Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa

A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

The primary objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease (NDD CKD) participants.

This was a phase 3, multicenter, randomized, open-label, active-controlled study. The study was planned to provide key efficacy and safety data for the approval of roxadustat in the treatment of anemia associated with CKD. Participants assigned to roxadustat treatment were administered roxadustat orally as a combination of tablets of different strengths. Participants assigned to darbepoetin alfa treatment were administered darbepoetin alfa subcutaneously or intravenously.

The study consisted of 3 study periods:

• Screening period: up to 6 weeks
• Treatment period: 104 weeks
• Follow-up period: 4 weeks until planned study end (end of year 2)

Inclusion Criteria:

• Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
• The mean of the subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
• Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.
• Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening.
• Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
• Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN.
• Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
• Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration.

Exclusion Criteria:

• Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization.

• Subject has received any dose of IV iron within 6 weeks prior to randomization.

• Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.

• Subject has a known history of myelodysplastic syndrome or multiple myeloma.

• Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD).

• Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.

• Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.

• Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization.

• Subject has active or chronic gastrointestinal bleeding.

• Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).

• Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.

• Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).

• Subject has known New York Heart Association Class III or IV congestive heart failure.

• Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.

• Subject has one or more contraindications for treatment with darbepoetin alfa:

  • Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization).
  • Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients.

• Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.

• Subject has a history of malignancy, except for the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.

• Subject is positive for any of the following:

  • human immunodeficiency virus (HIV).
  • hepatitis B surface antigen (HBsAg).
  • or anti-hepatitis C virus antibody (anti-HCV Ab).

• Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.

• Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.

• Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study.

• Subject will be excluded from participation if any of the following apply:

  • subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or
  • any condition which makes the subject unsuitable for study participation.

• Subject has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study.

• Subject has a history of alcohol or drug abuse within 2 years prior to randomization