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

“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.”

“A standard battery of two in vitro and one in vivo GLP-compliant genetic toxicology studies were completed with inclisiran: an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in cultured human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay. Inclisiran was neither mutagenic nor clastogenic in the three valid assays.”

“A standard battery of two in vitro and one in vivo GLP-compliant genetic toxicology studies were completed with inclisiran: an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in cultured human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay. Inclisiran was neither mutagenic nor clastogenic in the three valid assays.”

“A standard battery of two in vitro and one in vivo GLP-compliant genetic toxicology studies were completed with inclisiran: an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in cultured human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay. Inclisiran was neither mutagenic nor clastogenic in the three valid assays.”

“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.”

“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.”

“The applicant conducted a cardiovascular and respiratory safety study in conscious telemetered male Cynomolgus monkeys with SC injections of up to 250 mg/kg bw of inclisiran. Neither statistically significant effects on PR, QT or QTc intervals, or QRS duration, nor abnormal ECG waveforms or arrhythmias were attributed to administration of inclisiran.”