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 erythropoiesis-stimulating agents (ESAs) for treating anemia in patients with chronic kidney disease, offering the advantage of oral administration over injectable ESAs. 1, 2

Efficacy Profile

Desidustat demonstrates robust efficacy in correcting anemia in CKD patients not requiring dialysis. The DREAM-ND phase 3 trial showed that desidustat 100 mg three times weekly increased hemoglobin by 1.95 g/dL from baseline to weeks 16-24, compared to 1.83 g/dL with darbepoetin (difference: 0.11 g/dL; 95% CI: -0.12,0.34), meeting the prespecified non-inferiority margin. 2

• The hemoglobin responder rate (≥1 g/dL increase) was significantly higher with desidustat at 77.78% versus 68.48% with darbepoetin (p = 0.0181). 2
• Dose-response relationships are evident, with phase 2 data showing mean hemoglobin increases of 1.57,2.22, and 2.92 g/dL with 100,150, and 200 mg doses respectively over 6 weeks. 3
• KDIGO consensus confirms that desidustat, along with other HIF-PHIs, is superior to placebo and non-inferior to ESAs in increasing and maintaining hemoglobin concentration. 1

Mechanism and Iron Metabolism Advantages

Desidustat improves iron utilization more efficiently than traditional iron supplementation by stabilizing hypoxia-inducible factor (HIF), which stimulates both erythropoietin production and enhances iron absorption. 4, 5

• Desidustat significantly reduced hepcidin levels compared to darbepoetin at both week 12 (p = 0.0032) and week 24 (p = 0.0016), facilitating better iron mobilization. 2
• Unlike ferrous sulfate supplementation, desidustat increases circulating iron without excessive tissue iron deposition in liver and spleen, demonstrating more efficient iron utilization. 5
• The drug increases iron-dependent polychromatic normoblasts and orthochromatic normoblasts in bone marrow, indicating enhanced erythropoiesis. 5

Dosing and Monitoring Protocol

Start desidustat at 100 mg orally three times weekly in fasting conditions, with dose adjustments based on hemoglobin response to maintain target levels of 10-12 g/dL. 6, 2

• Lower starting doses should be considered for ESA-naïve patients compared to those transitioning from ESAs. 6
• Temporarily discontinue treatment if hemoglobin exceeds 12-13 g/dL to avoid supraphysiologic levels. 6
• Monitor hemoglobin levels regularly during the evaluation period (weeks 16-24) and adjust dosing accordingly. 6, 2
• If hemoglobin targets are not achieved despite dose escalation, consider discontinuation and evaluation for ESA resistance causes. 6

Safety Considerations

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. 1, 6, 3

• Phase 2 trials reported only mild treatment-emergent adverse events (TEAEs) in 5 patients, with no deaths or serious adverse events. 3
• No significant changes in vital signs, electrocardiographic parameters, or safety laboratory values were observed. 3
• The pleiotropic effects of HIF activation beyond erythropoiesis require consideration for long-term safety monitoring. 6
• Desidustat significantly reduced LDL cholesterol from baseline to week 24 compared to darbepoetin (p = 0.0269), though the clinical significance requires further evaluation. 2

Contraindications and Special Populations

Do not use desidustat in patients with polycystic kidney disease, pediatric CKD patients, or when treating potentially curable malignancies with chemotherapy. 6

• Polycystic kidney disease is an absolute contraindication due to preclinical evidence suggesting HIF activation may enhance cyst expansion. 6
• Pediatric patients under 18 years were excluded from clinical trials, making safety and efficacy data unavailable for this population. 6
• Avoid use during primary and adjuvant chemotherapy for potentially curable malignancies due to theoretical concerns about HIF's effects on tumor biology. 6
• Exercise caution in kidney transplant recipients given limited data and potential concerns about HIF-PHI effects on immune cell function. 6

Clinical Advantages Over ESAs

The oral route of administration provides significant practical advantages over injectable ESAs, particularly for non-dialysis and peritoneal dialysis patients. 6

• Eliminates the need for subcutaneous or intravenous injections three times weekly, improving patient convenience and adherence. 6
• Avoids the high peak serum EPO concentrations seen with injectable ESAs, potentially reducing cardiovascular risks. 1
• Maintains efficacy comparable to ESAs while offering superior iron mobilization through hepcidin suppression. 2

Hemoglobin Targets

Target hemoglobin levels of 10-12 g/dL should be maintained with desidustat, consistent with current guideline recommendations for ESAs. 1

• Available data do not support targeting higher hemoglobin levels with HIF-PHIs than the currently recommended targets established with ESAs. 1
• Historical trials with ESAs targeting higher hemoglobin levels (>13 g/dL) showed increased major adverse cardiovascular events, mortality, and thrombotic events. 1
• No HIF-PHI trials have compared hemoglobin normalization with currently recommended lower targets, making higher targets unjustified. 1

Regulatory Status

Desidustat received its first approval in India in March 2022 for treating anemia in adults with CKD, both dialysis-dependent and non-dialysis-dependent. 4

• The drug is currently in clinical development in China for CKD-associated anemia, in Mexico for COVID-19 management, and in the USA for chemotherapy-induced anemia. 4
• Regulatory approval was based on the DREAM-ND phase 3 trial demonstrating non-inferiority to darbepoetin. 2, 4