Daprodustat: The First Oral Agent for the Treatment of Anemia in Chronic Kidney Disease

Background

Chronic Kidney Disease

About 15% of adults in the United States (US) are estimated to have chronic kidney disease (CKD).1 When patients first develop CKD, they may be asymptomatic. However, the progressive nature of CKD leads patients to experience a decreased quality of life over months to years. Patients with CKD are at a higher risk for acute kidney injury (AKI), uremia, cardiovascular disease, drug toxicities, and many other complications.2 Due to the number of health consequences associated with CKD, it remains the leading cause of death in the US.1 Because most causes of CKD are irreversible, the goals of therapy are to slow the progression to renal failure. Once the kidneys start failing and patients are diagnosed with end-stage renal disease (ESRD), treatment options are limited to hemodialysis (HD) or transplantation. At this point in the course of CKD, patients most likely have developed the aforementioned complications and other common conditions such as anemia.2

Anemia of Renal Disease

Clinical trials have shown as the glomerular filtration rate (GFR) decreases, patients with CKD have a gradual decline in hemoglobin (Hb) concentration.2 The cause of this is most commonly due to a lack of endogenous erythropoietin (EPO) production due to impaired kidney function. However, nutritional deficiencies and blood loss due to dialysis may contribute.3 Because this is a common occurrence in those with CKD and is associated with increased morbidity and mortality, the 2012 KDIGO guidelines suggest monitoring all patients with CKD for anemia. The most common symptoms are fatigue, reduced exercise tolerance, and dyspnea. Diagnosis is made by obtaining a complete blood count (CBC), absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate levels. Patients are deemed anemic if they have a Hb concentration of <13 g/dL in males or <12 g/dL in females. For patients with adequate nutritional stores or who remain anemic despite supplementation, erythropoietin-stimulating agents (ESA) such as epoetin alfa and darbepoetin are used. Clinical trials have shown the benefit of treatment with ESAs for those on dialysis by controlling anemia and reducing the need for blood transfusions.4 However, ESAs are administered subcutaneously (SQ) or intravenously (IV), which is unattractive to some patients who prefer oral therapy. After nearly 35 years of parenteral ESAs being the only option for these patients, an oral option is now available.

Daprodustat (Jesduvroq)

In June 2020, daprodustat (Jesduvroq), manufactured by GlaxoSmithKline, was approved in Japan for the treatment of anemia in patients with CKD. Daprodustat is an oral small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (PHD) which prevents the degradation of hypoxia-inducible factor (HIF). HIF promotes endogenous EPO production, which is often the cause of anemia in CKD. Two phase 3 trials in Japan assessed the use of daprodustat in hemodialysis patients. One trial focused on initiating daprodustat in those not using an ESA, while the other compared daprodustat to darbepoetin alfa. Another phase 3 trial in Japan assessed daprodustat use in non-HD dependent patients (ESA naïve and ESA users). All three trials assessed Hb concentrations as the primary outcome and determined that daprodustat was effective and non-inferior to ESAs for treating anemia in CKD. Additionally, no significant differences in terms of safety were determined.5 Because of the success of daprodustat in Japan, international trials have been performed. The results of these trials subsequently led to FDA approval of daprodustat on February 2, 2023, for treating anemia due to CKD in adults who have been receiving dialysis for at least four months.6

Daprodustat Clinical Trials

Anemia Due to Chronic Kidney Disease in Adults on Dialysis

Used as the basis of FDA approval, the Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Dialysis (ASCEND-D) trial assessed the safety and efficacy of daprodustat. The ASCEND-D trial was a randomized, open-label, phase 3 trial that included 2964 patients across 431 centers in 35 countries. To be included in the trial, CKD patients had to have been undergoing dialysis for at least 90 days, had received