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

“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”

“A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”

“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”

“A safety pharmacology study assessed the effects of a single subcutaneous dose of 150 mg/kg givosiran on cardiovascular and respiratory function in male telemetered cynomolgus monkeys.”

“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”

“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”

“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”

“In a carcinogenicity study in Sprague Dawley rats administered 25, 50, or 100 mg/kg givosiran by subcutaneous injection every 28 days for up to 89 weeks (males) or 85 weeks (females), givosiran doses in rats were 2, 3, and 6 times, respectively, the MRHD based on body surface area. A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”

“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”

“A safety pharmacology study assessed the effects of a single subcutaneous dose of 150 mg/kg givosiran on cardiovascular and respiratory function in male telemetered cynomolgus monkeys. Givosiran produced no clear drug-related effects on cardiovascular and respiratory function under the conditions tested.”