Vafseo
vadadustat
Species
RatMouseDog
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 (plus 3-month mouse)
“General toxicology studies were conducted in mice (3-month), rats (4-week, 3-month, 6-month), and dogs (4-week, 3-month, 9-month) using the oral route of administration”
Why that species
Dose-related erythropoietic (pharmacological) response shown in mice, rats and dogs
“A dose-related erythropoietic response was observed in mice, rats, and dogs, showing that the appropriate pharmacological response occurs in the toxicological species used.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicology profile of vadadustat has been evaluated in single- and repeat-dose studies following oral administration across multiple species (mice, rats, and dogs) for up to 6 and 9 months in rats and dogs, respectively, and in reproductive and developmental toxicity studies in rats and rabbits.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“The toxicology profile of vadadustat has been evaluated in single- and repeat-dose studies following oral administration across multiple species (mice, rats, and dogs) for up to 6 and 9 months in rats and dogs, respectively, and in reproductive and developmental toxicity studies in rats and rabbits.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies (plus 3-month mouse)
“General toxicology studies were conducted in mice (3-month), rats (4-week, 3-month, 6-month), and dogs (4-week, 3-month, 9-month) using the oral route of administration”
Route in tox
Oral
“General toxicology studies were conducted in mice (3-month), rats (4-week, 3-month, 6-month), and dogs (4-week, 3-month, 9-month) using the oral route of administration”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; clastogenic in two in vitro assays; negative in vivo rat comet and chromosome aberration assays; not genotoxic overall
“Vadadustat was negative for mutagenicity in the Ames assay. Vadadustat yielded clastogenic activity from two in vitro assays but was negative for genotoxic activity when administered to Sprague Dawley rats in an in vivo COMET and chromosomal aberration study.”
Carcinogenicity
Not carcinogenic in rasH2 transgenic mice or Sprague Dawley rats (rat exposure up to ~0.3x clinical AUC)
“Vadadustat was not carcinogenic in RasH2 transgenic mice and was not carcinogenic in Sprague Dawley rats administered vadadustat up to approximately 0.3-fold the clinical dose of 600 mg, based on AUC.”
Reproductive & developmental
No effect on fertility and not teratogenic; lower fetal and pup weights and reduced ossification at maternally toxic doses
“Vadadustat did not affect fertility or cause teratogenicity, although lower fetal weight (-7%), lower pup weight (-5% to -11%), and reduced fetal skeletal ossifications occurred at dose levels associated with maternal toxicity.”
Safety pharmacology
Transient blood pressure decrease with compensatory heart rate increase (rat, dog); no meaningful hERG effect; no ECG changes
“In both rat and dog, vadadustat caused a transient decrease in blood pressure with a compensatory increase in HR. Vadadustat had no meaningful effect in the in vitro hERG assay and did not cause changes of P-QRS-T complexes in rats or dogs.”
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 Vafseo 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: Exaggerated erythropoiesis causing thromboses, tissue necrosis and deaths; NOAEL exposures below clinical exposure at 600 mg (FDA integrated review, p. 270)
NOAEL / key findings
Exaggerated erythropoiesis causing thromboses, tissue necrosis and deaths; NOAEL exposures below clinical exposure at 600 mg
“The predominate toxicity observed in nonclinical studies can be reasonably attributed to the exaggerated pharmacological effects of excessive erythropoiesis; the toxicity was marked by thromboses, tissue necrosis, and mortalities. Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD”
Risksopen answer page →
Immune & cytokine safety
No immunotoxic signals in rat and dog repeat-dose studies; no dedicated immunotoxicity studies
“It is considered acceptable that no information has been submitted on immunotoxicity as no relevant findings have been observed in the repeat-dose toxicity studies in rats and dogs to indicate an immunotoxic potential.”
Biodistribution & persistence
Crosses the placenta into fetal tissues and is secreted into milk (rat)
“Administered to pregnant rats and lactating rats, vadadustat related compounds were detected in the fetal tissues and the milk, demonstrating that vadadustat can cross placental tissues and can be delivered to newborns via nursing.”
Modality-specific risk
Exaggerated pharmacology: polycythemia/hyperviscosity with fibrin thrombosis and mortality at clinically relevant doses; heart valve findings
“In brief, several signals were detected that were considered relevant for translation to human administration, i.e. pharmacologically exaggerated toxicities such as polycythemia/hyperviscosity which resulted in fibrin thrombosis and mortalities at clinically relevant dose levels as well as heart valvular findings.”