Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Blincyto: what flexibility did regulators accept, and why?
blinatumomab · CD19 x CD3
Flexibility accepted
SpeciesAcceptedBeyond the letter
Chimpanzee the only relevant species; limited non-terminal chimpanzee studies plus mouse studies with murine surrogate muS103new
Why: Chimpanzee is the only relevant species and its use is ethically limited; surrogate similar in binding, lysis and T-cell activation · No relevant species · Other reason
“Since there are very limited possibilities to evaluate the toxicology of blinatumomab in the only non-clinical relevant species for ethical reasons, the applicant developed a surrogate BiTE molecule specific for murine CD3 and murine CD19 from rat monoclonal antibodies.”
“A murine surrogate (muS103new) was developed and is considered as similar to blinatumomab with regard to binding to CD19 and CD3 on respective cells, efficacy of redirected target cell lysis, and ability to activate T cells in a target cell-dependent manner.”
DARTVerdict not stated
No reproductive toxicity studies with blinatumomab; mouse embryo-foetal study with murine surrogate only
“Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity.”
DARTVerdict not stated
No fertility studies; reproductive organs assessed in surrogate repeat-dose toxicity studies
Why: No effects on male or female reproductive organs in murine surrogate toxicity studies
“No studies have been conducted to evaluate treatment-related effects on fertility. There were no effects on male or female reproductive organs in toxicity studies with the murine surrogate (SmPC section 5.3).”
Same question, other multispecifics
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
Kimmtrak
tebentafusp · CD3 x gp100 (TCR fusion)No in vivo toxicology; all toxicology in vitro with human tissues and cells (no relevant species for HLA-restricted TCR and human CD3)
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