Humira: which tox species, and why?

“The studies in cynomolgus monkeys are considered most relevant for human safety assessment.”

“In vitro, adalimumab is a potent inhibitor of TNFα from human, various primates including cynomolgus monkey, and dog (IC50s 10-10 –10-11 M). Neutralisation of murine TNFα was considerably weaker (>2.0 x 10-7), and adalimumab did not bind rat TNFα.”

“The studies in cynomolgus monkeys are considered most relevant for human safety assessment.”

“The studies in cynomolgus monkeys are considered most relevant for human safety assessment. Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”

“Effects on male fertility have not been studied. In females, no study beyond the developmental toxicity study in cynomolgus monkey has been performed.”

“No carcinogenicity study was performed with adalimumab. The lack of such studies is justified because there is no conventional or alternative model available, (i.e adalimumab has low/no affinity for mouse/rat TNFα, and MAHA developed after single doses).”

“Moreover, it prevented development of arthritis in two transgenic mouse models, the Tg197 (expressing a soluble human TNFα transgene) and Tg5453 (expressing a transgene that encodes human pro-TNFα), serving as disease models of polyarthritis.”