Vadadustat
Vadadustat is an oral HIF prolyl-hydroxylase inhibitor for anaemia of chronic kidney disease, approved in Japan (2020) and by the FDA in 2024 for dialysis patients after an initial 2022 rejection. It raises endogenous erythropoietin and is prohibited by WADA as a HIF activating agent.
01 Overview
Vadadustat (Vafseo) stabilises HIF-alpha via prolyl-hydroxylase inhibition, increasing endogenous EPO. The PRO2TECT and INNO2VATE trials assessed it against conventional ESAs; the FDA initially declined approval in 2022 over cardiovascular safety in non-dialysis patients but approved it in 2024 for dialysis-dependent CKD.\n\nBecause it is an oral erythropoiesis stimulant relying on the body's own EPO, it is attractive for doping and is covered by WADA's HIF activating agents category. Its safety story again centres on thromboembolic and cardiovascular risk.
02 Mechanism
Inhibits HIF prolyl-4-hydroxylase, stabilising HIF-alpha to upregulate erythropoietin and iron-handling genes, increasing erythropoiesis.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Dialysis anaemia (medical) | 150–600 mg/day | Oral | Once daily, titrated to haemoglobin |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Raised endogenous erythropoietinIncreases endogenous EPO to correct or maintain haemoglobin orally. | Hb maintained | Clinical | |
| Non-inferior to ESAs on haemoglobinTrials showed haemoglobin control comparable to conventional erythropoiesis-stimulating agents in dialysis patients. | Comparable Hb control | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Cardiovascular / thromboembolic eventsCardiovascular safety concerns delayed US approval; thromboembolic risk is a class feature. | Severe | Trial signal | Clinical | |
| Elevated liver enzymesTransaminase elevations and rare drug-induced liver injury reported. | Moderate | Uncommon | Clinical |