Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Removab: what flexibility did regulators accept, and why?
catumaxomab · EpCAM x CD3
Flexibility accepted
SpeciesAccepted
No relevant species: no repeat-dose, genotoxicity, carcinogenicity or reproductive toxicity studies submitted
Why: Absence of suitable animal models · No relevant species · Within the guideline
“Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity studies have not been performed.”
“The absence of many non-clinical studies is considered acceptable for an antibody, given the absence of suitable animal models.”
OtherCriticised but acceptedBeyond the letter
Toxicity assessed only with the mouse-CD3 surrogate antibody BiLu, considered of limited value; safety assessment relies on clinical data
Why: Lack of a relevant animal model; safety assessment depends on clinical data · No relevant species · Human data
“BiLu may thus not have similar toxicological and dynamic effects in the mouse as catumaxomab has in the human leaving the safety assessment of catumaxomab largely to the clinical studies.”
“Due to the lack of a relevant animal model, safety assessment of catumaxomab mainly depend on the clinical safety assessment.”
Impurity or metaboliteVerdict not stated
No toxicity studies with trace impurities
Why: No animal model permits testing of the full pharmacological activity · No relevant species
“"Since no animal model is available which permits toxicological testing of the full pharmacological activity of catumaxomab, toxicity studies with trace impurities were not performed."”
GLPVerdict not stated
Most pharmacokinetic studies not fully GLP-compliant
Why: Studies subjected to quality assurance evaluation
“Although not fully complying with GLP, most pharmacokinetic studies were subjected to quality assurance evaluation.”
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
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
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