Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Epkinly: what flexibility did regulators accept, and why?
epcoritamab · CD20 x CD3
Flexibility accepted
Study lengthAcceptedBeyond the letter
No 3-month monkey study; exposure could not be maintained with repeated dosing
Why: Exposure could not be maintained with repeated dosing; longer studies would not provide meaningful information · Pharmacology or kinetics
“A 3-month repeat-dose toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across the ICH regions (FDA, EMEA, and PMDA) based on the inability to maintain sufficient exposures to epcoritamab with repeated dosing.”
“We also agree that longer-duration repeat-dose toxicity studies in cynomolgus monkeys would not provide meaningful information and are not warranted.”
DARTAcceptedBeyond the letter
Embryo-fetal development study waived; weight-of-evidence risk assessment instead
Why: High immunogenicity in monkeys; weight of evidence from mechanism of action and other B-cell targeting agents · Weight of evidence · Class precedent · Pharmacology or kinetics
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys. A risk assessment-based on a weight of evidence approach was conducted considering the mechanism of action of epcoritamab and relevant information from other B-cell targeting agents (Module 2.6.6).”
“Based on the above information, an EFD study can be waived.”
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
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
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead