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.”
Species: general tox
Sprague Dawley rat (13-week, 6-month) and cynomolgus monkey (13-week, 9-month)
“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).”
Species: DART
SD rat (fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“GLP-compliant studies consisted of a fertility and early embryonic development (to implantation) study, an embryofetal development study, and a pre- and postnatal development study in SD rat, and an embryofetal development study in New Zealand White rabbit.”
Species: carcinogenicity
Rat and mouse (2-year)
“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”
Surrogate used in
Yes: rodent surrogate GalNAc-siRNA (AD-59206) in rat reproductive study; TTR, vitamin A, thyroxine reductions without adverse effects
“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.”
Genotox: Ames
Bacterial mutagenicity: 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.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: 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.”
Genotox: in vivo
Rat bone marrow micronucleus: 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 model
Rat SC every 4 or 12 weeks for 99 (males) / 86-87 (females) weeks: no increase in tumors
“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.”
Carcinogenicity timing
2-year rat and mouse studies ongoing at approval; final reports to be submitted post approval
“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.”
hERG / QT
Monkey telemetry (single SC doses up to 300 mg/kg): no consistent effects on heart rate, blood pressure or ECG
“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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Amvuttra don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 9)
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.”
Anti-drug antibodies: animals
Rat (6-month): no ADA; monkey (9-month): ADA in eight of 32, no impact on pharmacology, TK or toxicity
“No anti-drug-antibodies (ADAs) were discovered in the 6 months toxicity study in rats, whereas eight of the 32 monkeys in the 9 months chronic toxicity study developed ADAs that did not impact on the pharmacology, toxicokinetic or toxicity of vutrisiran.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 4/179 (2.2%); no impact on PK, PD, efficacy or safety
“Across Study 001 and HELIOS-A, the incidence of treatment-emergent ADA due to vutrisiran was 2.2% (4/179). The presence of ADA had no impact on the PK, PD, efficacy, or safety of vutrisiran.”
Label warnings
- Reduced Serum Vitamin A Levels and Recommended Supplementation
Metabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Amvuttra don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month SC cynomolgus monkey study (and 6-month rat); no recovery phase
“Given the generally mild effects, recovery periods did not follow the dosing phases of the 6 and 9 months toxicity studies.”
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”
DART package
Species: DART
SD rat (fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“GLP-compliant studies consisted of a fertility and early embryonic development (to implantation) study, an embryofetal development study, and a pre- and postnatal development study in SD rat, and an embryofetal development study in New Zealand White rabbit.”
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.”
PPND / ePPND: when
GLP PPND in rat completed and submitted with the marketing application; no adverse effects
“In a GLP pre- and postnatal development study in rat, SC administration of vutrisiran (0, 5, 10, or 20 mg/kg on GD 7, 13, and 19, and lactation days 6, 12, and 18) resulted in no adverse effects.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”
Carcinogenicity model
Rat SC every 4 or 12 weeks for 99 (males) / 86-87 (females) weeks: no increase in tumors
“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.”
Carcinogenicity timing
2-year rat and mouse studies ongoing at approval; final reports to be submitted post approval
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAELs (150 mg/kg rat, 300 mg/kg monkey monthly) ~600x and ~4400x human AUC at 25 mg Q3M
“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. Plasma exposures (AUC) at the NOAELs were ~600 and ~4400 times, respectively, those expected in humans at the proposed clinical dose of 25 mg once every 3 months, after adjusting for the 3-fold difference in dosing frequency.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
hTTR V30M transgenic mice and cynomolgus monkeys: up to >=98% serum TTR reduction
“Subcutaneous (SC) administration of vutrisiran to hTTR V30M transgenic mice and cynomolgus monkeys resulted in maximal reductions of ≥98% in serum TTR protein.”
Why that model
TTR binding region identical in human and monkey but not conserved in mice, rats, rabbits; in vivo work limited to monkeys and V30M transgenic mice
“As the binding region of vutrisiran in the TTR mRNA is identical between humans and monkeys, but is not conserved in mice, rats and rabbits, non-clinical in vivo “proof-of-concept” investigations were restricted to monkeys and transgenic mice expressing the most prevalent human valine to methionine variant of TTR at amino acid 30 (V30M).”
Reviewer's view of the efficacy data
EMA: vutrisiran effectively silenced TTR in monkeys and human transgenic mice; profile consistent with GalNAc-siRNA class
“Vutrisiran effectively silenced TTR transcript levels in monkeys and human transgenic mice. The general pharmacokinetic and toxicological properties of vutrisiran coincide with earlier experience gained with other members of this class of GalNAc-conjugated siRNAs.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies at approval; rat and mouse studies deferred to postmarketing requirements
Why: Serious indication with limited life expectancy; deferral previously agreed · Serious disease
“Carcinogenicity studies were not submitted in the NDA but are to be conducted post-approval (as PMRs), as agreed to by the division (DN1), if vutrisiran is approved.”
“Considering the proposed vutrisiran treatment of a serious indication with limited life-expectancy, the delayed completion of carcinogenicity studies post approval has been previously accepted (EMEA/H/SA/3876/1/2018/PA/III, 2018).”
DARTAccepted with a conditionBeyond the letter
Target-mediated reproductive and developmental effects not evaluated; rat and rabbit lack TTR sequence homology
Why: No sequence homology in rat or rabbit; Vitamin A deficiency effects on reproduction well known; supplementation recommended · No relevant species · Weight of evidence
“Target-mediated effects on reproductive function and development were not evaluated in rat or rabbit because of the lack of sequence homology;”
“The effects of Vitamin A deficiency on reproductive function and embryofetal development are well known (e.g., Clagett-Dame M, Knutson D. Nutrients 2011, 3, 385-428; doi:10.3390/nu3040385), and Vitamin A supplementation is to be recommended in patients with hTTR treated with vutrisiran.”
RecoveryVerdict not stated
No recovery periods in the 6-month rat and 9-month monkey toxicity studies
Why: Generally mild effects · Other reason
“Given the generally mild effects, recovery periods did not follow the dosing phases of the 6 and 9 months toxicity studies.”
OtherAccepted
No single-dose toxicity studies conducted
Why: In accordance with prevailing ICH and European guidance · Within the guideline
“Single dose toxicity studies have not been conducted with vutrisiran, which is endorsed in accordance with prevailing ICH and European guidance (EMA/CPMP/ICH/286/1995; EMA/CHMP/SWP/81714/2010).”
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