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

“It can be concluded that patisiran-LNP was not genotoxic in either the in vitro or in vivo assays.”

“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study.”

“No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”

“Increased body temperature and heart rate were seen in cynomolgus monkeys after a single IV 60min infusion dose at ≥3mg/kg (max dose at 6mg/kg), giving a NOEL and NOAEL for patisiran-LNP at 1mg/kg and a LOAEL of 3mg/kg”

“Patisiran-LNP (10 mg/mL) was neither mutagenic in the bacterial reverse mutation assay, nor clastogenic or aneugenic in the mammalian chromosome aberration assay in human blood peripheral lymphocytes.”

“Patisiran-LNP (10 mg/mL) was neither mutagenic in the bacterial reverse mutation assay, nor clastogenic or aneugenic in the mammalian chromosome aberration assay in human blood peripheral lymphocytes.”

“Single IV doses of patisiran-LNP at ≤ 30 mg/kg (MTD) did not induce micronucleus formation in the bone marrow of male and female CD-1 mice.”

“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”

“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”

“In-vitro hERG testing was not conducted for the ds-siRNA but only for the possible impact from the LNP (with patisiran exchanged for an insect luciferase siRNA with no target in the human genome). There was no indication that the LNP in itself can inhibit the hERG channel (see Discussion on non-clinical aspects).”