Leqvio

“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.”

“Inclisiran was also well-tolerated in repeat dose studies up to 29-weeks of duration in rats and 40-weeks of duration in monkeys.”

“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.”

“It is important to note that animals were dosed more frequently in toxicology studies (QD to Q4W) than in clinical studies (Q3M or Q6M).”

“Inclisiran was negative in an adequate panel of mutagenicity assays.”

“Inclisiran lacked tumorigenic potential in these studies.”

“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).”

“A dedicated safety pharmacology study to evaluate neurological function was not performed; however, neurological evaluations were incorporated into the 40- week repeat dose toxicology study where monkeys were administered 0, 30, 100 or 300 mg/kg inclisiran by subcutaneous injection every 28 days.”

“Since none of the findings were considered adverse, the NOAEL was 300 mg/kg/28 days and provides a 19-fold exposure multiple to clinical exposure based on body”

“In a 40-week toxicity study in NHPs, delayed or suppressed IgM (data not shown) and IgG (see Figure 1, below) responses were observed across the dose range at ≥ 2 times the clinical MRHD (BSA) (≥ 30 mg/kg Q4W) in response to keyhole limpet hemocyanin (KLH) sheep antigen”

“In rats, inclisiran-associated radioactivity widely distributed to most tissues with the highest concentrations (based on Cmax) observed at the subcutaneous dose site, and in the liver (target organ), and kidney cortex (site of elimination).”

“Toxicities with inclisiran were generally non-adverse and largely secondary to tissue accumulation of drug.”