A different mechanism of action

Vadadustat has been shown to inhibit hypoxia inducible factor-prolyl hydroxylase (HIF-PH), leading to stabilization and increased levels of HIFα. There are currently no approved therapies that utilize this mechanism of action.

Mechanism of Action

What is HIFα and what are its potential implications in the treatment of anemia secondary to CKD?

At high altitudes, the human body adjusts to low oxygen conditions through controlled, adaptive changes by activating the hypoxia response pathway. This pathway is called HIFα. The activation of HIFα results in short-term increases in respiratory function and longer-term changes in circulatory function, such as an increase in the production of oxygen-carrying red blood cells (RBCs). These changes help protect cells and tissues from damage when less oxygen is available.

Patients with chronic kidney disease (CKD) have reduced levels of erythropoietin (EPO) and iron in the body, which can result in decreased number of RBCs (anemia). The deficiency in RBCs causes inadequate oxygen delivery to cells and tissues. Current therapies to correct anemia in CKD include regular injections of EPO, which are associated with increased cardiovascular risk.

Vadadustat

Akebia Therapeutics is developing vadadustat, an investigational oral HIF-PH inhibitor, for the treatment of anemia secondary to CKD. Vadadustat simulates the hypoxia response pathway by stabilizing key regulatory proteins called HIFs. Under normal conditions, when sufficient oxygen is present, HIF proteins are targeted for degradation by HIF-PH to maintain homeostasis in RBC production. Under conditions of hypoxia, HIF-PH activity is reduced, resulting in HIF stabilization. Stable HIF moves to the nucleus, where it activates target genes that increase EPO synthesis, resulting in the production of new RBCs, and suppression of hepcidin to promote iron absorption and mobilization.

Vadadustat has been studied in more than 15 Phase 1 and Phase 2 clinical studies, including Phase 2 clinical studies in patients on dialysis and not on dialysis. Akebia Therapeutics has begun the next stage of development for vadadustat with INNO2VATE and PRO2TECT: global, multicenter, randomized Phase 3 programs in patients on dialysis and not on dialysis respectively.

For more information on the mechanism of action, please read our HIF biology section

Vadadustat is an investigational study drug and has not been approved for use by the U.S. Food and Drug Administration (FDA) or any regulatory authority.