Enarodustat

Summary

Enarodustat is an orally administered hypoxia‑inducible factor prolyl‑hydroxylase (HIF‑PH) inhibitor approved in Japan for treating anemia associated with chronic kidney disease (CKD), both in patients on dialysis and those not on dialysis. By enhancing the body’s own production of erythropoietin and improving iron handling, it aims to raise and maintain hemoglobin levels without the need for injectable erythropoiesis‑stimulating agents.

Mechanism of Action

Enarodustat blocks HIF‑prolyl‑hydroxylase enzymes, preventing degradation of the HIF‑α subunit under normal oxygen conditions. Stabilized HIF‑α translocates to the nucleus, where it drives transcription of erythropoietin (EPO) and genes involved in iron metabolism. The resulting rise in endogenous EPO, together with reduced hepcidin and increased total iron‑binding capacity, enhances red‑cell production and iron availability for hemoglobin synthesis.

What the Research Shows

Phase II placebo‑controlled trials in non‑dialysis CKD and hemodialysis patients showed dose‑dependent increases in hemoglobin, with over 70% of participants maintaining target hemoglobin (10–12 g/dL) after 30 weeks of therapy. Enarodustat lowered hepcidin and ferritin while raising total iron‑binding capacity, indicating improved iron mobilisation. Phase III comparative studies in Japan demonstrated non‑inferiority to darbepoetin alfa for hemoglobin control. Network meta‑analyses of multiple HIF‑PH inhibitors placed enarodustat among the agents that most effectively reduced hepcidin and improved TIBC, though direct head‑to‑head data remain limited.

Reported Benefits

Clinical trials report that enarodustat can correct anemia and sustain hemoglobin within the desired range in CKD patients, including those on dialysis. Its oral route offers a convenient alternative to injectable agents. The drug also appears to improve iron metabolism by decreasing hepcidin and ferritin and increasing total iron‑binding capacity, potentially reducing the need for intravenous iron supplementation.

Limitations of the Evidence

Evidence is largely derived from Japanese studies; data from other regions are sparse. Comparative effectiveness versus other HIF‑PH inhibitors, such as roxadustat, is limited, and meta‑analyses indicate that enarodustat’s hemoglobin‑raising effect may be modest relative to some alternatives. Long‑term safety and real‑world outcomes beyond the trial periods have not been fully established.

Safety Considerations

Across the reported trials, enarodustat was generally well tolerated, with no specific adverse events highlighted in the abstracts. While class‑wide concerns for HIF‑PH inhibitors include potential vascular or thrombotic events, none were uniquely attributed to enarodustat in the available literature. Ongoing monitoring for cardiovascular and thrombotic risks is advisable when initiating therapy.

How It Is Administered

Enarodustat is taken orally once daily. Phase II studies used fixed doses of 2, 4, or 6 mg, with subsequent open‑label periods allowing dose adjustments within a 2–8 mg range to keep hemoglobin between 10–12 g/dL. Formulations are tablet‑based and intended for chronic use in CKD‑related anemia.

Routes of Administration

Goals & Uses

• Reduction of ESA injectionsPatient Convenience / Treatment OptimizationHigh
• Hemoglobin stabilization in non-dialysis CKDNephrologyHigh
• Iron utilization improvementIron MetabolismModerate
• Treatment of renal anemiaHematology / NephrologyHigh

Contraindications

• Active malignancyOncologyModerateUse caution or avoid depending on agent and context
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Known hypersensitivity to enarodustatAllergyHigh
• Uncontrolled hypertensionCardiovascularModerate

Adverse Effects

• HypertensionCardiovascularCommonHigh blood pressure
• NasopharyngitisInfectiousCommon
• HeadacheNeurologicCommonPain in the head or upper neck
• Liver enzyme elevation (ALT/AST)HepaticUncommon
• Shunt thrombosis (dialysis access)VascularUncommon
• ThromboembolismCardiovascularUncommon

Drug Interactions

• Antihypertensive agentsModerate
• CYP enzymes / drug transportersLow
• Iron supplementsLow

Population Constraints

• Patients with active or recent malignancyOncologicRelative
• Pediatric patientsAgeRelative
• Patients with severe hepatic impairmentHepaticRelative
• Pregnant womenReproductiveAbsolute

Regulatory Status

• European UnionUnapprovedNot approved by the EMA as of the current knowledge cutoff.
• United StatesUnapprovedNot approved by the FDA as of the current knowledge cutoff; not in late-stage US clinical development.
• United KingdomUnapprovedNot approved by the MHRA as of the current knowledge cutoff.

Approved in Japan (2022) for renal anemia associated with CKD. Not approved by the FDA or EMA as of the current knowledge cutoff. It is a small molecule, not a peptide in the classical sense, but functions in the erythropoiesis-stimulating pathway.

Evidence & Sources

• Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence
  Journal ArticleModerateFujikawa R, et al.2022-01-01T00:00:00.000000Z
• A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease
  Journal ArticleHighChen J, et al.2023-01-01T00:00:00.000000Z
• A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial
  Journal ArticleModerateAkizawa T, et al.2019-01-01T00:00:00.000000Z
• Enarodustat: First Approval
  Journal ArticleModerateMarkham A2021-01-01T00:00:00.000000Z
• Network meta-analysis of HIF-prolyl hydroxylase inhibitors for anemia in dialysis-dependent and non-dialysis CKD: effects on hemoglobin, iron markers, and adverse clinical outcomes
  Journal ArticleHighNasiri H, et al.2025-01-01T00:00:00.000000Z
• Enarodustat, Conversion and Maintenance Therapy for Anemia in Hemodialysis Patients: A Randomized, Placebo-Controlled Phase 2b Trial Followed by Long-Term Trial
  Journal ArticleModerateAkizawa T, et al.2019-01-01T00:00:00.000000Z

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