HIF-PH Inhibitors for Anemia

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in oxygen, or hypoxia, in the cellular environment. The regulation of HIF impacts the body’s response to reduced oxygen, injury and infection. The ability to control HIF regulation may lead to treatments for many indications including anemia, fractures and wounds, and the enhancement of antibiotic therapy. Akebia is initially focusing HIF drug development efforts on anemia, due to the ability of HIF to induce the production of red blood cells via erythropoiesis.

HIF is most active during hypoxic conditions. In conditions of normal oxygenation, HIF is quickly hydroxylated via a Hypoxia inducible factor prolyl hydroxylase (HIF-PH) and subsequently degraded via the proteasome pathway. Patients with anemia of chronic kidney disease and anemia of inflammatory disease do not produce adequate amounts of EPO, the primary peptide hormone that directly stimulates the production of new red blood cells in the bone marrow, to maintain normal hemoglobin. By inhibiting HIF-PH, Akebia’s small molecule drug stabilizes HIF, which in turn enhances expression of EPO and other HIF-dependent genes that are required for efficient red blood cell production.

Akebia’s HIF-PH drug development program has yielded orally active compounds that increase endogenous erythropoietin (EPO) production in animals. The inhibition of the prolyl hydroxylase enzyme provides a potentially safer mechanism to elevate EPO levels than injectable EPO protein.