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.”
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.”
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.”