Amvuttra
vutrisiran
Species
MonkeyRatRabbit
Longest study
40 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey only pharmacologically active; rat for off-target/class tox); rabbit EFD
“The general toxicity of vutrisiran was tested in GLP-compliant subcutaneous (SC) toxicity studies in Sprague Dawley (SD) rat (13-week, 6-month) and cynomolgus monkey (13-week, 9-month).”
Why that species
TTR mRNA binding region fully homologous in human and cynomolgus, not in rodent or rabbit
“There is complete homology between human and cynomolgus monkey, but not rodent (mouse, rat) or rabbit, TTR mRNA binding regions. Therefore, vutrisiran is pharmacologically active only in monkey.”
Surrogate molecule
Yes: rodent surrogate GalNAc-siRNA AD-59206 in rat fertility/DART to assess TTR, vitamin A, thyroxine reduction
“Reductions in serum TTR, Vitamin A, and thyroxine following administration of AD-59206 (a rodent surrogate GalNAc-siRNA; 30 mg/kg/week for 3 doses SC prior to mating, then on GD 6, 12, and 17) were not associated with any adverse effects.”
Study lengthopen answer page →
Longest pivotal study
40 weeks
“In the pivotal general toxicology studies of SC vutrisiran in rat (13- and 26-week) and cynomolgus monkey (13- and 40-week), non-adverse findings were observed in the liver (both species), kidneys (rat), and lymph nodes (monkey).”
Pivotal GLP studies
Rat 13-week and 26-week SC monthly; monkey 13-week and 9-month (40-week) SC every 4 weeks
“Frequency of dosing: Every 4 weeks, Day 1 to Day 281 Route of administration: SC injection to the dorsal region”
Route in tox
Subcutaneous, monthly (every 4 weeks)
“Frequency of dosing: Every 4 weeks, Day 1 to Day 281 Route of administration: SC injection to the dorsal region”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all 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.”
Carcinogenicity
Not submitted at approval (PMR); later 2-year mouse and rat studies showed no tumor increase
“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”
Reproductive & developmental
Rat fertility (with surrogate), rat and rabbit EFD, rat PPND; rat EFD toxicity at maternally hepatotoxic doses
“The LD was the NOAEL for maternal and developmental toxicity.”
Safety pharmacology
Standalone monkey CV/respiratory telemetry (single dose up to 300 mg/kg); neuro exams in 13-week and 9-month monkey studies
“There were no adverse findings in neurological exams incorporated into the 13-week and 9-month studies in monkey.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL = high doses (150 mg/kg rat, 300 mg/kg monkey monthly); ~600x/~4400x human AUC; non-adverse liver, kidney, lymph node findings
“The no observed adverse effect levels (NOAELs) in the chronic studies were the high doses of 150 and 300 mg/kg/month in rat and monkey, respectively.”
Risksopen answer page →
Immune & cytokine safety
No ADA in rats; non-dose-related ADA in 8/32 monkeys without impact; no cytokine stimulation in vitro or in monkeys
“Vutrisiran did not stimulate various cytokines in human whole blood samples in vitro and in a 13 weeks DRF toxicity study in monkeys in vivo.”
Biodistribution & persistence
Rat QWBA: highest in liver, lymph nodes, kidneys; detectable in all tissues at 672 h; not in fetal tissue
“Based on the QWBA data, radioactivity in tissues generally peaked by 48 hours postdose, and was highest in liver, lymph nodes, kidneys, and thoracic ducts.”
Modality-specific risk
On-target vitamin A and thyroxine reduction (DART relevance); rat hepatocellular changes and renal basophilic granules
“vutrisiran was demonstrated to reduce circulating Vitamin A levels in monkey and human, consistent with TTR protein being a major carrier of Vitamin A.”