Kimmtrak
tebentafusp
Sources:FDA multi-discipline review ↗
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.”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”