Kimmtrak
tebentafusp
Species
no relevant
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 cell/tissue assays only
“There are no pharmacologically relevant animal species to evaluate tebentafusp toxicity.”
Why that species
TCR recognizes only human gp100:HLA-A*02:01; anti-CD3 scFv binds human T cells only, not mouse or monkey
“In vitro, the scFv portion of tebentafusp bound to T cells in human PBMCs but did not bind PBMCs from mouse or monkey.”
Surrogate molecule
No surrogate; in vitro human-cell approach instead of animal tox
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
Species: general tox
None (no relevant species; all toxicology studies in vitro)
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
Species: DART
Not conducted (specificity for human targets)
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species.”
Species: carcinogenicity
Not conducted
“No carcinogenicity or genotoxicity studies have been conducted with tebentafusp-tebn.”
Surrogate used in
No surrogate used; no relevant animal species, in vitro human-cell assays instead
“Since, tebentafusp is specific for human gp100 and CD3 with no affinity to e.g. monkey, rat or mice, secondary and safety pharmacology was evaluated using in vitro methods on human tissues and cells..”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
Pivotal GLP studies
No in vivo tox; GLP human tissue cross-reactivity (35 tissues) plus in vitro normal-cell, alloreactivity, whole-blood cytokine, platelet assays
“Tebentafusp was also investigated in toxicology studies to assess its cross‐reactivity with normal tissues in a GLP‐compliant tissue cross‐reactivity study.”
Route in tox
None for tox (in vitro); single IV or SC dose in non-GLP mouse PK/biodistribution studies
“These studies were non-GLP, PK and /or biodistribution studies and administered as single intravenous (IV) or subcutaneous (SC) dose.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (fusion protein; ICH S6/S9)
“Based on the biologic properties of tebentafusp, a fusion protein, genetic toxicology studies are not warranted.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not warranted for the proposed indication.”
Reproductive & developmental
Not conducted (no relevant species); weight-of-evidence; FDA concluded possible fetal harm to skin, inner ear, eye
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
Safety pharmacology
Not conducted (no relevant species; in vitro only)
“Therefore, no specific safety pharmacology studies were conducted.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted for tebentafusp in accordance with the ICH S6 guidance.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted for tebentafusp in accordance with the ICH S6 guidance.”
Genotox: in vivo
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted for tebentafusp in accordance with the ICH S6 guidance.”
Carcinogenicity model
Not conducted (not warranted for the advanced-cancer indication)
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
hERG / QT
Not conducted (no relevant species; human-specific protein)
“Safety pharmacology studies were not conducted for tebentafusp. Tebentafusp is a human specific protein and does not bind proteins from nonhuman species.”
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 Kimmtrak 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 (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM (FDA multi-discipline review, p. 41)
NOAEL / key findings
No NOAEL (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM
“Tebentafusp demonstrated broad loss of specificity for the target pHLA complex from 1 nM (1,000× MABEL), where consistent evidence of T cell activation (IFNγ release) and/or redirected killing (GrB release) was observed across the different normal cells tested.”
Risksopen answer page →
Immune & cytokine safety
Whole-blood assays: no cytokine increase <1 nM; IL-6, TNFa, IFNg at 10-100 nM; no alloreactivity or platelet activation
“Tebentafusp did not show evidence for increased release of 5 key cytokines in the presence of whole blood at < 1 nM.”
Biodistribution & persistence
Mouse non-GLP PK/biodistribution: tumor retention longer than other tissues (tumor t1/2 ~20-24 h vs blood 1.5 h); renal excretion
“Preclinical biodistribution studies demonstrate that tebentafusp is being retained in the melanoma tumor for a significantly longer timeframe compared to other non-target tissues, with a half-life of tumour retention of approximately 24 hours.”
Modality-specific risk
On-target/off-tumor melanocyte killing (rash, vitiligo) and CRS; HLA/peptide off-target cross-reactivity and alloreactivity
“Based on these [astrocyte and melanocyte] data, skin rash and potentially vitiligo were expected as the primary TCR mediated on‐target, off‐tumor toxicities.”
Anti-drug antibodies: animals
Not analysed; higher clearance and lower AUC after 5-day repeat dosing in mice possibly due to ADAs
“It should be mentioned that clearance was higher and AUC was lower after 5 days of repeat dosing and this was by the applicant attributed to possibly be due to ADAs, which however was not analysed for in this study (IM-CH-01-10).”
Anti-drug antibodies: patients
ADA in 36% (47/131, IMCgp100-102) and 28% (67/240, IMCgp100-202) of patients
“In studies IMCgp100-102 and IMCgp100-202, 36% (47/131) and 28% (67/240) of patients who were treated with tebentafusp-tebn at the recommended dosing regimen for up to 29 cycles and 45 cycles, respectively, developed anti-tebentafusp-tebn antibodies (ADA).”
Label warnings
Boxed warning: Boxed warning: cytokine release syndrome
- Cytokine Release Syndrome
- Skin Reactions
- Elevated Liver Enzymes
- Embryo-Fetal Toxicity
Cytokine release syndromeSkin reactionsHepatotoxicityEmbryo-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 Kimmtrak 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 (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM (FDA multi-discipline review, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (human HLA-restricted; all toxicology in vitro)
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
Pivotal GLP studies
No in vivo tox; GLP human tissue cross-reactivity (35 tissues) plus in vitro normal-cell, alloreactivity, whole-blood cytokine, platelet assays
“Tebentafusp was also investigated in toxicology studies to assess its cross‐reactivity with normal tissues in a GLP‐compliant tissue cross‐reactivity study.”
DART package
Species: DART
Not conducted (specificity for human targets)
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species.”
Reproductive & developmental
Not conducted (no relevant species); weight-of-evidence; FDA concluded possible fetal harm to skin, inner ear, eye
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
PPND / ePPND: when
No PPND or other in vivo DART studies (no relevant species); weight-of-evidence assessment
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity or genotoxicity studies have been conducted with tebentafusp-tebn.”
Carcinogenicity model
Not conducted (not warranted for the advanced-cancer indication)
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
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 (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM
“Tebentafusp demonstrated broad loss of specificity for the target pHLA complex from 1 nM (1,000× MABEL), where consistent evidence of T cell activation (IFNγ release) and/or redirected killing (GrB release) was observed across the different normal cells tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mice engrafted with HLA-A*02:01/gp100+ Mel526 human melanoma cells plus human PBMCs; tumor growth inhibition
“In vivo, the anti‐tumor activity of tebentafusp was evaluated in mice engrafted with HLA‐A*02:01/gp100‐positive Mel526 human melanoma cancer cells mixed with PBMCs isolated from human whole blood. In this study, administration of 5 doses of tebentafusp resulted in tumor growth inhibition compared to controls.”
Why that model
Tebentafusp is specific for human gp100 and CD3 with no affinity for monkey, rat or mouse; no relevant animal species
“Since, tebentafusp is specific for human gp100 and CD3 with no affinity to e.g. monkey, rat or mice, secondary and safety pharmacology was evaluated using in vitro methods on human tissues and cells..”
Reviewer's view of the efficacy data
EMA: mouse efficacy needed exposures above patients'; SCID model probably not predictive of clinically effective exposure
“Moreover, the exposure showing beneficial effects was higher as compared to patients. However, there is no doubt that effects (beneficial and adverse) are observed in clinical trials, hence the animal model (SCID mouse) is probably not predictive in terms of level of exposure providing reductions in tumour volume in patients.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No in vivo toxicology; all toxicology in vitro with human tissues and cells (no relevant species for HLA-restricted TCR and human CD3)
Why: Human-specific protein; no relevant animal species in which toxicology could be tested · No relevant species · Within the guideline
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro. Human tissue and cell-based in vitro approaches were taken to understand potential organ-specific toxicities that may arise in the clinical setting with tebentafusp.”
“As tebentafusp is a human-specific protein, there are no relevant animal species in which non-clinical toxicology of tebentafusp could be tested.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies; functional in vitro assays across human tissue cell types instead
Why: Tebentafusp only recognises human HLA · No relevant species
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro. Therefore, no specific safety pharmacology studies were conducted.”
“The FDA’s Assessment: FDA agrees.”
DARTAcceptedBeyond the letter
No embryo-fetal or other DART studies; literature-based weight-of-evidence assessment instead
Why: Human-specific targets; embryo-fetal studies cannot be conducted in nonclinical species · No relevant species · Weight of evidence
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
“No carcinogenicity, genotoxicity, or developmental and reproductive toxicity studies have been conducted with tebentafusp. This is acceptable.”
GLPVerdict not stated
In vitro human-blood safety studies, such as cytokine release assessment, conducted non-GLP
“The potential for cytokine release syndrome (CRS) was assessed in blood from 6 healthy HLA-A*02:01-positive donors incubated with increasing concentrations of tebentafusp, and samples were analyzed for evidence of cytokine release by multiplex. These studies were non-GLP.”
Safety marginAcceptedBeyond the letter
No in vitro margin for on-target melanocyte reactivity: patient serum concentrations exceed melanocyte EC50 (margin below 1)
Why: Skin adverse events, consistent with in vitro data, appear manageable in clinical trials · Human data
“In vitro studies suggest some safety margin between the two cell types, however not convincing. When comparing serum concentrations in patients just after infusion with EC50 in normal melanocytes, the safety margin is below 1.”
“High incidence of AEs related to the skin is well documented in the clinical trials but appear to be manageable. The high incidence is therefore consistent with these in vitro data.”
Similar precedents
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