What is the mechanism of Desidustat?

Desidustat is an orally administered hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor designed to mimic the body's natural response to low oxygen levels, a condition known as hypoxia. This mechanism is crucial for understanding how Desidustat can be used to treat anemia, particularly in patients with chronic kidney disease (CKD) who often face challenges related to insufficient erythropoietin (EPO) production.

The primary mechanism of Desidustat involves its inhibition of the enzymes known as prolyl hydroxylase domain (PHD) proteins. These enzymes are responsible for hydroxylating specific proline residues on the HIF-α subunits under normal oxygen conditions. Hydroxylation marks HIF-α for recognition and subsequent degradation by the von Hippel-Lindau (VHL) protein complex. This degradation prevents HIF-α from accumulating and translocating to the nucleus, where it would otherwise form a heterodimer with HIF-β and initiate the transcription of various genes, including those involved in erythropoiesis, angiogenesis, and iron metabolism.

Under hypoxic conditions, the activity of PHD enzymes is inhibited due to the lack of sufficient oxygen, leading to the stabilization and accumulation of HIF-α. The accumulated HIF-α enters the nucleus, dimerizes with HIF-β, and binds to hypoxia-responsive elements (HREs) in the promoter regions of target genes. This binding activates the transcription of genes that help the body adapt to low oxygen levels, including the EPO gene. EPO is a critical hormone for the production of red blood cells (RBCs), which transport oxygen from the lungs to tissues throughout the body.

Desidustat, by inhibiting PHD enzymes, emulates the effects of hypoxia even when oxygen levels are normal. This inhibition leads to the stabilization of HIF-α, promoting its accumulation and subsequent activation of HIF-responsive genes. One of the most important outcomes of this process is the increased production of EPO, which stimulates erythropoiesis and thereby increases RBC count. This mechanism is particularly beneficial for CKD patients, who often suffer from reduced EPO production due to impaired kidney function.

Moreover, the activation of HIF-responsive genes by Desidustat also induces the expression of other proteins that play roles in iron metabolism, such as transferrin, which helps in iron transport, and ferroportin, which aids in iron export from cells. These adjustments in iron regulation are essential for efficient erythropoiesis, as iron is a critical component of hemoglobin, the oxygen-carrying molecule in RBCs.

Desidustat's oral administration provides a convenient alternative to the injectable erythropoiesis-stimulating agents (ESAs) traditionally used to manage anemia in CKD patients. By mimicking the body's natural hypoxia response, Desidustat offers a physiologically coherent approach to correcting anemia, potentially reducing the need for transfusions and the associated risks.

In summary, Desidustat operates by inhibiting PHD enzymes, leading to the stabilization of HIF-α, which then activates the transcription of genes involved in erythropoiesis and iron metabolism. This mechanism enhances the body's natural ability to produce EPO and manage iron, offering an effective treatment for anemia, especially in the context of chronic kidney disease.