Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Tecvayli: what flexibility did regulators accept, and why?
teclistamab · BCMA x CD3
Flexibility accepted
Study lengthAcceptedBeyond the letter
Only a 5-week repeat-dose monkey study; no 13-week study
Why: No findings and neutralizing ADAs in the 5-week study; a 13-week study would not provide meaningful information · Weight of evidence
“Given the dearth of findings and the induction of neutralizing ADAs in the 5-week repeat-dose toxicity study in cynomolgus monkeys, a 13-week repeat-dose toxicity study would not provide meaningful information and is not warranted to support a BLA.”
SpeciesCriticised but acceptedBeyond the letter
No pharmacodynamic activity in the monkey toxicity study (lower monkey BCMA affinity, few target cells, neutralizing ADAs)
Why: PD absence attributed to lower monkey BCMA affinity, few BCMA-expressing target cells and neutralizing ADAs · Pharmacology or kinetics
“Teclistamab was administered at dose levels expected to be pharmacologically active, but there was no evidence of pharmacodynamic (PD) activity or teclistamab-related adverse effects.”
“Lack of teclistamab PD activity may be attributed to the lower binding affinity of teclistamab to cynomolgus monkey BCMA, the paucity of BCMA-expressing target cells in healthy cynomolgus monkeys, and the decreased teclistamab systemic exposure in animals affected by neutralizing ADAs.”
DARTAccepted
No reproductive and developmental toxicity studies; weight-of-evidence assessment using BCMA biology and BCMA-deficient mice
Why: No BCMA expression in human reproductive organs, so on-target/off-tumor risk in these tissues relatively low · Weight of evidence · Within the guideline
“The Applicant’s Position: No reproductive and developmental toxicity studies were conducted for teclistamab. In accordance with ICH S5(R3) and S6(R1) and the US FDA Guidance for Oncology, a weight of evidence based on the intended patient population, BCMA target biology including data from genetically modified mice that lack BCMA,”
“The FDA’s Assessment: We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity. There is no BCMA gene or protein expression in human reproductive organs; therefore, the risk of on-target/off-tumor toxicity in these tissues is relatively low.”
OtherVerdict not stated
Monkey toxicity study used IV dosing while the clinical route is subcutaneous
“This study evaluated the IV route of administration, whereas the clinical route of administration is subcutaneous (SC).”
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)
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