What are the considerations for using desidustat in patients with impaired renal (kidney) function and anemia?

Desidustat in Renal Disease: Considerations for Use in Impaired Kidney Function and Anemia

Desidustat is an effective oral HIF-prolyl hydroxylase inhibitor (HIF-PHI) for treating anemia in patients with chronic kidney disease, with demonstrated non-inferiority to darbepoetin alfa in both dialysis and non-dialysis dependent CKD patients. 1

Efficacy and Mechanism of Action

• Desidustat is an orally bioavailable HIF-PHI that inhibits prolyl hydroxylase domain enzymes, resulting in stabilization of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis 2
• In phase 3 trials (DREAM-ND), desidustat 100 mg administered three times weekly demonstrated non-inferiority to darbepoetin alfa in increasing hemoglobin levels in non-dialysis dependent CKD patients 1
• Desidustat showed a mean hemoglobin increase of 1.95 g/dL compared to 1.83 g/dL with darbepoetin alfa over 24 weeks, meeting the non-inferiority margin 1
• The hemoglobin response rate (≥1 g/dL increase) was significantly higher with desidustat (77.78%) compared to darbepoetin alfa (68.48%) 1

Dosing Considerations in Renal Impairment

• For non-dialysis dependent CKD patients, the recommended starting dose is 100 mg three times weekly 1
• Dose adjustments should be made based on hemoglobin response, with the goal of maintaining hemoglobin levels between 10-12 g/dL 3
• Treatment should be temporarily discontinued if hemoglobin levels exceed 12 or 13 g/dL, following protocols similar to other HIF-PHIs 3
• Lower starting doses should be considered for ESA-naïve patients compared to those transitioning from other ESAs 3

Advantages Over Traditional ESAs

• Oral administration provides convenience over injectable ESAs, particularly beneficial for non-dialysis and peritoneal dialysis patients 3
• Desidustat significantly reduces hepcidin levels (p=0.0016 at Week 24 vs. darbepoetin), potentially improving iron utilization 1
• Shows efficacy in erythropoietin-resistant states by decreasing hepcidin, reducing inflammation markers (IL-6, IL-1β), and improving iron utilization 4
• May reduce anti-EPO antibody formation, which is a cause of ESA resistance in some patients 4
• Demonstrates significant reduction in low-density lipoprotein levels compared to darbepoetin alfa 1

Safety Considerations

• Desidustat received approval in India in March 2022 for treatment of anemia in adults with CKD (both dialysis and non-dialysis dependent) 2
• In clinical trials, desidustat was generally well-tolerated with mostly mild treatment-emergent adverse events 5
• No significant changes in vital signs, electrocardiographic parameters, or safety laboratory values were observed in phase 2 studies 5
• Unlike some other HIF-PHIs, specific cardiovascular safety data for desidustat in large outcomes trials is limited compared to agents like roxadustat, vadadustat, and daprodustat 3

Special Population Considerations

• Desidustat should not be used in patients with polycystic kidney disease until adequate safety data emerge, as HIF activation may potentially enhance cyst expansion based on preclinical models 3
• Not recommended for use in pediatric CKD patients, as patients under 18 years were excluded from clinical trials 3
• Caution is advised in kidney transplant recipients due to limited data and potential concerns about HIF-PHIs affecting immune cell function 3
• Should not be used when the anticipated treatment outcome is cure, including with primary and adjuvant chemotherapy for potentially curable malignancies 3

Iron Management

• Iron status should be evaluated before initiating desidustat therapy and monitored regularly during treatment 6
• Desidustat improves iron utilization in iron deficiency anemia by increasing iron absorption and decreasing hepcidin levels 7
• Unlike iron supplementation, desidustat demonstrates more efficient iron utilization without excessive iron deposition in tissues 7
• Concurrent iron supplementation may be needed to optimize response to desidustat therapy 6

Monitoring Recommendations

• Regular monitoring of hemoglobin levels to maintain target range of 10-12 g/dL 6
• Evaluate iron parameters (serum iron, TIBC, ferritin) every 3 months during maintenance therapy 6
• Monitor for signs of ESA resistance, which may require evaluation for underlying causes such as iron deficiency, vitamin deficiencies, chronic inflammatory states, occult infection or blood loss 3
• Consider discontinuation if hemoglobin targets are not achieved despite dose escalation 3

Potential Pitfalls and Limitations

• Limited long-term cardiovascular safety data compared to other HIF-PHIs that have completed large cardiovascular outcomes trials 3
• Avoid using high doses in ESA-resistant patients without identifying and addressing underlying causes of resistance 3
• The pleiotropic effects of HIF activation beyond erythropoiesis must be considered when evaluating long-term safety 3
• Potential drug-drug interactions should be evaluated when used with other oral medications 3