What is desidustat (Oxemia) and how is it used to treat anemia in non‑dialysis chronic kidney disease patients?

Desidustat (Oxemia) for Anemia in Non-Dialysis Chronic Kidney Disease

Desidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that treats anemia in non-dialysis CKD patients by stimulating endogenous erythropoietin production, offering a convenient oral alternative to injectable ESAs with proven non-inferiority in hemoglobin correction. 1, 2

Mechanism of Action

• Desidustat inhibits prolyl hydroxylase domain enzymes, which stabilizes hypoxia-inducible factor (HIF) and triggers endogenous erythropoietin production rather than delivering exogenous hormone. 1, 3
• Unlike injectable ESAs, desidustat generates substantially lower peak serum erythropoietin concentrations, which may theoretically reduce cardiovascular risks associated with high EPO peaks. 1, 4
• The drug enhances enteric iron absorption and improves iron utilization by reducing hepcidin levels, potentially beneficial in functional iron deficiency states common in CKD. 1, 4, 2

Clinical Efficacy

• In the phase 3 DREAM-ND trial of 588 non-dialysis CKD patients, desidustat 100 mg three times weekly increased hemoglobin by 1.95 g/dL versus 1.83 g/dL with darbepoetin, meeting non-inferiority criteria (difference: 0.11 g/dL; 95% CI: -0.12,0.34). 1, 2
• The hemoglobin responder rate (≥1 g/dL increase) was significantly higher with desidustat at 77.78% compared to 68.48% with darbepoetin (p = 0.0181). 2
• Desidustat significantly reduced hepcidin levels at both Week 12 and Week 24 compared to darbepoetin (p = 0.0032 and p = 0.0016, respectively). 2

Dosing Protocol

• Start desidustat at 100 mg orally three times weekly for ESA-naïve non-dialysis CKD patients with baseline hemoglobin 7-11 g/dL. 4, 5
• Adjust doses stepwise every 4 weeks based on current hemoglobin level and rate of change to maintain the target range of 10-12 g/dL. 4, 5
• Temporarily discontinue desidustat if hemoglobin exceeds 12-13 g/dL, following protocols from phase 3 trials. 4, 5
• Lower starting doses are appropriate for ESA-naïve patients compared to those transitioning from other ESAs. 4, 6

Practical Advantages Over Injectable ESAs

• Oral administration eliminates subcutaneous injections, reducing injection-related pain and improving convenience, particularly for non-dialysis and peritoneal dialysis patients. 4, 5, 6
• Room temperature stability simplifies storage requirements compared to refrigerated ESAs. 6
• The drug avoids the high peak serum EPO concentrations seen with injectable ESAs. 1, 4

Monitoring Requirements

Hemoglobin Monitoring

• Check hemoglobin every 4 weeks during dose titration to maintain the 10-12 g/dL target. 4, 5
• Once stable on maintenance therapy, measure hemoglobin at least every 3 months in non-dialysis patients. 4
• Increase monitoring frequency after any bleeding event or during dose escalation. 4

Iron Status Monitoring

• Measure transferrin saturation (TSAT) and ferritin at least every 3 months while on desidustat. 4
• Conduct more frequent iron studies when starting therapy, after bleeding events, or when evaluating response to iron supplementation. 4
• Initiate intravenous iron (or a 1-3 month oral iron trial for non-dialysis patients) when TSAT ≤30% and ferritin ≤500 ng/mL. 4

Absolute Contraindications

• Active or recent malignancy: HIF activation raises theoretical concerns about tumor promotion through effects on cellular differentiation and growth; avoid desidustat when the anticipated treatment outcome is cure, including with primary and adjuvant chemotherapy. 1, 4, 6
• Polycystic kidney disease: Preclinical models suggest HIF activation may enhance cyst expansion; do not use until adequate safety data emerge. 4, 6
• Pediatric patients under 18 years: All phase 3 trials excluded this population, leaving no safety or efficacy data. 4, 5, 6

Populations Requiring Extreme Caution

• Kidney transplant recipients: Limited data exist on concomitant use with immunosuppression, and theoretical concerns about HIF-PHIs affecting immune cell function and potentially increasing graft rejection or malignancy risk warrant caution. 4, 6
• History of stroke: Potential HIF-mediated vascular effects and increased vascular risk require careful consideration. 4
• Prior malignancy: Even in patients not actively receiving curative therapy, great caution is warranted due to theoretical tumor-promoting mechanisms. 4

Critical Safety Limitations

The major limitation of desidustat is the absence of large cardiovascular outcomes trials comparable to daprodustat, vadadustat, and roxadustat, which have extensive cardiovascular endpoint data from non-inferiority designs. 5, 6

• HIF-mediated effects on vascular homeostasis, hemodynamics, inflammation, and cellular metabolism are well-documented in preclinical studies and could modify risks of cardiovascular disease, thrombosis, and malignancy. 1
• The extent to which non-erythropoietic signaling pathways are activated in patients receiving desidustat is difficult to predict and measure. 1
• Potential drug-drug interactions should be evaluated when desidustat is co-administered with other oral medications. 4, 6

Hemoglobin Target Guidance

• Maintain hemoglobin between 10-12 g/dL; available data do not support targeting higher levels with HIF-PHIs than the currently recommended targets established with ESAs. 4, 6
• Intentionally raising hemoglobin above 13 g/dL should be avoided, as large trials with ESAs have linked higher levels to increased cardiovascular events, stroke, and mortality. 4
• In general, keep hemoglobin below 11.5 g/dL in adult CKD patients, with adjustments only for specific quality-of-life considerations. 4

Alternative Therapies

• Erythropoiesis-stimulating agents (epoetin, darbepoetin) remain the primary alternatives, with mandatory iron supplementation before initiating any ESA. 4
• Red blood cell transfusions are indicated for hemoglobinopathies, bone marrow failure, or ESA resistance, but should be minimized in transplant-eligible patients to reduce allosensitization risk. 4

Common Pitfalls to Avoid

• Do not use desidustat in ESA-hyporesponsive patients without supporting evidence, as data on efficacy in this subgroup are limited despite theoretical advantages through hepcidin lowering. 5, 6
• Do not combine desidustat with ESAs, as combination therapy is not supported by available data and should not be used in clinical practice. 6
• Do not use in patients with marked systemic inflammation without caution, as trial participants with elevated C-reactive protein showed only modest hemoglobin responses. 5
• Adherence may be more difficult to assess compared to in-clinic ESA administration, requiring specific attention during follow-up. 6