Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Hemlibra: what flexibility did regulators accept, and why?
emicizumab · FIXa x FX
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies for a chronic prophylactic antibody; written carcinogenicity assessment used instead
Why: No pharmacologically relevant rodent species; sponsor's carcinogenicity assessment judged sufficient, with ECAC concurrence · No relevant species · Within the guideline · Weight of evidence
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
“The Sponsor subsequently submitted the requested carcinogenicity assessment to the IND on July 9, 2015, and upon our review the Division agreed that the carcinogenicity assessment was sufficient to waive the requirement for additional nonclinical carcinogenicity studies.”
DARTVerdict not stated
No reproductive or developmental toxicity studies (fertility, embryo-fetal, pre/postnatal)
Why: Hemophilia A is X-linked recessive; 99% of patients are male, so use in females exceedingly rare · Other reason
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner. Males represent 99% of the patients with hemophilia A, thus it would be exceedingly rare for females to be prescribed this drug.”
Efficacy modelCriticised but acceptedBeyond the letter
Monkey acquired hemophilia A efficacy models poorly characterised at initial application
Why: Adequate justification of the parameters measured was subsequently provided · Other reason
“While the results are supportive of the proposed use, at the time of initial application, the models were poorly characterised. However, adequate justification of the choice of parameters measured was subsequently provided.”
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
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