Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Korjuny: what flexibility did regulators accept, and why?
catumaxomab · EpCAM x CD3
Flexibility accepted
SpeciesAcceptedBeyond the letter
No pharmacologically relevant species; limited single-dose studies plus partially active murine surrogate BiLu
Why: No cross-reactivity with CD3 or EpCAM in any routine species, including NHPs · No relevant species
“None of the animal species analysed is suitable for assessing the safety of catumaxomab. Any in vivo study with catumaxomab provides results on safety of catumaxomab with limited information for humans.”
“Therefore, the non-clinical programme is based on in vitro studies and a tailored in vivo programme with catumaxomab and a surrogate mAb BiLu, that is cross-reactive with CD3 and therefore partially active in mice. This is accepted.”
Study lengthVerdict not stated
No repeat-dose toxicity studies with catumaxomab
Why: No appropriate animal species · No relevant species
“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: No appropriate animal species; patients with late-stage malignant disease · No relevant species · Within the guideline
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
Safety marginVerdict not stated
Surrogate BiLu mouse NOAEL equivalent to the clinical catumaxomab dose (no margin)
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg). This mouse dose is equivalent to the catumaxomab dose used in the clinical regimen; the maximum human dose is 100 µg (i.e. 1.43 µg/kg in a 70 kg person).”
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)
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