Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Kimmtrak: what flexibility did regulators accept, and why?
tebentafusp · CD3 x gp100 (TCR fusion)
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.”
Same question, other multispecifics
Blincyto
blinatumomab · CD19 x CD3Chimpanzee the only relevant species; limited non-terminal chimpanzee studies plus mouse studies with murine surrogate muS103new
Columvi
glofitamab · CD20 x CD3No repeat-dose study longer than 4 weeks; 13-week monkey study waived
Elrexfio
elranatamab · BCMA x CD3No reproductive or developmental toxicity studies; reproductive organs assessed in the 3-month study in sexually mature monkeys
Epkinly
epcoritamab · CD20 x CD3No 3-month monkey study; exposure could not be maintained with repeated dosing
Hemlibra
emicizumab · FIXa x FXNo carcinogenicity studies for a chronic prophylactic antibody; written carcinogenicity assessment used instead
Imdelltra
tarlatamab · DLL3 x CD3Monkey used as the only toxicology species although DLL3 is intracellular in normal tissues, so toxicity may be underrepresented
Korjuny
catumaxomab · EpCAM x CD3No pharmacologically relevant species; limited single-dose studies plus partially active murine surrogate BiLu
Lunsumio
mosunetuzumab · CD20 x CD3Monkey embryo-fetal and pre-/postnatal development study waived; weight-of-evidence assessment using other anti-CD20 antibodies
Lynozyfic
linvoseltamab · BCMA x CD3Planned 26-week monkey study shortened after declining body condition in all dose groups; no 26-week study
Ordspono
odronextamab · CD20 x CD3No embryo-fetal development study; literature and nonclinical data risk assessment instead
Removab
catumaxomab · EpCAM x CD3No relevant species: no repeat-dose, genotoxicity, carcinogenicity or reproductive toxicity studies submitted
Rybrevant
amivantamab · EGFR x METNo embryo-fetal development study; weight-of-evidence assessment of reproductive and embryo-fetal risk instead
Talvey
talquetamab · GPRC5D x CD3No cross-reactivity of talquetamab with monkey GPRC5D; pivotal monkey toxicology used a surrogate tool molecule (JNJ-64024701)
Tecvayli
teclistamab · BCMA x CD3Only a 5-week repeat-dose monkey study; no 13-week study
Vabysmo
faricimab · VEGF-A x Ang-2No rodent carcinogenicity studies for a chronic ophthalmic product; weight-of-evidence assessment instead
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead