Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Talvey: what flexibility did regulators accept, and why?
talquetamab · GPRC5D x CD3
Flexibility accepted
SpeciesVerdict not stated
No cross-reactivity of talquetamab with monkey GPRC5D; pivotal monkey toxicology used a surrogate tool molecule (JNJ-64024701)
Why: Talquetamab lacks cross-reactivity to monkey GPRC5D
“Due to the lack of cross reactivity of talquetamab to cynomolgus monkey GPRC5D, the tool molecule (JNJ-64024701) was developed.”
Study lengthCriticised but acceptedBeyond the letter
No 13-week study; longest general toxicology study was 1 month with the tool molecule
Why: ADAs reduced tool molecule exposure, so longer studies would add no value; limited PD alone not accepted as a reason · Pharmacology or kinetics
“Exposure to JNJ-64024701 was compromised following the development of ADAs in the 1-month repeat-dose toxicity study in cynomolgus monkeys. Longer-duration general toxicology studies with JNJ-64024701 would not provide meaningful information and are not warranted to support a BLA.”
“The limited PD effect observed in healthy monkey was expected and is not considered as an acceptable argument to omit the 13-week study. However, considering the reduced exposure and/or faster elimination of JNJ-64024701 due to ADA presence in almost all animals at this end of the study, it is obvious that a longer animal study with the tool molecule will add no additional value”
DARTAcceptedBeyond the letter
No embryo-fetal or enhanced pre- and postnatal development study; weight-of-evidence assessment instead
Why: ADAs would prevent adequate exposure throughout organogenesis in a monkey developmental toxicity study · Weight of evidence · Pharmacology or kinetics
“The FDA’s Assessment: We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”
“Adequate drug exposure would not be maintained throughout organogenesis in a cynomolgus monkey developmental toxicity study, based on the development of ADAs in cynomolgus monkeys that reduced exposure of talquetamab in the single-dose pharmacokinetic study (Mod4.2.2.2/CP2017PK002)”
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
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