Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Rybrevant: what flexibility did regulators accept, and why?
amivantamab · EGFR x MET
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development study; weight-of-evidence assessment of reproductive and embryo-fetal risk instead
Why: Risks to human development can be communicated from existing scientific information without further animal studies · Weight of evidence
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
“Taken together, the view that the risks of amivantamab to human development can be communicated appropriately to patients and prescribers based on the existing scientific information without conducting additional developmental animal studies is agreed.”
OtherCriticised but acceptedBeyond the letter
Highest dose in monkey repeat-dose studies not fully justified (dose volume above recommended maximum)
Why: EGFR and MET are well characterised targets and the indication is advanced cancer · Pharmacology or kinetics · Serious disease
“Taken together, the highest dose level employed in the repeat-dose toxicity studies is not considered fully justified but given that EFGR and MET are rather well characterised targets, and that amivantamab is indicated for treatment of patients with advanced cancer, no further studies are needed.”
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
Removab
catumaxomab · EpCAM x CD3No relevant species: no repeat-dose, genotoxicity, carcinogenicity or reproductive toxicity studies submitted
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