Exploring the promise of hypoxia inducible factor (HIF) technology

ELEVATION 5,350 ft

Akaishi Mountains, Japan

HIF regulation harnesses the body’s natural strategy for adapting to low oxygen levels

HIF: A primary regulator involved in multiple major biological pathways

HIF technology

HIF is the primary regulator of the production of red blood cells (RBCs) in the body and a potentially novel mechanism of treating anemia. This novel mechanism of action is referred to as hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors. HIF-PH inhibitors act by simulating the body’s natural response to anemia. This allows a controlled, adaptive stimulation of the erythropoietic system in the body. This activation of the whole system results in both increased red blood cell (RBC) production and improved stabilization of the bone marrow’s iron supply, which ensures the proper incorporation of iron into hemoglobin necessary for such RBC production. This adaptive simulation is very similar to the natural response that is induced when a person ascends in altitude. At higher altitudes, low levels of oxygen circulating in the bloodstream lead to reduced HIF-PH activity in relevant cells in the kidney and liver. The reduced HIF-PH activity stabilizes and increases intracellular levels of proteins HIF1α and HIF2α (referred to as HIFα collectively). For most cells the stabilization of HIF2α is greater than that of HIF1α, which ultimately leads to an increase in erythropoietin (EPO) secretion and a subsequent increase in RBC production.

HIF-PH inhibitors work by blocking the effect of the prolyl hydroxylase enzymes, which promote the breakdown of HIFα proteins. As the breakdown is inhibited, the level of these HIFα proteins increases in cells. These HIFs are the primary protein mediators that enable the body and all of its individual cells to adapt to changes in levels of oxygen. Both HIFα proteins are consistently produced and their levels in cells are adjusted by the activity of the HIF-PH enzymes, which target the HIFα proteins for degradation. HIF1α helps cells survive under very low oxygen conditions, whereas HIF2α helps cells and the body to adapt to modest changes in oxygen, such that would occur with a change in altitude from sea level to up to 7500 feet.

When HIFα is stabilized, it travels to the nucleus of the cell, where it binds to the protein HIFß. When bound together, they induce the genetic signal for the production of EPO and several other proteins. The HIF-PH inhibitors increase HIFα levels much in the same way that a reduction in oxygen increases HIFα levels by inhibiting the HIF-PH enzymes in the body. With continued stabilization of HIFα (either by staying at higher altitude or by daily dosing of the HIF-PH inhibitor), the level of hemoglobin and RBCs will rise in order to increase the amount of oxygen circulating in the blood. In this way, once-daily dosing of vadadustat (also known as AKB-6548) may have the potential to restore the normal level of EPO for a patient with anemia.

Vadadustat, our lead compound in development, works by inhibiting HIF-PH, leading to stabilization and increased levels of HIFα, and improved production of hemoglobin and RBCs, while maintaining normal levels of EPO in patients. In addition, we believe that vadadustat’s mechanism of action provides for the ability to induce a more prominent HIF2α response (as naturally occurs with a moderate increase in altitude), and an enhancement in the normal diurnal variation of EPO, which is the normal rise and fall of EPO during each day.