Vyondys 53: genotox, carcinogenicity and repro: done or skipped?

“Golodirsen was negative in an adequately conducted standard battery of in vitro (Ames, chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”

“No carcinogenicity studies have been conducted. The sponsor has conducted dose-ranging (DR) studies (reviewed below) to support planned carcinogenicity studies.”

“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”

“In the only in vivo safety pharmacology study, golodirsen (0, 5, 40, or 320 mg/kg IV) had no effects on CNS, cardiovascular, or respiratory parameters in four male cynomolgus monkeys.”

“Golodirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”

“Golodirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”

“Golodirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”

“Administration of golodirsen 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, 30, 100, or 300 mg/kg) weekly for up to 102 weeks by intravenous injection resulted in no increase in neoplasms.”

“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”

“Results of the hERG assay gave an IC50 of greater than 300 µM. Therefore, SRP-4053 is not predicted to result in hERG-mediated cardiotoxicity.”