Exondys 51: which tox species, and why?

“The pivotal toxicity studies were conducted in mdx or C57BL mice (12-week, 3-month, and 26-week), cynomolgus monkey (12- and 39-week), and juvenile Sprague-Dawley rat (10-week).”

“For mdx mouse, the pharmacological activity of the human product cannot be tested because of differences in the dystrophin gene mutation, requiring use of a mouse-specific PMO, exon 23 skipping AON and, therefore, resulting in a different truncated dystrophin.”

“In the 3-month and 26-week studies, the mouse surrogate, AVI-4225, was administered to mdx and C57BL mice according to the same study design.”

“The pivotal toxicity studies were conducted in mdx or C57BL mice (12-week, 3-month, and 26-week), cynomolgus monkey (12- and 39-week), and juvenile Sprague-Dawley rat (10-week).”

“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs in toxicity studies.”

“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”

“In the 3-month and 26-week studies, the mouse surrogate, AVI-4225, was administered to mdx and C57BL mice according to the same study design.”