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

“Elexacaftor was not genotoxic in a bacterial and a mammalian in vitro assay in the presence or absence of S9 metabolizing mix. Elexacaftor was also not genotoxic in a chromosomal aberration assay in vivo.”

“A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested. A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor. No evidence of tumorigenicity was observed in rats at elexacaftor oral doses up to 10 mg/kg/day”

“In conclusion, the NOAEL for reproductive toxicity was determined to be 55 mg/kg/day in males and 25 mg/kg/day in females based on lower male and female fertility, male copulation, and female conception indices at 75 mg/kg/day (males) and 35 mg/kg/day (females).”

“Effects of elexacaftor on the cardiovascular system were assessed in telemetered dogs. A single dose of elexacaftor up to a nominal dose of 30 mg/kg (24.78 mg/kg actually measured) did not result in any changes in body temperature, blood pressure, pulse pressure, heart rate, or ECGs.”

“Elexacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro mammalian cell micronucleus assay in TK6 cells, and in vivo mouse micronucleus test.”

“Elexacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro mammalian cell micronucleus assay in TK6 cells, and in vivo mouse micronucleus test.”

“Elexacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro mammalian cell micronucleus assay in TK6 cells, and in vivo mouse micronucleus test.”

“A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested. A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor.”

“negative in teratogenicity and carcinogenicity assays (based on the 6-month study in mouse only; the 2-year carcinogenicity study in rat will be completed as a post-marketing requirement)”

“VX-445 inhibited potassium hERG channel by only 31.2 ± 2.4% at 30 μM, suggesting a low risk for QT prolongation at clinical relevant plasma concentrations.”