Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Ziihera: what flexibility did regulators accept, and why?
zanidatamab · HER2 x HER2 (biparatopic)
Flexibility accepted
DARTAccepted
No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead
Why: Embryo-fetal toxicity a likely class effect of HER2-binding antibodies per literature (ICH S5(R3)) · Within the guideline · Class precedent · Weight of evidence
“On the basis of a weight-of-evidence analysis supported by published literature indicating that embryo-fetal toxicity is a likely class effect of HER2 binding antibodies (ICH S5(R3) Section 1.2.2) (ICH, 2020), Jazz proposes that zanidatamab should be considered an embryofetal toxicant.”
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab. The FDA’s Assessment: The FDA generally agrees with the Applicant’s Position.”
DARTVerdict not stated
No fertility studies; fertility assessed by reproductive organ histopathology and weights in the repeat-dose monkey study
“Fertility studies have not been performed with zanidatamab but its potential to impair fertility was assessed by histopathology and organ weight analysis as part of the pivotal repeat dose toxicity study.”
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
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