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.”
Species: general tox
Rat (6-month) and dog (9-month), 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”
Species: DART
Rat and rabbit
“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.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“The carcinogenic potential of vadadustat was evaluated in a 2-year rat study and a 6-month transgenic mouse study, both under GLP compliance.”
Surrogate used in
No surrogate used
“A dose-related erythropoietic response was observed in mice, rats, and dogs, showing that the appropriate pharmacological response occurs in the toxicological species used.”
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.”
Genotox: Ames
Negative
“Vadadustat was negative for mutagenicity in the in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
CHO chromosomal aberration positive; GreenScreen equivocal
“Vadadustat was negative for mutagenicity (Ames assay) but positive results were obtained in the in vitro CHO assay for chromosomal aberrations and the GreenScreen assay. The positive in vitro chromosome aberration assay with CHO cells and equivocal GreenScreen assay suggested that vadadustat may be clastogenic and/or aneugenic.”
Genotox: in vivo
Rat peripheral blood lymphocyte chromosomal aberration and comet assays: negative
“Vadadustat exhibited clastogenic activity in vitro but was negative in the in vivo chromosomal aberration assay in peripheral blood lymphocytes and comet assay in rats. Based on the weight of evidence, vadadustat is not considered genotoxic.”
Carcinogenicity model
2-year rat and 6-month Tg rasH2 mouse: not carcinogenic (rat exposure ~0.3x clinical AUC)
“The carcinogenic potential of vadadustat was evaluated in a 6-month RasH2 transgenic mouse study and in a 2-year rat study. 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.”
Carcinogenicity timing
2-year rat and 6-month transgenic (rasH2) mouse GLP studies completed before the marketing application
“The carcinogenic potential of vadadustat was evaluated in a 2-year rat study and a 6-month transgenic mouse study, both under GLP compliance.”
hERG / QT
No meaningful hERG effect; no ECG (P-QRS-T) changes in rats or dogs
“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.”
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.
Label warnings
Boxed warning: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS
- Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access
- Hepatotoxicity
- Hypertension
- Seizures
- Gastrointestinal Erosion
- Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis
- Malignancy
Thrombosis & embolismCardiovascularHepatotoxicityNeurotoxicityGastrointestinalNephrotoxicityCytopeniasSecondary malignancy
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dog with 3-month (13-week) treatment-free recovery
“A partial recovery was observed after 3 months of a treatment-free period in both the 3-month and 9-month dog studies.”
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”
DART package
Species: DART
Rat and rabbit
“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.”
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.”
PPND / ePPND: when
Rat PPND study completed and reviewed in the NDA
“AKB-6548: An Oral Study for Effects on Pre- and Postnatal Development including Maternal Function in Rats (Study No. 1817-037)”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“The carcinogenic potential of vadadustat was evaluated in a 2-year rat study and a 6-month transgenic mouse study, both under GLP compliance.”
Carcinogenicity model
2-year rat and 6-month Tg rasH2 mouse: not carcinogenic (rat exposure ~0.3x clinical AUC)
“The carcinogenic potential of vadadustat was evaluated in a 6-month RasH2 transgenic mouse study and in a 2-year rat study. 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.”
Carcinogenicity timing
2-year rat and 6-month transgenic (rasH2) mouse GLP studies completed before the marketing application
“The carcinogenic potential of vadadustat was evaluated in a 2-year rat study and a 6-month transgenic mouse study, both under GLP compliance.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: NOAEL exposures in all species below human exposure at 600 mg QD
“Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Healthy normoxic mice and rats (EPO and erythropoiesis increases); no anemia model
“Vadadustat was evaluated in exploratory studies of healthy, normoxic mice and rats but not in any animal model of anemia.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: healthy-animal studies show intended erythropoietic pharmacology but do not capture pharmacology in the context of anemia
“These studies provide a demonstration of the intended pharmacology of increased erythropoiesis downstream of HIF-PHD inhibition; however, they do not capture potential differences in the pharmacology within the context of anemia.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
No exposure margin: NOAEL exposures in all species below human exposure at 600 mg QD
Why: Toxicity reflects polycythemia in healthy animals; in anemic patients erythropoiesis is the treatment intent and a monitoring endpoint · Pharmacology or kinetics
“Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD (Table 63). Key to interpreting the toxicology data is to understand that the nonclinical toxicology studies were conducted in healthy and non-anemic animals, in which vadadustat produces polycythemia.”
“However, a similar exposure-response to vadadustat would not necessarily occur in patients with anemia for whom increased erythropoiesis is the intent of treatment, and for which the degree of induced erythropoiesis is a primary efficacy and safety monitoring endpoint.”
CarcinogenicityVerdict not stated
Rat carcinogenicity study scheduled for 104 weeks terminated early (week 85/86 females, week 94 males)
Why: No pre-neoplastic changes or other toxicity increasing over time
“The carcinogenicity study in rats was scheduled for 104 weeks of daily treatment, however it was terminated at week 85/86 for females and week 94 for males as no signs of pre-neoplastic changes was observed or any other sign of toxicity increasing over time.”
GenotoxicityAcceptedBeyond the letter
Clastogenic in in vitro CHO chromosomal aberration and GreenScreen assays; negative in vivo chromosome aberration and comet assays
Why: Negative in vivo chromosome aberration and comet assays plus negative Ames; weight of evidence not genotoxic · Weight of evidence
“Vadadustat was negative for mutagenicity (Ames assay) but positive results were obtained in the in vitro CHO assay for chromosomal aberrations and the GreenScreen assay.”
“Overall, the in vivo chromosome aberration assay and COMET assays tested negative and, in conjunction with the negative Ames assay result, the weight of evidence suggests that vadadustat is not genotoxic, which is agreed.”
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