studies subjected to quality assurance evaluation
“Although not fully complying with GLP, most pharmacokinetic studies were subjected to quality assurance evaluation.”
Similar precedents
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