Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Lunsumio: what flexibility did regulators accept, and why?
mosunetuzumab · CD20 x CD3
Flexibility accepted
DARTAccepted
Monkey embryo-fetal and pre-/postnatal development study waived; weight-of-evidence assessment using other anti-CD20 antibodies
Why: Further monkey testing unlikely to add information; anti-CD20 class effects known · Weight of evidence · Class precedent · Within the guideline
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993).”
“Based on the justification provided by the Applicant, and in accordance with ICH S6 (R1) it is agreed that no further testing is required in order to elucidate the reproductive toxicity of mosunetuzumab in cynomolgus monkeys, as it is not likely it will add further information to the current nonclinical and clinical knowledge to support the mitigation of this risk in humans.”
Safety marginVerdict not stated
No NOAEL; CRS and infections in monkeys at exposure multiples of 0.008 to 1.84
“When applying the corrections of AUC, estimations of exposure multiples resulted in values of 0.008 to 1.84, implying that CRS related effects and immunosuppression leading to infections occur at clinically relevant dose levels.”
OtherVerdict not stated
No tissue cross-reactivity study: no robust IHC assay could be developed
Why: Poor analytical sensitivity and specificity of the antibody as an IHC reagent
“Due to technical limitations it was not possible to develop a robust, reproducible and accurate IHC assay to assess specific tissue binding and determine the potential cross-reactivity of mosunetuzumab in human and cynomolgus monkey tissue, as mosunetuzumab exhibits poor analytical sensitivity and specificity as an IHC reagent.”
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
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