Tivdak
tisotumab vedotin
Species
MonkeyRat
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only for ADC; rat and monkey for MMAE payload
“The data suggests that the cynomolgus monkey was the only relevant toxicological species.”
Why that species
Tisotumab binds human and cynomolgus TF similarly; no binding to mouse, rat, rabbit, pig or dog TF
“Tisotumab did not bind to mouse, rat, rabbit, pig, or dog TF.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey, payload (MMAE) separately in rat and monkey
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Species: general tox
Cynomolgus monkey (ADC, 13-week); rat (4-week) and monkey (11-week) for MMAE payload
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Species: DART
Rat (MMAE embryo-fetal development only); ADC reproductive organ effects assessed in monkey repeat-dose study
“The Applicant assessed the effects tisotumab vedotin on reproductive organs as part of the repeat-dose toxicology study in monkeys and provided results from an EFD study in rats evaluating the MMAE payload.”
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Surrogate used in
Unconjugated tisotumab used as surrogate for tisotumab vedotin in many pharmacology studies
“Many of the studies were conducted with tisotumab as surrogate for tisotumab vedotin.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Pivotal GLP studies
13-week GLP monkey ADC (q3w IV, 6-week recovery); MMAE 4-week rat, 11-week monkey; 13-week monkey naked antibody
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
Route in tox
IV (clinical route)
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
“Genetic toxicology studies were not conducted with tisotumab vedotin; rather, the applicant submitted studies that evaluated the payload.”
Carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic/embryolethal; male repro toxicity in monkey
“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ICH S9); MMAE hERG in vitro
“Additionally, safety pharmacology endpoints for tisotumab vedotin representative of the cardiovascular (ECG and heart rate), central nervous (cageside observations) and respiratory systems (breaths per minute) were assessed as part of the repeat-dose toxicity studies as outlined in ICH S9 guideline.”
Genotox: Ames
MMAE: negative in Ames assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE: negative in L5178Y TK+/- mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); FDA agreed
“The FDA agrees with the Applicant’s position; carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer in accordance with ICH S9.”
hERG / QT
ADC not tested; MMAE <50% hERG inhibition up to 100 µM
“In vitro inhibition of the hERG channel was not evaluated with tisotumab vedotin; however, up to 100 µM MMAE had limited (<50%) inhibition on hERG potassium channel.”
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 Tivdak 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 ADCs
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: Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg (EMA assessment report, p. 50)
NOAEL / key findings
Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg
“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”
Risksopen answer page →
Immune & cytokine safety
ADA in most monkeys after repeat dosing, reduced exposure in some; immunotoxic potential minimal
“Most monkeys developed ADAs following repeated doses of tisotumab vedotin.”
Biodistribution & persistence
Monkey 89Zr-PET: highest uptake liver and bone marrow (~20% each); MMAE fecal elimination
“In cynomolgus monkeys, liver and bone marrow received the highest percent (approx. 20% each) of the injected dose of 89Zr-tisotumab and long persistence were noted.”
Modality-specific risk
Target-mediated skin and ocular toxicity plus MMAE myelosuppression, testicular toxicity; bleeding (TF/coagulation)
“Skin and ocular toxicities could be expected from the TF-directed antibody portion of tisotumab vedotin as tisotumab was shown to positively stain skin epithelial cells (squamous epidermis, hair follicle), and corneal and conjunctiva epithelial cells, in both human and monkey in a tissue cross reactivity study.”
Anti-drug antibodies: animals
Monkey ADA after repeat dosing, mainly at 5 mg/kg; no apparent effect on Cmax or total exposure
“After repeated dosing, animals developed anti-drug antibodies (ADA) especially at the high dose of 5 mg/kg, but ADA did not appear to affect the peak plasma concentration or total exposure.”
Anti-drug antibodies: patients
5.7% (innovaTV 301) and 5.4% (innovaTV 204); neutralizing 0% and 2.2%
“the incidence of anti-tisotumab vedotin-tftv antibody formation was 5.7% (12/211) and 5.4% (5/93), respectively. The incidence of neutralizing anti-tisotumab vedotin-tftv antibody formation was 0% (0/211) in innovaTV 301 using cell-based assay, and the incidence was 2.2% (2/93) in innovaTV 204 using Enzyme-linked Immunosorbent Assay (ELISA)-based assay.”
Label warnings
Boxed warning: Ocular toxicity
- Ocular Adverse Reactions
- Peripheral Neuropathy
- Hemorrhage
- Pneumonitis
- Severe Cutaneous Adverse Reactions
- Embryo-Fetal Toxicity
Ocular toxicityNeurotoxicityBleedingImmune-mediated reactionsSkin reactionsEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
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 Tivdak 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 ADCs
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: Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg (EMA assessment report, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey (IV every three weeks, five doses) with 6-week recovery
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
Pivotal GLP studies
13-week GLP monkey ADC (q3w IV, 6-week recovery); MMAE 4-week rat, 11-week monkey; 13-week monkey naked antibody
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
DART package
Species: DART
Rat (MMAE embryo-fetal development only); ADC reproductive organ effects assessed in monkey repeat-dose study
“The Applicant assessed the effects tisotumab vedotin on reproductive organs as part of the repeat-dose toxicology study in monkeys and provided results from an EFD study in rats evaluating the MMAE payload.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic/embryolethal; male repro toxicity in monkey
“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”
PPND / ePPND: when
No pre- and postnatal development study; not needed for advanced cancer (ICH S9)
“Fertility and early embryonic development and pre- and post-natal studies were not needed to support the proposed advanced cancer population in accordance with ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); FDA agreed
“The FDA agrees with the Applicant’s position; carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer in accordance with ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey HNSTD 3 mg/kg ~1.35-2.56x human exposure (Cmax and AUC)
“The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”
NOAEL / key findings
Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg
“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cervical cancer patient-derived xenograft (PDX) models in mice
“In vivo, anti-tumor activity and/or tumor regression was seen in cervical cancer patient derived xenograft (PDX) models when mice were administered tisotumab vedotin at 4 mg/kg twice in the first week of study via intravenous dosing.”
Why that model
Tisotumab does not bind mouse, rat, rabbit, pig or dog TF
“Tisotumab did not bind to mouse, rat, rabbit, pig, or dog TF.”
Reviewer's view of the efficacy data
EMA: activity in 5 of 6 cervical PDX models; TF expression measured in only 1, so its influence is unclear
“For the cervical cancer PDX models, a positive effect of tisotumab vedotin was noted in 5 out of 6 models, primarily at dose of 2-4 mg/kg. It should be noted that TF expression was only determined for one out of six cervical cancer PDX models and it is therefore unclear how the level of TF expression has affected the results in these models.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No embryo-fetal development study with the ADC; rat EFD study of the MMAE payload (from brentuximab vedotin) relied on
Why: MMAE payload EFD study in rats, previously reviewed for brentuximab vedotin
“Dedicated embryo-fetal developmental toxicity studies were not conducted with tisotumab vedotin. However, MMAE (SGD-1010) was evaluated in rats as part of a GLP embryo-fetal developmental and TK study that was initially reviewed by the FDA under BLA 125388 for brentuximab vedotin.”
Similar precedents
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