Attruby
acoramidis
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“There were no histopathology findings consistent with kidney injury in chronic toxicology studies in two non-human species (Study 20141689, 26-week toxicity study in rats and Study 21141692, 39-week toxicity study in dogs)”
Why that species
PK profiles in rats and dogs comparable to humans; species appropriate for acoramidis and its metabolites
“Overall, there was no significant difference observed in PK profiles between animals and humans that would limit the interpretation of animal toxicology studies and the nonclinical species used were considered appropriate for the safety of acoramidis and its metabolites in human.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat-dose toxicity studies were conducted in rats for up to 26 weeks with oral dose levels ranging from 50 to 1000 mg/kg/day.”
Species: general tox
Rat (26-week) and dog (39-week), oral gavage
“Repeated dose toxicity studies comprised studies in rats and dogs with once daily administration of acoramidis by oral gavage during up to 26 and 39 weeks, respectively.”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Developmental and reproductive toxicology studies comprised studies on male and female fertility and early embryonic development, in rats, embryo-fetal development, in rats and rabbits, and pre- and post-natal development, in rats.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”
Surrogate used in
No surrogate used; acoramidis tested directly
“Repeat-dose toxicity studies were conducted in rats for up to 26 weeks with oral dose levels ranging from 50 to 1000 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Repeated dose toxicity studies comprised studies in rats and dogs with once daily administration of acoramidis by oral gavage during up to 26 and 39 weeks, respectively.”
Pivotal GLP studies
4-, 13- and 26-week rat and 4-, 13- and 39-week dog oral studies
“The pivotal repeated dose toxicity studies comprised studies of 4, 13 and 26 weeks in rats, and of 4, 13 and 39 weeks in dogs.”
Route in tox
Oral gavage, once daily
“Repeated dose toxicity studies comprised studies in rats and dogs with once daily administration of acoramidis by oral gavage during up to 26 and 39 weeks, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, rat micronucleus and alkaline comet assays
“Acoramidis showed no mutagenic or clastogenic activity in a standard battery of genotoxicity studies, which included a bacterial reverse-mutation study and rat micronucleus and alkaline comet assays (Table 70).”
Carcinogenicity
2-year rat and 26-week rasH2 mouse: no carcinogenic potential
“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”
Reproductive & developmental
Rat PPND: reduced pup weight gain and learning deficits at 1,000 mg/kg/day; no adverse effects at 350 mg/kg/day (~18x AUC)
“Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18-times the clinical exposure at the MRHD based on AUC.”
Safety pharmacology
hERG IC50 >50 µM (>33-fold margin over free clinical exposure); no QT effect in dog telemetry
“The reported IC50 of >50 µM represents a >33-fold margin over the free fraction of the high clinical exposure estimated at 12,300 ng/mL. A GLP dog telemetry study demonstrated no concentration QT effect at multiple plasma concentrations above the high clinical exposure estimated at 12,300 ng/mL”
Genotox: Ames
Negative up to 5000 µg/mL (GLP Ames)
“Acoramidis was not mutagenic in a standard and valid GLP-compliant Ames assay up to 5000 µg/ml.”
Genotox: in vitro mammalian
Not conducted; battery was Ames plus in vivo micronucleus and comet assays
“The genotoxic potential of acoramidis was assessed in a battery of three genotoxicity studies and includes an in vitro Ames test (8358481) and two in vivo studies: micronucleus and comet assays (8358482).”
Genotox: in vivo
Rat micronucleus and alkaline comet assays: negative
“There was no evidence of mutagenic or clastogenic potential with acoramidis in a standard battery of tests that included the in vitro bacterial reverse mutation assay and the in vivo rat micronucleus and alkaline comet assays.”
Carcinogenicity model
2-year rat (no carcinogenicity up to 50/350 mg/kg/day M/F); 26-week Tg rasH2 mouse (no tumors)
“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 104-week rat completed; reviewed under the IND before the NDA
“Both studies were reviewed previously under the IND and were concluded to be negative.”
hERG / QT
hERG IC50 >50 µM (>33-fold over free high clinical exposure); no QT effect in dog telemetry
“The reported IC50 of >50 µM represents a >33-fold margin over the free fraction of the high clinical exposure estimated at 12,300 ng/mL. A GLP dog telemetry study demonstrated no concentration QT effect at multiple plasma concentrations above the high clinical exposure estimated at 12,300 ng/mL”
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 Attruby 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 small molecules 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: Rat 26-week NOAEL 50 mg/kg/day (males, body weight loss) and 600 mg/kg/day (females) (FDA integrated review, p. 131)
NOAEL / key findings
Rat 26-week NOAEL 50 mg/kg/day (males, body weight loss) and 600 mg/kg/day (females)
“The no observed adverse effect level (NOAEL) was determined to be 50 mg/kg/day in male rats based on significant body weight reductions (>10%), and 600 mg/kg/day in female rats”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No tissue accumulation or retention; no selective association with melanin-containing tissues in pigmented rats
“Overall, there was no accumulation or retention of radioactivity in tissues. The data also suggested that [14C]acoramidis derived radioactivity did not selectively associate with melanin containing tissues in the pigmented rat.”
Modality-specific risk
Spatial learning deficits in offspring of rats given 350 or 1000 mg/kg/day
“In the water-maze test performed on PND 63 acoramidis-related effects on proximal and spatial learning deficits were noted for pups from animals administered 350 or 1000 mg/kg/day.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
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 Attruby 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 small molecules 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: Rat 26-week NOAEL 50 mg/kg/day (males, body weight loss) and 600 mg/kg/day (females) (FDA integrated review, p. 131)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral gavage dog study with 28-day recovery
“A 39-Week Study of AG10 by Oral Gavage in Dogs With a 28-Day Recovery Period”
Pivotal GLP studies
4-, 13- and 26-week rat and 4-, 13- and 39-week dog oral studies
“The pivotal repeated dose toxicity studies comprised studies of 4, 13 and 26 weeks in rats, and of 4, 13 and 39 weeks in dogs.”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Developmental and reproductive toxicology studies comprised studies on male and female fertility and early embryonic development, in rats, embryo-fetal development, in rats and rabbits, and pre- and post-natal development, in rats.”
Reproductive & developmental
Rat PPND: reduced pup weight gain and learning deficits at 1,000 mg/kg/day; no adverse effects at 350 mg/kg/day (~18x AUC)
“Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18-times the clinical exposure at the MRHD based on AUC.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal developmental toxicity study, pregnant rats received oral administration of acoramidis at doses of 0, 50, 350, or 1,000 mg/kg/day throughout pregnancy and lactation (Gestation Day 6 to Lactation Day 20).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”
Carcinogenicity model
2-year rat (no carcinogenicity up to 50/350 mg/kg/day M/F); 26-week Tg rasH2 mouse (no tumors)
“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 104-week rat completed; reviewed under the IND before the NDA
“Both studies were reviewed previously under the IND and were concluded to be negative.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week NOAEL approximately equal to (males) and 32x (females) human AUC at MRHD
“These AUC values are approximately equivalent to or 32-times the AUC at the maximum recommended human dose (MRHD) in males and females, respectively (Table 66).”
NOAEL / key findings
Rat 26-week NOAEL 50 mg/kg/day (males, body weight loss) and 600 mg/kg/day (females)
“The no observed adverse effect level (NOAEL) was determined to be 50 mg/kg/day in male rats based on significant body weight reductions (>10%), and 600 mg/kg/day in female rats”
Efficacy evidenceopen answer page →
Efficacy evidence
TTR stabilisation measured in serum from acoramidis-dosed dogs and monkeys (in vivo pharmacodynamics)
“The in vivo pharmacodynamics of acoramidis were assessed by correlating its circulating levels in serum samples from dogs and monkeys with its ability to stabilise TTR.”
Why that model
No animal model recapitulates the human ATTR phenotype (cardiac fibril deposition)
“Animal models of amyloidosis that can recapitulate the human phenotype of ATTR are not available. Therefore, no in vivo proof of concept studies of the efficacy of acoramidis were conducted.”
Reviewer's view of the efficacy data
In vitro and in vivo/ex vivo studies across species adequately described the targeted pharmacology
“The in vitro and in vivo/ex vivo studies in multiple species, including human subjects with ATTR-CM wild type and variant, have described the targeted pharmacology of acoramidis.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
No exposure margin at the NOEL for learning deficits in rat offspring of the pre- and postnatal development study
Why: Learning effects adverse only at exposures with a 21-fold margin at the NOAEL; clinical relevance considered low · Other reason
“No effects were seen in the 50 mg/kg/day group which is the NOEL for this effect. Based on AUC-exposure data at the NOEL of 50 mg/kg/day, no safety margin to human exposure at the MRHD exists for this effect.”
“Considering that the findings on learning and memory in rats are adverse only at exposures with sufficient safety margin (21-fold at the NOAEL) to the human exposure at the maximum dose, the clinical relevance is considered to be low.”
DARTAcceptedBeyond the letter
Fertility and pre- and postnatal development studies without toxicokinetics; exposure estimated from rat repeat-dose studies
Why: Exposure estimated from rat repeat-dose toxicity data · Pharmacology or kinetics
“The study has not included a toxicokinetic analysis. Based on data from the repeated dose toxicity studies in rats, it is estimated that systemic exposure (AUC) in rats at 350 mg/kg/day was 21-fold human exposure.”
“The package of developmental and reproductive toxicology studies is considered adequate.”
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