AND017 is an oral HIF-PHI being developed to treat a broad range of anemia conditions. HIF is a master regulator of cellular responses to hypoxia (insufficient oxygen supply). Under normoxia (normal oxygen levels), PHDs hydroxylate the proline residues on the HIF-α. Hydroxylated HIF-α is then recognized and targeted for degradation, suppressing HIF signaling pathway and limiting the expression of hypoxia-responsive genes. Under hypoxia, PHD activity is inhibited, and HIF-α is not hydroxylated, and thus HIF-α is stabilized — thereby activating the HIF signaling pathway and inducing hypoxia-responsive gene expression.

AND017 works by selectively binding to and inhibiting PHDs, thereby mimicking the hypoxia condition. When PHDs are inhibited, HIF-α is prevented from degradation and becomes stabilized. The stabilized HIF-α translocates to the nucleus and forms a complex with HIF-β. This complex binds to hypoxia response elements (“HREs”) in the genome to drive downstream gene expression that coordinates RBC production and cellular adaptation to hypoxia and anemia. Through these mechanisms, AND017 may improve both the quantity and quality of RBCs via complementary pathways.

Abbreviations: PDK1, pyruvate dehydrogenase kinase 1; LHDA, lactate dehydrogenase A; HRE, hypoxia response element; CFU-E, colony forming unit-erythroid; EBs, erythroblast; BNIP3, BCL2 interacting protein 3.