Vyndaqel
tafamidis
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
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Why that species
Rat and dog expected to show a pharmacologic response to tafamidis similar to humans
“These findings add relevance to the rat, rabbit and dog toxicology studies as they can be expected to exhibit a similar pharmacologic response to tafamidis as in humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Species: DART
Rat and rabbit (chosen for background data and TTR homology with humans)
“Rats and dogs were selected for use in general toxicology studies and rats and rabbits were selected for reproductive and developmental toxicity studies based on extensive background information available in these species and because of the high homology between TTR in humans, rats, rabbits, and dogs.”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Surrogate used in
No surrogate used; tafamidis tested directly
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Route in tox
Oral
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and in vivo rat micronucleus assays
“Fx-1006A was negative for genotoxicity in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo rat micronucleus assay.”
Carcinogenicity
26-week rasH2 mouse and 2-year rat: no drug-related tumors
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Reproductive & developmental
Rat PPND: reduced offspring survival and weight, delayed male sexual maturity, impaired learning and memory at 15 mg/kg/day
“Reduced survival, birth weight, postweaning body weight, delayed male sexual maturity, and impaired learning and memory were observed in the offspring of dams dosed at 15 mg/kg/day.”
Safety pharmacology
No effects on CNS, cardiovascular or pulmonary systems in core GLP battery
“In the core GLP battery of safety pharmacology studies, tafamidis meglumine had no effects on the central nervous, cardiovascular, and pulmonary systems.”
Genotox: Ames
Negative
“Fx-1006A was negative for genotoxicity in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo rat micronucleus assay.”
Genotox: in vitro mammalian
Negative: chromosomal aberration assay in human lymphocytes
“Fx-1006A was negative for genotoxicity in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo rat micronucleus assay.”
Genotox: in vivo
Negative: rat micronucleus
“Fx-1006A was negative for genotoxicity in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo rat micronucleus assay.”
Carcinogenicity model
26-week Tg.rasH2 mouse (10-90 mg/kg/day) and 2-year rat (3-30 mg/kg/day); both negative
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies completed before the US marketing application
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
hERG / QT
No clinically relevant hERG effect (≤9.3% stimulation, 5.4% inhibition); IC50 not calculable
“In a definitive GLP hERG assay, tafamidis meglumine stimulated hERG current by (mean ± standard error of the mean) 0.5% at 1 μM, 4.7% at 10 μM, and 9.3% at 30 μM and inhibited hERG current by 5.4% at 3 μM, versus 0.1% in control. An IC50 could not be calculated, however no clinically relevant effect on hERG current was apparent.”
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 Vyndaqel 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: 26-week rat NOAEL 30 mg/kg/day, the highest dose tested (FDA pharmacology/toxicology review, p. 13)
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day, the highest dose tested
“In the pivotal 26-week oral toxicity study in rat (with a 13-week interim sacrifice), the NOAEL was determined at high dose of 30 mg/kg/day”
Risksopen answer page →
Immune & cytokine safety
No specific immunotoxicity studies submitted
“No specific immunotoxicity studies were submitted.”
Biodistribution & persistence
Crosses placenta (3-4% of dose to fetal tissues); more than 30% of dose transferred to milk in rats
“Tafamidis was observed to cross the placental barrier and distribute to the foetal tissues to an extent of 3-4% of the administered dose in rats. More than 30% of the dose of tafamidis was transferred to milk when administered to lactating rats.”
Modality-specific risk
Hepatotoxicity: liver the target organ across species
“The CHMP noted that liver appeared as the target organ for toxicity in the different species tested.”
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 Vyndaqel 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: 26-week rat NOAEL 30 mg/kg/day, the highest dose tested (FDA pharmacology/toxicology review, p. 13)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral gavage GLP study in dogs; 4-week recovery only after the 13-week arm
“Dogs were administered daily oral gavage doses of tafamidis meglumine at 0, 5, 15, or 45 mg/kg/day for 13 or 39 weeks in a pivotal subchronic/chronic toxicity study (Study SYI00013) that included a 4-week recovery phase after 13 weeks of dosing.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”
DART package
Species: DART
Rat and rabbit (chosen for background data and TTR homology with humans)
“Rats and dogs were selected for use in general toxicology studies and rats and rabbits were selected for reproductive and developmental toxicity studies based on extensive background information available in these species and because of the high homology between TTR in humans, rats, rabbits, and dogs.”
Reproductive & developmental
Rat PPND: reduced offspring survival and weight, delayed male sexual maturity, impaired learning and memory at 15 mg/kg/day
“Reduced survival, birth weight, postweaning body weight, delayed male sexual maturity, and impaired learning and memory were observed in the offspring of dams dosed at 15 mg/kg/day.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In pre- and postnatal study, pregnant rats received oral administration of tafamidis meglumine at doses of 0, 5, 15, or 30 mg/kg/day throughout pregnancy and lactation”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Carcinogenicity model
26-week Tg.rasH2 mouse (10-90 mg/kg/day) and 2-year rat (3-30 mg/kg/day); both negative
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies completed before the US marketing application
“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 39-week no-effect level: at least 9-fold (females) and 11-fold (males) human steady-state AUC
“In the dog, at dose levels up to 15 mg/kg in males and 5 mg/kg in females for 39 weeks, the exposure ratios of at least 11-fold in males and 9-fold in females based on the human AUC at steady state were achieved at the no-observable-effect level.”
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day, the highest dose tested
“In the pivotal 26-week oral toxicity study in rat (with a 13-week interim sacrifice), the NOAEL was determined at high dose of 30 mg/kg/day”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro only: TTR binding and tetramer stabilisation under acid/urea denaturation and physiologic conditions
“The pharmacologic activity of tafamidis was demonstrated only in vitro, through its binding to TTR at the thyroxine binding sites and stabilisation of the TTR tetramer under non-physiologic (acid and urea denaturation conditions) and physiologic conditions.”
Why that model
No ATTR animal model available; transgenic animals do not reproduce the human pathology
“The CHMP considered that at the time of the preclinical development of tafamidis, an animal model of ATTR-PN that would reflect the clinical disease or resemble the pathology was not available, and that none of the transgenic animals described in the literature reproduce the pathology seen in ATTR patients.”
Reviewer's view of the efficacy data
CHMP: no relevant disease model; dose regimen derived from in vitro/ex vivo PK/PD and clinical PK extrapolation
“Since there is no relevant preclinical disease model, the CHMP considered that the best dose regimen was established from understanding of in vitro and ex vivo PK/PD experiments, combined with an extrapolation of clinically observed pharmacokinetics to select a dose that would achieve therapeutically relevant concentrations.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelAcceptedBeyond the letter
No in vivo pharmacology studies; efficacy supported by in vitro TTR stabilisation only
Why: No animal model reproducing ATTR pathology was available · Other reason
“No in vivo studies were performed by the applicant. The CHMP considered that at the time of the preclinical development of tafamidis, an animal model of ATTR-PN that would reflect the clinical disease or resemble the pathology was not available, and that none of the transgenic animals described in the literature reproduce the pathology seen in ATTR patients.”
“The CHMP agreed to the justification for absence of these studies.”
CarcinogenicityAcceptedBeyond the letter
No long-term rodent carcinogenicity study in the original EU dossier; 26-week rasH2 mouse study only
Why: Severe, rare disease; no alert signals in nonclinical studies including rasH2 mouse · Serious disease · Rare disease / unmet need · Weight of evidence
“The carcinogenic potential of tafamidis was not studied in a long term rodent carcinogenicity study. This was considered acceptable given the severity and low incidence of the disease together with the fact that no alert signals were identified in the nonclinical studies conducted including the TgrasH2 mouse model.”
Similar precedents
AttrubySmall molecules · acoramidis · Transthyretin (stabiliser)Rodent + dog or minipig · 39 wkEkterlySmall molecules · sebetralstat · Plasma kallikreinMonkey + rodent · 26 wkAgamreeSmall molecules · vamorolone · Glucocorticoid receptor (dissociative)Rodent + dog or minipig · 39 wkAlyftrekSmall molecules · vanzacaftor, tezacaftor and deutivacaftor · CFTRRodent + dog or minipig · 39 wkAqneursaSmall molecules · levacetylleucine · Neuronal metabolism (proposed)Rodent + dog or minipig · 39 wkDaybueSmall molecules · trofinetide · IGF-1 tripeptide analogueRodent + dog or minipig · 39 wk