What are some alternative erythropoiesis-stimulating agent (ESA) injections to Epogen (Epoetin alfa) for patients with anemia related to chronic kidney disease (CKD) or chemotherapy?

Alternative Erythropoiesis-Stimulating Agents to Epogen

Several ESA injections are available as alternatives to Epogen (epoetin alfa), including darbepoetin alfa, epoetin beta, epoetin theta, and epoetin zeta, all of which have demonstrated similar efficacy in treating anemia related to CKD and chemotherapy. 1

FDA-Approved ESA Alternatives

Traditional ESAs (Epoetins)

• Epoetin beta: Administered at 30,000 IU subcutaneously once weekly or divided over 3-7 times per week for cancer patients 1
• Epoetin theta: Dosed at 20,000 IU subcutaneously once weekly independent of body weight, with possible dose doubling after 4 weeks if hemoglobin has not increased by at least 1 g/dL 1
• Epoetin zeta: Given at 450 IU/kg subcutaneously once weekly, or 150 IU/kg subcutaneously 3 times per week 1

Longer-Acting ESAs

• Darbepoetin alfa (Aranesp): The most clinically significant alternative due to its extended half-life, allowing less frequent dosing at 500 μg (6.75 μg/kg body weight) subcutaneously once every 3 weeks, or 2.25 μg/kg subcutaneously once weekly 1, 2
• Epoetin beta pegol: Another long-acting formulation mentioned in recent guidelines 1

Biosimilar Options

Biosimilars of epoetin alfa have been approved by the European Medicines Agency and FDA, demonstrating similar safety and therapeutic equivalence to originator products in clinical practice. 1

• Both ASCO/ASH guidelines confirm that biosimilars may be offered to patients with chemotherapy-associated anemia with the same indications as reference ESAs 1
• The 2019 ASCO/ASH update specifically states that biosimilars have similar efficacy and safety to reference products, though evidence in cancer remains somewhat limited 1

Novel Oral Alternatives (HIF-PHIs)

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) represent a new class of oral agents that may offer advantages over injectable ESAs, particularly for non-dialysis CKD patients. 1

Available HIF-PHIs:

• Roxadustat: Dosed at 70-100 mg three times weekly based on weight 1
• Daprodustat: Administered at 1-4 mg once daily 1
• Vadadustat: Started at 300 mg once daily, then adjusted to 150,450, or 600 mg 1
• Enarodustat, desidustat, and molidustat: Additional agents approved in certain regions 1

HIF-PHI Advantages:

• Oral dosing provides convenience for patients who prefer to avoid injections 1
• May improve iron utilization, particularly with oral iron supplementation 1
• Potentially more effective in chronic inflammatory states (CRP >5 mg/L) 1

HIF-PHI Disadvantages:

• Difficult to monitor adherence compared to in-clinic ESA administration 1
• Less extensive clinical experience than traditional ESAs 1
• Potential risks include tumor growth enhancement, worsening retinopathy, and cyst growth in autosomal dominant polycystic kidney disease 1
• Non-inferiority trials showed some concerning cardiovascular signals, with roxadustat demonstrating HR 1.10 for MACE and vadadustat showing HR 1.17 1

Clinical Context and Selection Considerations

For Cancer Patients:

ESAs (including biosimilars) should only be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to <10 g/dL. 1

• ESAs should not be offered to most patients with non-chemotherapy-associated anemia, except selected patients with myelodysplastic syndromes 1
• During ESA treatment, hemoglobin should be increased only to the lowest concentration needed to avoid transfusions 1

For CKD Patients:

The choice between traditional ESAs and HIF-PHIs depends on patient preference for route of administration, dialysis status, and individual cardiovascular risk profile. 1

• Darbepoetin alfa offers the advantage of less frequent dosing (every 2-3 weeks) compared to epoetin alfa (2-3 times weekly), which may improve adherence 1, 3
• HIF-PHIs may be particularly useful for non-dialysis CKD patients who prefer oral therapy 1

Important Safety Considerations

Thrombotic Risk:

• All ESAs increase the risk of thrombotic events, with darbepoetin alfa showing a 92% increase in relative risk of stroke when targeting hemoglobin of 13 g/dL 4
• Meta-analyses report 48-69% increased relative risk of thrombotic events with ESA use 4

Iron Supplementation:

Iron replacement should be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESAs, with or without iron deficiency. 1

• The majority of CKD patients require supplemental iron during ESA therapy 4
• Intravenous iron compounds include ferric gluconate, iron sucrose, iron dextran, iron isomaltoside, and ferric carboxymaltose 1

Monitoring:

• Monitor for thrombotic complications rather than thrombocytopenia when using ESAs 4
• Avoid high ESA doses driven by hyporesponsiveness 3
• Review all medications for potential interference with ESA response, particularly ACE inhibitors 1, 4