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

“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate and negative.”

“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”

“The LD was the NOAEL for maternal and developmental toxicity.”

“There were no adverse findings in neurological exams incorporated into the 13-week and 9-month studies in monkey.”

“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate and negative.”

“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate and negative.”

“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate and negative.”

“Subcutaneous administration of vutrisiran to male rats (0, 4, 7.5, or 15 mg/kg once every 4 weeks or 15 mg/kg once every 12 weeks) for 99 weeks and to female rats (0, 6, 12.5, or 25 mg/kg once every 4 weeks or 25 mg/kg once every 12 weeks) for 86-87 weeks resulted in no increase in tumors.”

“The potential carcinogenicity of vutrisiran is being assessed in ongoing 2-year studies in rat and mouse; final reports will be submitted post approval per prior agreement with the Division.”

“No consistent drug-related effects on heart rate, blood pressure, ECG, body temperature, or respiration rate were observed in a safety pharmacology study in telemetered male cynomolgus monkeys administered single doses of up to 300 mg/kg SC vutrisiran.”