Sephience: genotox, carcinogenicity and repro: done or skipped?

“Based on the weight of evidence, SEPHIENCE is not genotoxic. SEPHIENCE was negative in the Ames assay. SEPHIENCE was positive in an in vitro chromosomal aberration assay without metabolic activation but not with metabolic activation. SEPHIENCE was negative in the in vivo (micronucleus and comet) assays in rats.”

“The 2-year carcinogenicity bioassay was not included in this submission. Even though there was a negative finding in the 6-month transgenic mouse carcinogenicity study”

“There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1000 mg/kg/day, which was the NOAEL of the study; the AUC0-24 at this dose is approximately 9-fold the exposure at the MRHD (Table 53).”

“In vivo studies in male and female marmoset monkeys showed no cardiovascular effects at doses up to 1000 mg/kg/day. Overall, no sepiapterin-related adverse effects were observed in these safety pharmacology studies.”

“CNSA-001 (sepiapterin) was not mutagenic in the Ames test, the in vivo micronucleus (MN), and Comet assays in rats (Table 61).”

“However, CNSA-001 showed a positive response in vitro chromosome aberration test at 3hr and 20hr treatment without S9.”

“CNSA-001 (sepiapterin) was not mutagenic in the Ames test, the in vivo micronucleus (MN), and Comet assays in rats (Table 61).”

“Sepiapterin was administrated for 26 weeks in Tg mice at dose of 30, 100 and 300 mg/kg/day in males and 100, 300 and 1000 mg/kg/day in females. No carcinogenic effect related to sepiapterin administration was observed at any dose level in males or females in this study.”

“Therefore, a postmarketing requirement for a 2-year carcinogenicity study in rats to evaluate the carcinogenicity risk is warranted.”

“Sepiapterin had no discernible effects at the highest tested concentration of 30 µM (or approximately 7117 ng/mL, which is 2978× the mean sepiapterin free Cmax of 2.39 ng/mL at the highest targeted therapeutic dose of 60 mg/kg/day)”