SUMMARY: Anemia is a common complication of advanced renal failure. This is due to decreased Erythropoietin (EPO) production primarily due to the inability of the diseased kidney to adequately respond to hypoxia and/or anemia. Patients with Chronic Kidney Disease (CKD) are often given EPO replacement therapy which can be either recombinant human EPO (rhEPO) or reengineered preparations of recombinant EPO, and these agents are collectively referred to as Erythropoietin Stimulating Agents (ESA). These agents are administered by parenteral route and can reduce cardiovascular morbidity associated with anemia, blood transfusion requirements and improve quality of life. However, ESA given to normalize the hemoglobin level to 13-14.0 g/dl, as well as supraphysiologic dosing of ESA has been associated with increased risk of cardiovascular events, venous thromboembolism, CKD progression and overall mortality.
Systemic hypoxia increases plasma EPO levels, which in turn results in increased production of Red Blood Cells. New novel therapies include oral small molecule inhibitors that activate Hypoxia Inducible Factor (HIF) and stimulate endogenous EPO production.
HIF prolyl hydroxylase under conditions of normal oxygen concentrations breaks down the HIF. Daprodustat is an orally active HIF prolyl hydroxylase inhibitor that stimulates endogenous erythropoietin production by stabilizing the HIF-α subunit, allowing it to dimerize with the HIF-β subunit and to stimulate genes involved in protection against hypoxia, including the erythropoietin gene. In summary, Daprodustat increases hemoglobin levels as well as Total Iron Binding Capacity, and decreases the levels of ferritin and hepcidin. Daprodustat demonstrated a good safety profile and had efficacy over 24 weeks in Phase II trials involving patients with CKD.
In the current ASCEND-ND (Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Non-Dialysis) trial, the reserachers evaluated the efficacy and safety of the HIF prolyl hydroxylase inhibitor Daprodustat, as compared with the conventional ESA Darbepoetin alfa, in patients with CKD who were not undergoing dialysis. In this open-label, Phase III trial, 3872 patients were randomly assigned 1:1 to receive oral Daprodustat or subcutaneous Darbepoetin alfa. Eligible patients had stage 3-5 CKD and were not currently receiving dialysis or scheduled to start dialysis within 90 days, met the hemoglobin and ESA criteria, and had a serum ferritin level of more than 100 ng/ml and a transferrin saturation above 20%. Patients who had anemia that was unrelated to CKD, a recent cardiovascular event, or current or recent cancer were excluded.
The starting dose of Daprodustat was between 1 and 4 mg orally daily, according to the baseline hemoglobin level if the patient was not receiving an ESA, and according to the ESA dose if the patient was receiving an ESA, and dose adjustments ranged from 1 to 24 mg. The starting dose of subcutaneous Darbepoetin alfa was based on the patient’s weight and hemoglobin level at the time of randomization if the patient was not receiving an ESA or on the previous ESA dose if the patient was receiving an ESA. Dose increments were predefined, and the dose was increased by 25 to 33%. The study included a provision for the use of IV iron, PRBC transfusion, or both. The mean baseline hemoglobin levels were similar in the two treatment groups and was 9.9 plus or minus 0.9 g/dl. The researchers used a trial-specific algorithm for both treatment groups to achieve and maintain a hemoglobin level in the target range of 10-11 g/dl. Patient characteristics were well balanced in both treatment groups. Patients were evaluated at least every 4 weeks during the first year of the study and at least every 12 weeks thereafter. The Primary noninferiority outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52, and the first occurrence of a Major Adverse Cardiovascular Event (MACE- a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). These and other cardiovascular events were adjudicated by a blinded independent committee.
Daprodustat was noted to be noninferior and as effective as Darbepoetin alfa in increasing and maintaining hemoglobin levels in patients with CKD and anemia who were not receiving dialysis, and this benefit on hemoglobin levels was consistent across prespecified subgroups. Daprodustat was also noninferior to Darbepoetin alfa with respect to cardiovascular safety in the primary analysis. During a median follow up of 1.9 years, a first MACE occurred in 19.5% of patients in the Daprodustat group and 19.2% of patients in the Darbepoetin alfa group, and this met the prespecified noninferiority margin. There was no difference in the rates of thromboembolic events and hospitalization for heart failure among the treatment groups.
It was noted that patients in the Daprodustat group had more esophageal or gastric erosions (3.6%), compared to 2.1% in the Darbepoetin alfa group. Because of the activation of the HIF pathway by HIF prolyl hydroxylase inhibitor, cancer incidence and progression is a concern and the researchers observed a higher incidence of cancer-related death or tumor progression or recurrence in the Daprodustat group (3.7%) compared to 2.5% in the Darbepoietin alfa group (Relative Risk=1.47)
It was concluded from this study that among patients with CKD and anemia who were not undergoing dialysis, Daprodustat was noninferior to Darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. However, the safety of HIF prolyl hydroxylase inhibitors in cancer patients will require longer follow up.
Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. Singh AK, Carroll K, McMurray JV, et al. for the ASCEND-ND Study Group. N Engl J Med 2021; 385:2313-2324.