Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Imdelltra: what flexibility did regulators accept, and why?
tarlatamab · DLL3 x CD3
Flexibility accepted
SpeciesQuestioned
Monkey used as the only toxicology species although DLL3 is intracellular in normal tissues, so toxicity may be underrepresented
Why: Monkey chosen because tarlatamab binds human and monkey CD3 and DLL3 similarly in vitro
“Though the monkey was chosen for toxicity testing based on the ability of tarlatamab to bind human and monkey CD3 and DLL3 similarly in in vitro assays, toxicity associated with tarlatamab may be underrepresented in the monkey given that immunohistochemistry data described above indicates that DLL3 is expressed intracellularly in normal tissues and cells.”
DARTAcceptedBeyond the letter
Embryo-fetal development assessed only in mice with a murine surrogate (muS757), not with tarlatamab
Why: Surrogate muS757 binds mouse CD3 and DLL3; developed at FDA's proposal · Pharmacology or kinetics
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
“The FDA generally agrees with the Applicant’s conclusion and acknowledges that muS757 (a tarlatamab surrogate that binds mouse CD3 and DLL3) crossed the placental barrier.”
DARTAccepted
No dedicated fertility studies
Why: Not needed to support marketing of a drug for patients with advanced cancer · Within the guideline · Serious disease
“In addition, the Applicant did not conduct dedicated studies to assess fertility. In general, these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
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
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
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead