What is Roxadustat (Roxadustat)?

Roxadustat: A Novel Oral Treatment for Anemia in Chronic Kidney Disease

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that effectively treats anemia in chronic kidney disease patients by stimulating endogenous erythropoietin production and improving iron metabolism. Roxadustat has demonstrated non-inferiority to erythropoiesis-stimulating agents (ESAs) in maintaining hemoglobin levels in dialysis patients, but shows potential cardiovascular safety concerns in non-dialysis patients 1, 2.

Mechanism of Action

Roxadustat works through a unique mechanism:

• Inhibits prolyl hydroxylase enzymes that normally degrade hypoxia-inducible factor (HIF)
• Stabilized HIF increases endogenous erythropoietin production
• Decreases hepcidin levels, improving iron availability
• Enhances intestinal iron absorption
• Results in lower peak serum erythropoietin levels compared to injectable ESAs 2

Clinical Efficacy

Roxadustat has demonstrated significant efficacy in treating anemia in CKD:

• In dialysis patients: Non-inferior to ESAs in maintaining hemoglobin levels, with maintenance rates of 74.4-92.3% within target range (10-12 g/dL) 1, 3, 4
• In non-dialysis patients: Superior to placebo in increasing hemoglobin levels, with mean increases of 1.85-2.00 g/dL and response rates of 86% vs 6.6% for placebo 5
• Reduces need for rescue therapy (red blood cell transfusions, IV iron) compared to placebo 5
• Improves iron utilization through hepcidin reduction and increased transferrin levels 6

Safety Profile and Concerns

Several safety considerations should be evaluated when using roxadustat:

• Cardiovascular safety: In non-dialysis CKD patients, roxadustat showed potential increased risk of major adverse cardiovascular events (MACE) compared to placebo (HR 1.10; 95% CI: 0.96-1.27), with higher risk in on-treatment analysis (HR 1.38; 95% CI: 1.11-1.70) 1
• Malignancy risk: Theoretical concerns exist due to HIF's role in tumor progression; avoidance recommended in patients with active malignancy 2
• Metabolic effects: Reduces total cholesterol, LDL and HDL levels 1, 3
• Common adverse events: Hypertension, arteriovenous fistula thrombosis, headache, and diarrhea 3
• Serious adverse events: Higher incidence of serious treatment-emergent adverse events in non-dialysis CKD patients compared to controls (OR: 1.15; 95% CI: 1.02-1.29) 6

Dosing and Administration

Roxadustat is administered orally with specific dosing recommendations:

• Starting dose: Weight-based dosing
  • 70 mg three times weekly for patients weighing 45-70 kg
  • 100 mg three times weekly for patients weighing ≥70 kg 2, 4
• Dose adjustments:
  • Adjust in stepwise fashion based on hemoglobin levels and rate of change
  • Target hemoglobin range: 10-12 g/dL
  • Temporarily discontinue if hemoglobin exceeds 12 g/dL 2
• Monitoring:
  • Hemoglobin: Initially weekly, then monthly
  • Iron status: Maintain TSAT ≥20% and ferritin ≥100 ng/mL 2

Patient Selection

Optimal candidates for roxadustat therapy:

• CKD patients with anemia (Hb <10 g/dL) where other causes have been ruled out
• Patients with inflammation or functional iron deficiency who may be ESA-hyporesponsive
• Patients who prefer oral therapy over injections
• Patients with adequate iron stores (TSAT ≥20%, ferritin ≥100 ng/mL)

Avoid in patients with:

• Active malignancy
• Recent history of myocardial infarction or stroke
• High risk for thromboembolic events 2

Clinical Implications

Roxadustat represents a significant advancement in anemia management for CKD patients, offering an oral alternative to injectable ESAs with potential benefits in iron metabolism. However, the cardiovascular safety profile, particularly in non-dialysis patients, requires careful consideration when selecting appropriate patients for therapy. Regular monitoring of hemoglobin levels and potential adverse events is essential for optimal management.