Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Columvi: what flexibility did regulators accept, and why?
glofitamab · CD20 x CD3
Flexibility accepted
Study lengthAcceptedBeyond the letter
No repeat-dose study longer than 4 weeks; 13-week monkey study waived
Why: High ADA incidence in monkeys caused loss of exposure and effect; effects similar to other B-cell depleting agents · Pharmacology or kinetics · Class precedent
“Studies longer than 4 weeks were not performed, as glofitamab was highly immunogenic in cynomolgus monkeys leading to loss of exposure and loss of the pharmacologic effect.”
“The waiver for omitting the 13-week study is therefore accepted, also as the observed effects of glofitamab is similar to that observed for other B-cell depleting agents, and no unexpected findings have been observed.”
DARTAccepted
No animal reproductive or developmental toxicity studies; weight-of-evidence risk assessment instead
Why: Weight-of-evidence per ICH S6(R1); further testing unlikely to add to current nonclinical and clinical knowledge · Weight of evidence · Within the guideline · Class precedent
“While no animal studies were conducted to assess the reproductive and developmental risks of glofitamab, a weight of evidence (WoE)-based risk assessment report was submitted.”
“Based on the justification provided, and in accordance with ICH S6 (R1) it is agreed that no further testing is required in order to elucidate the reproductive toxicity of glofitamab in cynomolgus monkeys, as it is not likely it will add further information to the current non-clinical and clinical knowledge to support the mitigation of this risk in humans.”
Safety marginAccepted
Monkey exposures below clinical: AUC multiples 0.03 to 0.28 in studies without obinutuzumab pretreatment
Why: Advanced cancer indication; adverse effects from exaggerated pharmacology; no alternative species besides monkey · Serious disease · Within the guideline · Pharmacology or kinetics
“In summary, obtained exposure levels in toxicology studies conducted without Gpt did not exceed those obtained in the clinical setting, as estimations of exposure multiples resulted in values of 0.03 to 0.28 (based on AUC), implying that CRS-related effects occur at clinically relevant dose levels.”
“The low exposure multiples are considered acceptable, taking into account the indication (advanced cancer), that the expected adverse effects of glofitamab occurs mainly due to exaggerated pharmacology or secondary to it, and that no obvious alternative animal species besides the monkey are available for toxicology studies.”
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
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)
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