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

“Acoramidis showed no mutagenic or clastogenic activity in a standard battery of genotoxicity studies, which included a bacterial reverse-mutation study and rat micronucleus and alkaline comet assays (Table 70).”

“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”

“Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18-times the clinical exposure at the MRHD based on AUC.”

“The reported IC50 of >50 µM represents a >33-fold margin over the free fraction of the high clinical exposure estimated at 12,300 ng/mL. A GLP dog telemetry study demonstrated no concentration QT effect at multiple plasma concentrations above the high clinical exposure estimated at 12,300 ng/mL”

“Acoramidis was not mutagenic in a standard and valid GLP-compliant Ames assay up to 5000 µg/ml.”

“The genotoxic potential of acoramidis was assessed in a battery of three genotoxicity studies and includes an in vitro Ames test (8358481) and two in vivo studies: micronucleus and comet assays (8358482).”

“There was no evidence of mutagenic or clastogenic potential with acoramidis in a standard battery of tests that included the in vitro bacterial reverse mutation assay and the in vivo rat micronucleus and alkaline comet assays.”

“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”

“Both studies were reviewed previously under the IND and were concluded to be negative.”

“The reported IC50 of >50 µM represents a >33-fold margin over the free fraction of the high clinical exposure estimated at 12,300 ng/mL. A GLP dog telemetry study demonstrated no concentration QT effect at multiple plasma concentrations above the high clinical exposure estimated at 12,300 ng/mL”