Prolia: which tox species, and why?

“Since denosumab recognizes and neutralizes RANKL in non human primates, the cynomolgus monkey was identified as a relevant species and the main studies have been conducted in ovariectomized animals.”

“This absence is acceptably justified by the fact that the RANKL domain to which denosumab binds is entirely conserved between cynomolgus monkeys and humans.”

“Several studies have been conducted with a transgenic huRANKL knock-in mouse model expressing chimeric RANKL that can be recognized and neutralized by denosumab.”

“In the 1 month repeat dose toxicity study (101447) in young adult Cynomolgus monkeys, as the only potentially drug-related change of statistically significant elevated thyroid weights were noted in females of the high dose group that were not confirmed by histopathological findings.”

“The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse").”

“No carcinogenicity studies were conducted in accordance with available regulatory guidance.”

“Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered ("knockout") mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab.”