Reproductive toxicity of denosumab in cynomolgus monkeys

- Denosumab is a monoclonal antibody that inhibits bone resorption.
- No maternal, developmental toxicity or teratogenicity was seen in an EFD study.
- Increased stillbirths were seen in the PPND study.
- No effect on maternal mammary gland histomorphology, lactation, or fetal growth.
- Postnatal mortality, decreased growth/development, lymph node agenesis in infants.

Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, an essential mediator of osteoclast formation, function, and survival. Reproductive toxicity of denosumab was assessed in cynomolgus monkeys in an embryofetal development study (dosing GD20-50) and a pre-postnatal toxicity study (dosing GD20-parturition). In the embryofetal toxicity study, denosumab did not elicit maternal toxicity, fetal harm or teratogenicity. In the pre-postnatal toxicity study, there were increased stillbirths, and one maternal death due to dystocia. There was no effect on maternal mammary gland histomorphology, lactation, or fetal growth. In infants exposed in utero, there was increased postnatal mortality, decreased body weight gain, and decreased growth/development. Denosumab-related effects in infants were present in bones and lymph nodes. There was full recovery at 6 months of age from most bone-related changes observed earlier postpartum. The effects observed in mothers and infants were consistent with the pharmacological action of denosumab.