Leqvio: which tox species, and why?

“The drug was pharmacologically active in both rats and NHPs, and therefore these assessments represent characterization of both on-target and off-target effects.”

“The applicant states that the nucleotide sequence of inclisiran exhibits complete homology to the analogous sequences in the human and Cynomolgus monkey PCSK9 genes and partial homology to the rat and mouse PCSK9 gene sequences.”

“Sequence homology was sufficient to result in pharmacologic activity (LDL-C decreases) of inclisiran in all three species.”

“Toxicological characterization of inclisiran was performed in studies of 29 weeks in rats and 40 weeks in NHPs at doses up to 8 times (≤ 250 mg/kg Q4W) and 19 times (300 mg/kg Q4W) the MRHD (based on BSA), respectively.”

“Embryo-fetal assessments in rats and rabbits and a pre and postnatal development study in rats did not demonstrate evidence of reproductive or developmental risk at any dose tested, representing up to 5 and 10 times clinical MRHD (BSA), respectively (≤ 150mg/kg/day in both species). Inclisiran produced no adverse impact on fertility or early embryonic development in rats at up to 8 times the MRHD (BSA) (≤ 250 mg/kg/day).”

“Inclisiran was evaluated in a lifetime (2 year) rat carcinogenicity study at up to 8 times the clinical MRHD (BSA) (≤ 250 mg/kg Q4W) and in a 6-month study in Tg rasH2 mice (≤ 1500 mg/kg Q4W). Inclisiran lacked tumorigenic potential in these studies.”

“Sequence homology was sufficient to result in pharmacologic activity (LDL-C decreases) of inclisiran in all three species.”