What is the role of Desidustat (hypoxia-inducible factor prolyl hydroxylase inhibitor) in treating anemia related to chronic kidney disease (CKD) in adult or geriatric patients?

Desidustat for CKD-Related Anemia

Desidustat is an effective oral HIF-prolyl hydroxylase inhibitor that is non-inferior to erythropoiesis-stimulating agents (ESAs) for treating anemia in adult CKD patients, offering the practical advantage of oral administration over injectable ESAs, though long-term cardiovascular safety data remain more limited compared to other HIF-PHIs like roxadustat, vadadustat, and daprodustat. 1, 2

Efficacy Profile

Desidustat demonstrates robust efficacy in raising and maintaining hemoglobin levels in CKD patients:

• In the DREAM-ND phase 3 trial (588 patients with non-dialysis CKD), desidustat 100 mg three times weekly increased hemoglobin by 1.95 g/dL from baseline to weeks 16-24, meeting non-inferiority criteria compared to darbepoetin (1.83 g/dL increase), with a difference of 0.11 g/dL (95% CI: -0.12,0.34). 2

• Hemoglobin responders (≥1 g/dL increase) were significantly higher with desidustat (77.78%) compared to darbepoetin (68.48%, p=0.0181). 2

• The KDIGO consensus confirms desidustat is superior to placebo and non-inferior to ESAs in increasing and maintaining hemoglobin concentration across both dialysis and non-dialysis CKD populations. 3, 1

Dosing and Administration

Starting dose and titration strategy:

• Initiate desidustat at 100 mg orally three times weekly (TIW) for both ESA-naïve and ESA-treated patients. 3

• Target hemoglobin range is 10-12 g/dL, consistent with current ESA guidelines—available data do not support targeting higher hemoglobin levels with HIF-PHIs. 1, 4

• Temporarily discontinue treatment if hemoglobin exceeds 12-13 g/dL to avoid cardiovascular risks associated with excessive hemoglobin levels. 1, 4

• Regular hemoglobin monitoring is necessary to maintain the 10-12 g/dL target range. 1, 4

Mechanistic Advantages

Desidustat offers several theoretical benefits beyond simple erythropoiesis stimulation:

• The oral route provides significant practical advantages over injectable ESAs, particularly for non-dialysis and peritoneal dialysis patients who would otherwise require clinic visits or self-injection. 3, 1

• Desidustat avoids the high peak serum EPO concentrations seen with injectable ESAs, potentially reducing cardiovascular risks. 3, 1

• HIF-PHI mechanism enhances enteric iron absorption and iron utilization by reducing hepcidin levels—desidustat significantly decreased hepcidin at weeks 12 and 24 (p=0.0032 and p=0.0016, respectively) compared to darbepoetin. 3, 2

• Desidustat may be more effective in chronic inflammatory states where ESA resistance occurs, though this remains an area of ongoing investigation. 3

Safety Considerations and Contraindications

Critical safety restrictions must be observed:

• Do not use in polycystic kidney disease (ADPKD): HIF activation may potentially enhance cyst expansion based on preclinical models, and adequate safety data are lacking. 1

• Do not use in pediatric patients: Patients under 18 years were excluded from clinical trials. 1

• Avoid in active or recent malignancy: Do not use when the anticipated treatment outcome is cure, including with primary and adjuvant chemotherapy for potentially curable malignancies, due to concerns about HIF-mediated effects on tumor growth. 3, 1

• Use caution in kidney transplant recipients: Limited data exist, and there are potential concerns about HIF-PHIs affecting immune cell function. 1

• Never combine with ESAs: Combining desidustat with erythropoietin creates additive erythropoietic stimulation, substantially increasing the risk of exceeding safe hemoglobin targets (>12 g/dL), which is associated with increased cardiovascular events, stroke, and mortality. 4

Pleiotropic Effects and Long-term Safety

Important caveats regarding HIF activation beyond erythropoiesis:

• HIF-mediated effects on cellular differentiation and growth, vascular homeostasis, inflammation, and cellular metabolism are well documented in preclinical studies and could modify the risk of cardiovascular disease, thrombosis, and malignancy. 3

• Unlike roxadustat, vadadustat, and daprodustat, specific cardiovascular safety data for desidustat in large outcomes trials is limited—the DREAM-ND trial was only 24 weeks in duration. 1, 2

• The advantages of HIF-PHIs must be balanced against their potential risks, and controversy persists surrounding their long-term safety profile. 3

• Potential drug-drug interactions should be evaluated when desidustat is used with other oral medications due to polypharmacy concerns. 3, 1

Monitoring Requirements

Essential monitoring parameters during desidustat therapy:

• Monitor hemoglobin levels regularly to maintain the 10-12 g/dL target range. 1, 4

• Monitor iron status (transferrin saturation and ferritin) at least every 3 months during treatment. 4

• Evaluate for adherence, which can be difficult to monitor with oral therapy compared to in-clinic ESA administration. 3

Clinical Context for Use

When to consider desidustat over ESAs:

• Desidustat is particularly advantageous for non-dialysis CKD patients and peritoneal dialysis patients who would benefit from avoiding injectable therapy. 3, 1

• Consider desidustat in patients with chronic inflammatory states where ESA resistance may occur, though definitive evidence of superiority in this context is still emerging. 3

• The oral formulation is stable at room temperature, eliminating cold chain requirements necessary for ESAs. 3