Wainua: which tox species, and why?

“Eplontersen is pharmacologically active in monkey but not mouse.”

“The target sequence of eplontersen and inotersen is 100 % complementary to human and Cynomolgus monkey TTR mRNA, whereas 8 mismatches in mice and rats preclude effective hybridisation and, hence, pharmacological activity in these animals.”

“A parallel group administered 10 mg/kg SC ION-1184986, the mouse-specific ASO, showed reduction of ~82% in hepatic TTR mRNA, compared to controls; no adverse effects were observed.”

“The nonclinical studies of eplontersen submitted to the NDA included general toxicology studies of up to 26 weeks (mouse) and 9 months (monkey) in duration”

“The potential for adverse effects on fertility and embryofetal development (EFD) was assessed in a combined fertility and EFD study in mouse”

“Based on the negative outcome of this investigation in Tg.rasH2 mice, the lack of genotoxicity, immunosuppressive or proliferative findings in other toxicity studies, as well as the similarity of eplontersen and inotersen, which was not carcinogenic in rats, the lack of a 2 years rat carcinogenicity study is acceptable”

“Nevertheless, a mouse-specific TTR analogue ASO harbouring the same GalNAc conjugate and mixed phosphorothioate and phosphodiester backbone (ION-1184986) like eplontersen was included in the chronic repeat-dose toxicity as well as the combined fertility and embryonic development studies in mice”