Bizengri
zenocutuzumab · HER2 x HER3No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Vabysmo: what flexibility did regulators accept, and why?
faricimab · VEGF-A x Ang-2
Flexibility accepted
CarcinogenicityAccepted
No rodent carcinogenicity studies for a chronic ophthalmic product; weight-of-evidence assessment instead
Why: Not fully cross-reactive in rodents; anti-angiogenic mechanism and weight of evidence suggest no carcinogenic potential (ICH S6 (R1)) · Within the guideline · No relevant species · Weight of evidence
“No standard rodent carcinogenicity studies have been conducted as faricimab is not fully cross-reactive in rodents. The intended anti-angiogenic effects of faricimab and the weight of evidence do not suggest a carcinogenic potential of faricimab.”
“Faricimab is a biotechnology-derived pharmaceutical, and the need for animal studies for carcinogenic potential of faricimab has been assessed, consistent with ICH S6 (R1) guidance.”
DARTAcceptedBeyond the letter
No pre- and postnatal development study; literature on VEGF-A/ANG-2 knockouts used for risk
Why: ADA formation and exposure loss in monkeys prevent sufficient systemic exposure · Pharmacology or kinetics · Weight of evidence
“A pre- and postnatal development study could not be conducted in cynomolgus monkeys due to ADA formation and exposure loss observed in general toxicology studies preventing sufficient systemic exposure with faricimab in such a study.”
“This reviewer agrees with the Applicant conclusions.”
DARTAccepted with a conditionBeyond the letter
Fertility assessed only by reproductive organ weights and histopathology in the 6-month study; menstrual cycling not monitored
Why: Risk to female reproductive function already established; label states possible risk to reproductive capacity · Pharmacology or kinetics
“The Applicant explained that menstrual cycling was not explicitly monitored in the 6-month monkey study as it would not have contributed to human risk assessment in view of the already established risk of perturbation of female reproductive function.”
“As the mechanism of action support a theoretical risk for effects on fertility, this reviewer agrees with including language in the proposed label that faricimab may pose a risk to reproductive capacity (Sections 8.3 and 13.1).”
Safety marginCriticised but acceptedBeyond the letter
Exposure margin at the ocular NOAEL (0.5 mg/eye/dose, 6-month monkey) only around 1x human
Why: Ocular immune-mediated effects seen in animals were not recorded in the clinical program · Human data
“the exposure margin at the NOAEL of 0.5 mg/eye/dose (based on the animal immune mediated ocular effects in the 6 month monkey study) with mean AUC(0-72h) = 20200 ng•hr/mL and a mean Cmax = 220 ng/mL on Day 141, is only around 1 when compared to values of human exposure”
“The ocular immune-mediated effects observed in animal studies were not recorded in the completed clinical development program with faricimab.”
First doseAccepted with a conditionBeyond the letter
At IND, nonclinical data supported the 0.5 mg/eye starting dose but not the 6.0 mg/eye high dose
Why: Unclear whether ocular inflammation is direct or ADA-mediated; clinical protocol adjustment recommended
“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”
“Since it is not known whether RO6867461 causes direct inflammation or indirect inflammation through an ADA response in the eye, it is recommended that the clinical protocol be adjusted to accommodate safety concern.”
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)
Tecvayli
teclistamab · BCMA x CD3Only a 5-week repeat-dose monkey study; no 13-week study
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead