Qalsody: which tox species, and why?

“From the PK point of view, the monkey was the most relevant species for non-clinical efficacy and safety studies.”

“Furthermore, a single base-pair mismatch to the Cynomolgus monkey gene suggests it may be active in NHPs, thereby enabling assessment of possible on-target effects, while wild-type animals of all other species appear not to be suitable due to at least four or more mismatches in the target sequence.”

“No ASO specifically targeting rat and mouse SOD1 was used in toxicology studies, due to the lack of sequence homology of tofersen in rodents.”

“In agreement with the CHMP (EMA/CHMP/SAWP/229464/2019) carcinogenicity studies with tofersen are regarded dispensable with respect to the life-threatening nature of ALS, the negative genotoxic potential and the absence of (pre)neoplastic changes, cell proliferation, and immune or endocrine dysfunction in chronic toxicity studies in mice and NHP’s.”

“The reproductive and developmental toxicity of tofersen was investigated in a combined study on fertility and embryo-foetal development in mice, a study on embryo-foetal development in rabbits, and on pre￾postnatal development in mice.”

“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”

“No ASO specifically targeting rat and mouse SOD1 was used in toxicology studies, due to the lack of sequence homology of tofersen in rodents.”