What is the current approach to using hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors, such as Roxadustat (FG-4592), in treating anemia in chronic kidney disease?

Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors in Anemia of Chronic Kidney Disease

HIF-PHIs are effective oral medications for treating anemia in chronic kidney disease patients, with comparable efficacy to ESAs but with potential advantages in iron metabolism, though long-term safety monitoring is required particularly regarding cardiovascular events and malignancy risk. 1

Mechanism and Available Agents

HIF-PHIs work by inhibiting prolyl hydroxylase enzymes, which:

• Stabilize hypoxia-inducible factor (HIF)
• Increase endogenous erythropoietin production
• Improve iron metabolism by decreasing hepcidin levels
• Enhance intestinal iron absorption 1, 2

Currently available HIF-PHIs include:

• Roxadustat
• Daprodustat
• Vadadustat
• Desidustat
• Enarodustat
• Molidustat 1

Efficacy Data from Clinical Trials

Phase 3 trials have demonstrated that HIF-PHIs are effective in:

1. Non-dialysis CKD patients:

   • Roxadustat significantly increased hemoglobin compared to placebo (mean difference 1.85 g/dL) 3
   • 86% of patients achieved target hemoglobin response with roxadustat vs. 6.6% with placebo 3
   • Meta-analysis showed roxadustat increased hemoglobin (WMD=1.22 g/dL) and improved iron metabolism markers 4

2. Dialysis CKD patients:

   • Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in patients previously on ESA therapy 5
   • 84.2% of roxadustat patients achieved target hemoglobin without rescue therapy vs. 82.4% with ESAs 5

Advantages Over Traditional ESA Therapy

HIF-PHIs offer several potential benefits:

• Oral administration (versus injectable ESAs)
• Lower peak serum EPO levels compared to injectable ESAs
• Improved iron utilization through hepcidin reduction
• Potentially effective in ESA-hyporesponsive patients with inflammation 1, 2
• Decreased LDL cholesterol levels (observed with roxadustat and daprodustat) 1, 5
• Reduced need for IV iron supplementation 2

Safety Considerations and Monitoring

Cardiovascular Safety

• Most HIF-PHIs have demonstrated non-inferiority to ESAs for major adverse cardiovascular events (MACE) in dialysis patients
• In non-dialysis patients, some studies showed higher MACE rates with vadadustat compared to darbepoetin alfa 1

Malignancy Risk

• Theoretical concern due to HIF's role in tumor progression
• ASCEND-ND trial showed higher cancer-related events with daprodustat (3.7%) vs. darbepoetin (2.5%)
• No consistent signal across all HIF-PHIs
• Avoidance recommended in patients with history of malignancy 1

Other Safety Concerns

• Potential increased risk of sepsis with roxadustat in non-dialysis patients
• Theoretical concern for worsening diabetic retinopathy (not observed in trials)
• Central hypothyroidism reported with roxadustat
• Hyperkalemia and low serum bicarbonate reported in some studies 1

Dosing Recommendations

1. Starting dose:

   • Lower doses for ESA-naïve patients
   • Follow drug-specific label recommendations
   • Example: Roxadustat 70 mg three times weekly for patients weighing 45-70 kg, 100 mg for ≥70 kg 1

2. Dose adjustments:

   • Adjust in stepwise fashion based on current hemoglobin and rate of change
   • Temporarily discontinue when hemoglobin exceeds 12-13 g/dL
   • Target hemoglobin range: 10-12 g/dL 1, 6

3. Monitoring:

   • Regular hemoglobin monitoring (initially weekly, then monthly)
   • Iron status assessment (TSAT ≥20% and ferritin ≥100 ng/mL recommended) 6

Special Populations

ESA-Hyporesponsive Patients

• HIF-PHIs may be more effective in patients with inflammation or functional iron deficiency
• Preliminary data suggest HIF-PHIs may not require higher doses in patients with elevated C-reactive protein levels 1

Patients with History of Malignancy

• Avoid HIF-PHIs in patients with recent or active malignancy due to theoretical concerns about cancer progression 1

Clinical Application Algorithm

1. Patient Selection:

   • Confirm anemia is due to CKD (Hb <10 g/dL)
   • Rule out other causes of anemia
   • Assess iron status (ensure TSAT ≥20%, ferritin ≥100 ng/mL)
   • Consider contraindications (active malignancy)

2. Initiation:

   • Choose appropriate HIF-PHI based on availability and regulatory approval
   • Start with lower dose in ESA-naïve patients
   • Target hemoglobin range: 10-12 g/dL

3. Monitoring and Adjustment:

   • Monitor hemoglobin weekly initially, then monthly
   • Adjust dose based on hemoglobin response
   • Aim for hemoglobin rise of no more than 1 g/dL per month
   • Temporarily discontinue if hemoglobin exceeds 12 g/dL

4. Long-term Management:

   • Monitor for adverse events (cardiovascular, malignancy)
   • Continue to assess iron status
   • Consider switching to ESA if concerns about specific adverse effects arise

Conclusion

HIF-PHIs represent an important advancement in the treatment of anemia in CKD patients, offering comparable efficacy to ESAs with the advantage of oral administration and potentially improved iron utilization. However, careful patient selection and monitoring are essential due to potential safety concerns, particularly regarding cardiovascular events and malignancy risk. Long-term post-marketing surveillance will be crucial to fully establish their safety profile.