What flexibility did FDA and EMA accept for approved multispecifics?

“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.”

“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.”

“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 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.”

“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro. Therefore, no specific safety pharmacology studies were conducted.”

“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”

“In vitro studies suggest some safety margin between the two cell types, however not convincing. When comparing serum concentrations in patients just after infusion with EC50 in normal melanocytes, the safety margin is below 1.”

“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.”

“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.”

“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 FDA’s Assessment: We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”

“A 3-month repeat-dose toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across the ICH regions (FDA, EMEA, and PMDA) based on the inability to maintain sufficient exposures to epcoritamab with repeated dosing.”

“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys. A risk assessment-based on a weight of evidence approach was conducted considering the mechanism of action of epcoritamab and relevant information from other B-cell targeting agents (Module 2.6.6).”

“A subsequent toxicology study was initially planned as a 26-week repeat-dose study with once weekly dosing at 1, 5, and 20 mg/kg; the FDA did not request the study to be 26 weeks in duration. The study protocol was amended due to the declining body conditions across all dose groups compared to control.”

“Standalone fertility studies were not conducted by the applicant as male and female fertility endpoints were evaluated in the 5-week study and specific immunotoxicology endpoints were evaluated in both the 5- and 9- or 14-week studies repeat dose toxicity studies.”

“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”

“Taken together, the highest dose level employed in the repeat-dose toxicity studies is not considered fully justified but given that EFGR and MET are rather well characterised targets, and that amivantamab is indicated for treatment of patients with advanced cancer, no further studies are needed.”

“None of the animal species analysed is suitable for assessing the safety of catumaxomab. Any in vivo study with catumaxomab provides results on safety of catumaxomab with limited information for humans.”

“BiLu may thus not have similar toxicological and dynamic effects in the mouse as catumaxomab has in the human leaving the safety assessment of catumaxomab largely to the clinical studies.”

“Since there are very limited possibilities to evaluate the toxicology of blinatumomab in the only non-clinical relevant species for ethical reasons, the applicant developed a surrogate BiTE molecule specific for murine CD3 and murine CD19 from rat monoclonal antibodies.”

“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.”

“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.”

“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”

“Embryo-fetal developmental toxicology studies were not conducted with odronextamab. A risk assessment based on available nonclinical data and literature was provided. This approach is agreed and is in line with previous CHMP conclusions on other members of this class of bispecific antibodies.”