Roxadustat - A Closer Look at the First Globally Approved Cure for Renal Anemia

Overview

Roxadustat is a potent hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) used to treat anemia of chronic kidney disease (CKD) patients. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) belong to a new class of orally administered erythropoiesis-stimulating agents (ESAs). Roxadustat is an N-acyl glycine compound formed by formal condensation of the amino group in glycine with the carboxyl group in 4-hydroxy-1-methyl-7-phenyl isoquinoline-3-carboxylic acid. It is an aromatic ether and a member of isoquinolines.

The first global approval of Roxadustat has been achieved, and its use is approved in various countries like Japan, China, South Korea, and Chile for treating renal anemia. The efficacy and risk assessment of Roxadustat is under progress by the regulatory review committee in the European Union. Roxadustat is not yet authorized for marketing in the United States but received marketing authorization in Japan in September 2019 and the People’s Republic of China in December 2018.

The US Food and Drug Administration’s (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting held on 15th July 2021 has declined the approval of Roxadustat in CKD patients analyzing the benefit-risk profile of Roxadustat. However, The FDA has considered reviewing the new drug application (NDA) following additional clinical trials. The FDA’s final approval for the Roxadustat NDA remains pending.

What Are the Indications of Roxadustat?

Roxadustat induces endogenous erythropoietin (EPO) production and is indicated for treating anemic conditions that particularly arise as secondary complications in various systemic disorders.

Some of the common indications of Roxadustat are as follows -

• Renal anemia in chronic kidney disease (CKD).

• In dialysis-dependent (DD) CKD patients.

• In adult patients with CKD who are non-dialysis-dependent (NDD).

• For treating anemic conditions in chronic inflammatory diseases.

• In symptomatic anemia associated with CKD.

• To treat anemia in patients having myelodysplastic syndromes.

Therapeutic Uses of Roxadustat

The therapeutic use of Roxadustat is attributed to its anti-anemic activity, which includes -

• It stabilizes hypoxia-inducible factor (HIF), which enhances the production of erythropoietin (EPO) both from renal and extrarenal sites (liver). Hence, EPO is induced even in severe kidney damage, and CKD patients do not need external EPO injections.

• Induced EPO production stimulates the synthesis of red blood cells (RBC) and corrects anemia.

• Roxadustat also improves iron metabolism by increasing its availability and, in turn, increases hemoglobin levels.

• Roxadustat reduces iron overload, commonly encountered in continued external EPO administration.

Dosage Forms and Strengths

• Roxadustat is available in film-coated tablet form.

• Dosage Strengths (Japanese Market) - 20, 50, and 100 mg (Japanese Pharmaceuticals and Medical Devices Agency).

• Dosage Strengths (European Market) - 20, 50, 70, 100, and 150 mg (European Medicines Agency 2021).

Dosage and Administration

• Route of Administration - Oral administration.

• Dosage - Administered two to three times weekly to treat anemia in CKD patients.

• No significant drug accumulation is seen as the drug levels in plasma between the doses generally return to minimal levels.

• For patients on hemodialysis, the recommended dose is three times per week (on the day of hemodialysis).

Contraindications

The contraindications for using Roxadustat are associated with its prothrombotic effects or dysregulated metabolism. Use of Roxadustat is contraindicated in the following conditions -

• Patients prone to thrombotic risks such as stroke and myocardial infarction (MI).

• Patients with an increased risk of tumor progression or recurrence in a few malignancies.

• Severe liver cirrhosis.

Warnings and Precautions

Based on the reports from clinical trials, the People’s Republic of China has introduced safety information and restricted the use of Roxadustat in clinical conditions like -

• Increased risk of cardiovascular events.

• Vascular access thrombosis.

• Deep vein thrombosis.

• Seizures.

• Severe infections.

The Japanese label of Roxadustat contains the boxed warning for the following medical conditions such as -

• Severe thromboembolism.

• Cerebral infarction.

• Myocardial infarction (MI).

• Pulmonary embolism.

• Shunt occlusion.

• Seizures.

Use in Specific Populations

• Roxadustat is predominantly metabolized in the liver. Hence hepatic impairment affects the plasma levels of Roxadustat.

• The European Drug Administration has recommended reducing the dosage by half in patients with moderate liver cirrhosis.

• In severe liver cirrhosis, Roxadustat is not recommended.

For Patients

How Does Anemia Occur in Chronic Kidney Disease?

Chronic kidney disease (CKD) is a clinical condition where normal kidney function is drastically reduced due to the damage of tissues present in the kidney (renal tubules). When the kidneys are damaged, they produce decreased levels of erythropoietin (EPO), a hormone that activates bone marrow (the spongy part inside the bones) to produce red blood cells (RBCs). When EPO levels are reduced, fewer RBCs are produced, and oxygen supply to the organs and tissues is greatly reduced, resulting in anemia. CKD patients with anemia also have low hemoglobin and iron levels involved with the normal production of red blood cells.

Anemia is a major complication of CKD that starts developing during the early stages of CKD and worsens with its progression. CKD patients with anemia show clinical symptoms of decreased energy and well-being and experience poor quality of life associated with cognitive impairment. If anemia in patients with CKD is left untreated, it leads to severe cardiovascular complications such as stroke and heart failure. Also, it results in a poor prognosis of renal replacement therapy and increased mortality.

How Is Anemia Treated in Chronic Kidney Disease?

The therapeutic interventions to treat anemia in CKD patients in current clinical practice involve the following ways -

• Administering iron supplements as tablets or intravenous (IV) infusions.

• Erythropoiesis stimulating agents (ESAs) are given during dialysis or as parenteral (IV or subcutaneous) injections.

• Blood transfusions are recommended during severe anemia.

The use of these therapeutic options involves chances of developing certain health risks. Parenteral iron injections could build up iron content in the body, causing iron overload. Blood transfusions often carry the risk of developing antibodies that could lead to organ rejection during renal transplant. The use of ESAs in patients with CKD is often associated with an increased risk of major adverse cardiovascular events (MACE). In recent years, the use of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) like Roxadustat has been showing positive results in overcoming the shortcomings.

How Does Roxadustat Work?

Anemia leads to a hypoxic condition characterized by inadequate oxygen transport to the cells and tissues because of the reduced number of red blood cells, insufficient hemoglobin, and decreased serum iron levels. Hypoxia-inducible factor (HIF) acts as an oxygen sensor, detects decreased oxygen levels, and immediately enhances the production of EPO, which in turn promotes RBC production. This HIF factor is activated only in hypoxic conditions, and during normal oxygen availability (normoxic conditions), it is deactivated by prolyl hydroxylase (PH) enzymes.

Roxadustat is a newly approved oral hypoxia-inducible factor prolyl hydroxylase inhibitor that shows considerable safety and efficacy in the therapeutic outcome of renal anemia. It is an effective hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that decreases the degradation of the HIF factor and enhances its activity under normoxic conditions. Inducing HIF activation by Roxadustat and thereby enhancing EPO production under normal oxygen availability reduces the hypoxic stress on the kidney and regulates iron metabolism without excessive iron accumulation.

What Are the Benefits of Using Roxadustat in Renal Anemia?

All the currently available erythropoiesis-stimulating agents (ESAs) are administered parenterally (by the intravenous or subcutaneous routes). Roxadustat became the first orally administered ESA. Through inhibiting HIF-PH enzymes, Roxadustat stimulates a well-regulated erythropoietic response endogenously (inside the body). Some of the benefits of Roxadustat are as follows -

• Roxadustat increases the plasma endogenous(within the body) erythropoietin (EPO) levels which in turn increases red blood cell mass and hemoglobin (Hb) levels in anemic patients.

• It regulates iron transport by reducing hepcidin (a protein that causes iron deposition) activity. This improves iron bioavailability,

• Roxadustat lowers the need for RBC transfusions and related risks such as blood-borne infections, transfusion reactions, and fluid overload.

• Transfusions are contraindicated for the end-stage renal disease (ESRD) population and also cause allosensitization (production of antibodies) that increases the risk of transplant rejection.

• Roxadustat avoids the undesirable side effects of excessive administration of exogenous erythropoietin (EPO injections).

• Roxadustat is advantageous over other ESAs because of its convenient oral dosage form.

What Are the Adverse Side Effects of Roxadustat?

The adverse reactions of Roxadustat involve thrombus (blood clot) formation.

Some of the side effects of Roxadustat include -

• Diarrhea.

• Nausea.

• Edema.

• Vomiting.

• Headache.

• Seizures.

• Dyspnea.

• Fatigue.

• Blocking of coronary stents.

• Irregular heartbeats.

• Upper respiratory tract infection.

• Risk of developing cancers.

What Are the Precautionary Measures in Roxadustat Therapy?

The precautionary measures should be followed in Roxadustat therapy to avoid developing side effects.

Some of the important precautions in the use of Rivaroxaban are as follows -

• The presence of food does not affect the absorption of Roxadustat; hence it could be taken along with food or in a fasting state.

• Any allergic reaction should be reported to the doctor immediately.

• Liver problems should be reported and evaluated before starting Roxadustat therapy.

• Any occurrence of clinical symptoms related to thrombotic events should be reported to a medical professional.

• Excess intake of dosage or missed doses should be reported immediately to the doctor.

• Patients should not self-adjust the missed doses.

For Doctors

Clinical Pharmacology

Roxadustat is the first-in-class of orally administered ESAs that promotes erythropoiesis (production of RBCs) by directly inhibiting HIF-PH enzymes. Pharmacotherapeutically it is classified as anti-anemic preparation. The pharmacological characteristics of Roxadustat greatly influence its current status in treating renal anemia, its efficacy, and its associated side effects.

Chemical Taxonomy of the Roxadustat

Kingdom - Organic compounds.

Super Class - Organic acids and derivatives.

Class - Carboxylic acids and derivatives.

Sub Class - Amino acids, peptides, and their analogs.

Direct Parent Compound - N-acyl-alpha amino acids.

Alternative Parent Compound - Diarylethers, isoquinolines, and their derivatives, pyridine carboxylic acids, phenol ethers, phenoxy, heteroaromatic, and vinylogous acids.

Substituents - Aromatic hetero polycyclic compound, 2-heteroaryl carboxamide, benzenoid, carbonyl group, carboxylic acid, and diaryl ether.

Molecular Framework - Aromatic hetero polycyclic compounds.

External Descriptors - Data not available.

Pharmacodynamics

Roxadustat improves iron bioavailability, increases the mean red blood cell mass, and enhances hemoglobin production in anemic patients with CKD. It maintains a significant hemoglobin level for two years in non-dialysis-dependent (NDD) CKD patients with progressive anemia. It has relatively higher efficacy than erythropoietin-stimulating agents in establishing increased Hb response. Roxadustat has been found to reduce cholesterol levels from baseline, irrespective of the use of lipid-lowering agents (statins).

What Is the Mechanism of Action of Roxadustat?

Role of Hypoxia-Inducible Factor

• Hypoxia-inducible factor (HIF) is a transcription factor that senses oxygen tension in the blood and gets activated in the hypoxic state.

• As a response to low oxygen levels, the HIF protein induces erythropoietin release, subsequently activating red blood cell production.

• Under physiological (normoxic) conditions, these HIF proteins are constantly inactivated and degraded by the action of prolyl hydroxylase domain (PHD) enzymes.

• During hypoxia, these PHD enzymes are downregulated, and the levels of HIF proteins remain high.

• HIF proteins enhance the expression of the erythropoietin (EPO) gene in renal parenchymal cells to secrete EPO and also other genes involving iron transporter molecules (ferroportin).

• Under the HIF-induced EPO stimulus, red blood cell (RBC) production is activated in bone marrow, and also ferroportin increases iron absorption from the small intestine.

• Thus, these regulatory mechanisms recruit new reticulocytes, and hemoglobin concentrations elevate to counterbalance the reduced oxygen tension.

• The prolyl hydroxylase domain (PHD) enzymes are the key regulators of hypoxia-inducible factor (HIF) stability and its response to oxygen availability.

• During the limited availability of oxygen, the inhibition of PHD allows the stabilization of HIF and facilitates cellular adaptation to hypoxia.

• Under normoxic (adequate oxygen availability) conditions, HIF constantly degrades and does not function.

Drug Action of Roxadustat

• Roxadustat inhibits this prolyl hydroxylase domain (PHD) enzyme that causes degradation of HIF (during a normoxic state).

• Roxadustat facilitates a coordinated positive erythropoietic response even when adequate oxygen is present by inhibiting HIF-PH enzymes.

• Roxadustat reversibly and effectively inhibits HIF-PHD enzymes and increases functional HIF levels, eventually increasing plasma endogenous EPO production.

• Roxadustat facilitates erythropoiesis and indirectly suppresses hepcidin (iron regulator that reduces intestinal iron absorption).

• Hepcidin levels are increased due to inflammatory changes in chronic kidney disease.

• Roxadustat also facilitates iron transporter proteins and regulates iron metabolism by elevating plasma transferrin levels, increasing intestinal iron absorption, and favoring the release of stored iron in CKD patients (DD and NDD) with anemia.

• Overall, Roxadustat dose-dependently increases hematocrit values (red cell mass) and Hb levels and improves iron bioavailability.

Pharmacokinetics

Absorption

• Orally administered Roxadustat is rapidly absorbed.

• Its oral absorption is independent of the presence or absence of food.

• It reaches a maximum plasma concentration within two hours of ingestion.

Bioavailability

• Roxadustat is a lipophilic compound. Hence it tightly binds(nearly 99 %) to plasma proteins (mainly albumin) and is not markedly removed during dialysis.

• Roxadustat maximum plasma concentration (Cmax) increases dose-dependently and proportionately to the recommended therapeutic dosages.

• Its volume of distribution at steady-state is nearly 24 L.

• Unchanged Roxadustat is the major circulating component in the plasma. The presence of its metabolites is less than 10 % in the plasma.

Metabolism

• Roxadustat is transported to the liver, where it is metabolized.

• In the liver, it undergoes oxidation by the action of cytochrome (P450 2C8) enzymes and subsequent glucuronidation by uridine diphosphate glucuronyltransferase (UGT1A9) enzymes.

• The primary metabolites of Roxadustat are hydroxy-Roxadustat and Roxadustat-O-glucuronide.

Elimination

• The elimination half-life of Roxadustat is nearly 9.6 to 16 hours in healthy subjects. In comparison, it is increased to 18 hours in patients with renal impairment.

• Its metabolites are eliminated mainly through urine.

Clinical Toxicity

Roxadustat is associated with the risk of developing severe thromboembolic events.

Some of the clinical toxicities associated with Roxadustat are as follows -

• Signs of thromboembolism such as headaches, seizures, and dizziness.

• Hyperkalemia.

• Arterial hypertension.

• Elevated levels of serum potassium.

• Occlusion of stents or indwelling catheters.

• Reduced levels of serum bicarbonate.

• Thrombosis.

• Thromboembolic events like stroke, myocardial infarction, and pulmonary embolism.

• Heart failure.

• Pure red cell aplasia.

• Risk of developing malignancies.

• Recurrence or progression of certain leukemias.

Precautionary Measures While Prescribing Roxadustat

• Roxadustat is recommended according to Hb levels. It is more effective in Hb levels between 9.0 and 10.0 g/dL.

• The Hb level should be maintained at a constant value. If Hb increases above 11.5 g/dL, Roxadustat should be lowered accordingly.

• Roxadustat should be discontinued if the Hb levels do not respond sufficiently in an escalation period of 12 weeks.

• Regular monitoring for early signs of thrombosis, such as hypertension, seizures, and chest pain, should be checked accurately.

Drug Interactions

Patients with CKD are often treated with various drugs. Interaction of Roxadustat with other drugs should be considered before starting Roxadustat therapy.

• Lanthanum carbonate, Omeprazole, carbon adsorbents, and Warfarin do not interact with Roxadustat.

• Phosphorus-lowering drugs (calcium acetate and Sevelamer) reduce the absorption of Roxadustat by forming insoluble chelates.

• Roxadustat considerably increases the plasma levels of statins. So their doses should be lowered, or the duration between the Roxadustat doses should be widened.

Summary

Roxadustat is an effective HIF activator that increases erythropoietin production. Countries including China, Japan, the European Union, Chile, and South Korea have approved its clinical use for treating renal anemia. Numerous ongoing clinical studies report its safety and effectiveness in maintaining Hb levels in CKD patients. Roxadustat is a novel promising oral erythropoietin-stimulating agent that could be increasingly opted for treating anemia in patients with CKD.