What is the role of Desidustat in treating anemia in patients with chronic kidney disease?

Desidustat for Anemia in Chronic Kidney Disease

Desidustat is an effective oral HIF-prolyl hydroxylase inhibitor that is non-inferior to ESAs for treating anemia in both dialysis-dependent and non-dialysis-dependent CKD patients, with the significant advantage of oral administration and favorable effects on iron metabolism. 1, 2, 3

Efficacy and Clinical Role

• Desidustat demonstrates non-inferiority to standard ESA therapy in both dialysis-dependent and non-dialysis-dependent CKD populations, with hemoglobin increases comparable to darbepoetin and epoetin alfa 4, 1, 2, 3

• In non-dialysis CKD patients, desidustat achieved a mean hemoglobin increase of 1.95 g/dL compared to 1.83 g/dL with darbepoetin over 24 weeks, with significantly higher responder rates (77.78% vs 68.48%, p=0.0181) 2

• In dialysis-dependent CKD patients, desidustat produced a hemoglobin change of 0.95 g/dL versus 0.80 g/dL with epoetin alfa, with superior response rates (59.22% vs 48.37%, p=0.0382) 3

• The oral route of administration provides substantial practical advantages over injectable ESAs, particularly for non-dialysis and peritoneal dialysis patients, avoiding high peak serum EPO concentrations that may increase cardiovascular risks 1

Dosing Strategy

• Start with 100 mg orally three times weekly for most CKD patients, with dose adjustments based on hemoglobin response 1, 2, 3

• Lower starting doses should be considered for ESA-naïve patients compared to those transitioning from other ESAs 1

• Dose escalation options include 150 mg and 200 mg three times weekly, with dose-dependent hemoglobin responses demonstrated (mean increases of 1.57,2.22, and 2.92 g/dL for 100,150, and 200 mg respectively) 5

• Temporarily discontinue treatment if hemoglobin exceeds 12-13 g/dL, following protocols similar to other HIF-PHIs 1

Target Hemoglobin and Monitoring

• Maintain target hemoglobin levels of 10-12 g/dL, consistent with current guideline recommendations for ESAs 1

• Regular hemoglobin monitoring is necessary to maintain this target range, with dose adjustments as needed 1

• Available data do not support targeting higher hemoglobin levels with desidustat than the currently recommended targets established with ESAs 1

• Consider discontinuation if hemoglobin targets are not achieved despite dose escalation 1

Advantages Over Traditional ESAs

Iron Metabolism Benefits

• Desidustat significantly reduces hepcidin levels (p=0.0032 at Week 12, p=0.0016 at Week 24), improving iron utilization compared to darbepoetin 2

• Desidustat increases iron absorption and serum iron while demonstrating efficient iron utilization without excessive tissue iron deposition, unlike iron supplementation which increases hepcidin 6

• Desidustat improves erythroid population architecture, particularly iron-dependent polychromatic and orthochromatic normoblasts, indicating more efficient erythropoiesis 6

Lipid Profile Effects

• Desidustat produces statistically significant reductions in LDL cholesterol from baseline to Week 24 (p=0.0269) compared to darbepoetin 2

Absolute Contraindications

• Do not use in patients with polycystic kidney disease until adequate safety data emerge, as HIF activation may potentially enhance cyst expansion based on preclinical models 1

• Do not use in pediatric CKD patients under 18 years, as they were excluded from clinical trials 1

• Do not use when the anticipated treatment outcome is cure, including with primary and adjuvant chemotherapy for potentially curable malignancies 1

Special Populations Requiring Caution

• Exercise caution in kidney transplant recipients due to limited data and potential concerns about HIF-PHIs affecting immune cell function 1

• Evaluate potential drug-drug interactions when desidustat is used with other oral medications 1

Safety Profile

• Desidustat has a favorable safety profile with predominantly mild adverse events, though long-term cardiovascular safety data are more limited compared to other HIF-PHIs like roxadustat, vadadustat, and daprodustat that have undergone large cardiovascular outcomes trials 1

• In phase 2 trials, only 5 patients reported drug-related mild adverse events, with no deaths or serious adverse events 5

• The safety profile in phase 3 trials was comparable to epoetin alfa and darbepoetin, with no new or increased risks identified 2, 3

• The pleiotropic effects of HIF activation beyond erythropoiesis must be considered when evaluating long-term safety 1

Common Pitfalls to Avoid

• Do not administer desidustat with food—it should be given in fasting conditions for optimal absorption 5

• Avoid using desidustat in patients with active malignancies or those receiving curative-intent chemotherapy 1

• Do not assume cardiovascular safety equivalence with extensively studied HIF-PHIs; desidustat has more limited cardiovascular outcomes data 1

• Recognize that while desidustat improves iron utilization, baseline iron status should still be evaluated and corrected before initiating therapy, following standard CKD anemia management principles 1