Amondys 45: which tox species, and why?

“The pivotal (GLP) general toxicity studies were conducted in adult male C57BL/6NCrl mouse and cynomolgus monkey.”

“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”

“Proof of concept for the exon-skipping mechanism was demonstrated in studies conducted under IND 77429 using the MDX mouse model of muscular dystrophy.”

“The pivotal (GLP) general toxicity studies were conducted in adult male C57BL/6NCrl mouse and cynomolgus monkey.”

“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”

“Administration of casimersen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”

“In that model, the mutation is located in exon 23 of the dystrophin gene; therefore, a surrogate murine antisense oligonucleotide was developed (AVI-4225) to demonstrate the pharmacology of the exon-skipping activity.”