Daprodustat: A Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor for Anemia of Chronic Kidney Disease

Abstract

Objective:

The objective was to review the safety and efficacy of daprodustat, a hypoxia-inducible factor–prolyl hydroxylase inhibitor (HIF-PHI) in the treatment of anemia of chronic kidney disease (CKD).

Data Sources:

A literature search was conducted in MEDLINE, EMBASE, and ClinicalTrials.gov using the keywords “daprodustat,” “GSK1278863,” and “hypoxia-inducible factor-prolyl hydroxylase inhibitors” from January 2010 through November 2023.

Study Selection and Data Extraction:

Literature was included if it evaluated pharmacology, pharmacokinetics, efficacy, and/or safety of daprodustat in human subjects and was reported in English. The manufacturer’s product monograph was also utilized.

Data Synthesis:

Daprodustat significantly increased hemoglobin levels in CKD patients on dialysis (difference 0.18 g/dL) and not on dialysis (difference 0.08 g/dL) over 52-week treatment periods compared with erythropoiesis stimulating agents (ESA) in Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat (ASCEND)-D and ASCEND-ND, respectively. First occurrence of major adverse cardiovascular events (MACEs) was similar between daprodustat and ESAs in both trials.

Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:

Daprodustat can be used in patients with CKD on dialysis and already receiving an ESA for at least 6 weeks to further increase serum hemoglobin levels without increasing the risk of MACE. Adverse effects of daprodustat that may occur more than ESAs include headache, emesis, and thrombosis.

Conclusions:

Daprodustat is a novel oral, non-iron therapy for treatment of anemia of CKD. It was Food and Drug Administration approved in 2023 in patients already receiving dialysis for at least 4 months but not in non-dialysis patients. Long-term data for safety and additional benefits are pending.

Keywords

daprodustat chronic kidney disease anemia renal failure hypoxia-inducible factor–prolyl hydroxylase inhibitor

Introduction

Chronic kidney disease (CKD), defined as abnormalities in kidney structure or function for at least 3 months, affects over 10% of adults worldwide and 1 in 7 adults in the United States.¹ With major risk factors such as hypertension and diabetes rising at exponential rates, it is likely that rates of CKD will continue to increase. As a progressive disease, left untreated, CKD can result in significant morbidity and mortality, dramatically decreasing overall quality of life and significantly increasing the risk of several complications, including metabolic disease, cardiovascular (CV) disease, and CKD-associated complications such as anemia of CKD and CKD-mineral and bone disorder (CKD-MBD). Therefore, timely diagnosis and appropriate management strategies to mitigate the development of complications of CKD are paramount.²

Anemia is a common complication of CKD, with an incidence of approximately 50% across all spectrums of CKD. Although complications of CKD, including anemia, typically arise when patients’ glomerular filtration rate (GFR) declines to <60 mL/min, it can be seen in earlier stages of the disease, as well.³ However, the incidence of anemia of CKD dramatically rises as renal disease progresses, with approximately 75% of patients with end-stage renal disease (ESRD) presenting with the condition. Despite lower incidences of the condition in early-stage CKD, it can provide substantial burden to patients. In early stages of anemia, the signs and symptoms of anemia of CKD are not characteristically different from anemia of other causes. However, the presence of anemia of CKD is associated with increased risk of CV disease, progression of cardiorenal syndrome, reduced quality of life, and increased utilization of health care resources.⁴

Physiologically, several factors interplay that result in the falling hemoglobin (Hgb) seen in CKD. The kidneys’ inability to produce sufficient erythropoietin as renal function declines physiologically contributes to the development anemia of CKD. Lower Hgb levels are also frequently observed in patients with CKD due to frequent laboratory draws and uremia-associated platelet dysfunction. Hemodialysis line access, in addition to laboratory draws, can also account for lower Hgb, whereas iron loss, especially for those individuals utilizing erythropoiesis stimulating agents (ESAs), can further decrease Hgb.⁵

Erythropoiesis stimulating agents are currently a mainstay of therapy for patients with anemia attributable to CKD after sufficient iron repletion.⁶ Erythropoiesis stimulating agents stimulate the production of erythropoietin from bone marrow, therefore increasing Hgb levels. They exert their action by binding to and stimulating the erythropoietin receptor, thereby stimulating the proliferation and maturation of red blood cells, and thus, increasing overall iron demand. Therefore, ESAs’ efficacy is reliant on the assumption that iron stores are sufficient in order to stimulate erythropoiesis. Currently, available ESAs used in the treatment of anemia of CKD include epoetin alfa and biosimilar agents, darbepoetin alfa, and methoxy pegylated-epoetin beta. Erythropoiesis stimulating agents can be administered intravenously or subcutaneously, with patients receiving hemodialysis usually receiving intravenous doses at dialysis sites, and non–dialysis-dependent patients self-administering subcutaneous doses or receiving them at outpatient injection centers.⁶

Although ESAs previously were standard of care for anemia of CKD in all spectrums of CKD, guidelines recommend more conservative use of these agents. Erythropoiesis stimulating agents are traditionally dosed based upon Hgb levels to minimize potential toxicities. Erythropoiesis stimulating agents can be initiated in dialysis-dependent patients at serum Hgb 9 to 10 g/dL, and the decision to initiate an ESA in non–dialysis-dependent patients may occur at Hgb levels less than 10 g/dL using an individualized approach, with an assumption that treatment will be monitored to ensure that Hgb will not exceed serum Hgb levels of greater than 11 to 11.5 g/dL in dialysis-dependent patients and greater than 10 g/dL in the non–dialysis-dependent population to prevent the potential for serious complications. Risks of death, stroke, and other serious CV and thromboembolic events increase at Hgb levels above 13 g/dL and have been seen with ESA administration. Therefore, ESAs should not be initiated in patients with uncontrolled hypertension and should be used with great caution, or not at all, in those with a history of cancer or stroke.⁶

Although several different treatment strategies for anemia of CKD exist, controversy in management approaches continues to be prevalent in practice, with evidence suggesting that anemia of CKD is largely undertreated, further contributing to negative health care outcomes in CKD patients.⁴ The introduction of novel agents that are oral, thus, may be promising to improve overall management and outcomes in anemia of CKD.

Hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHI) are a new class of oral agents that endogenously increase erythropoietin production. Vadadustat, enarodustat, roxadustat, molidustat, and desidustat are HIF-PHIs that have been studied in dialysis-dependent and non–dialysis-dependent patients and are approved for use in countries outside of the United States.⁷ Daprodustat is the first HIF-PHI to be approved in the United States by the Food and Drug Administration (FDA). Its approval in February 2023 for patients with anemia due to CKD who have been dialysis-dependent for at least 4 months was based on the results of the Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat (ASCEND)-D trial.^8,9 The purpose of this article is to review the efficacy and safety of daprodustat for the treatment of anemia of CKD.

Data Sources and Extraction

A literature search was conducted using MEDLINE, EMBASE, and ClinicalTrials.gov from January 2010 through November 2023. Keywords used were “daprodustat,” “GSK1278863,” and “hypoxia-inducible factor-prolyl hydroxylase inhibitor.” Literature was included if it evaluated the pharmacology, pharmacokinetics, efficacy, and/or safety of daprodustat in human subjects and was reported in English. The manufacturer’s product monograph and information from the FDA was also utilized.

Data Synthesis

Daprodustat Pharmacology

Mechanism of action

Daprodustat increases endogenous erythropoietin levels by stimulating transcription of the HIF-response genes, including erythropoietin, in the kidneys and liver. It is a reversible inhibitor of HIF-PH1, PH2, and PH3 and leads to stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors.⁸ Physiologically, daprodustat has been shown to stabilize factors that induce hypoxia and, in turn, promote the transcription of factors that increase oxygen, such as erythropoietin. The pharmacotherapeutic effects of daprodustat are similar to the body’s compensatory mechanisms to adjust to high altitude.^10,11

Indication

Daprodustat was approved by the FDA on February 1, 2023 for the treatment of anemia of CKD in patients who have been dialysis-dependent for at least 4 months. It is not indicated to improve fatigue, quality of life, or patient well-being and is not an alternative to red blood cell transfusions for immediate anemia correction.⁸

Dosing, administration, and dosage forms

Daprodustat is administered as a once daily oral tablet and can be taken without regard to food. Starting doses of daprodustat are based on pretreatment Hgb levels and may be adjusted based on liver function, interacting medications, and subsequent Hgb levels during treatment monitoring. For ESA-naive patients with Hgb levels less than 9 g/dL, the general recommended starting dose of daprodustat is 4 mg once daily; for Hgb levels between 9 and 10 mg/dL, daprodustat 2 mg daily is recommended; and for Hgb levels greater than 10 g/dL, daprodustat 1 mg daily should be initiated. After initiation, the dose should not be adjusted more than every 4 weeks and in no more than 1 dosing level increments. For patients transitioning from an ESA to daprodustat, recommended starting doses are 4 mg daily, 6 mg daily, or 8 mg daily depending on the ESA and its coinciding dose. The maximum daily dose of daprodustat is 24 mg daily. If Hgb rises rapidly, meaning more than 1 g/dL in 2 weeks or more than 2 g/dL in 4 weeks, or if Hgb exceeds 11 g/dL, the dose of daprodustat should be decreased. Treatment should be halted if Hgb levels exceed 12 g/dL and re-initiated at a lower dose once Hgb levels fall into target range. If no improvements in Hgb levels are noted at 24 weeks, daprodustat is to be discontinued.⁸

Monitoring

Serum Hgb levels should be monitored judiciously while using daprodustat. The package insert recommends that serum Hgb should be measured at baseline before starting daprodustat, every 2 weeks for the first month, and then every 4 weeks thereafter. In addition, iron indices, including serum ferritin and transferrin saturation (TSat) levels should be monitored, and iron supplementation should occur at ferritin levels < 100 ng/mL or TSat < 20%. Liver function tests, including serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin should be measured at baseline to determine appropriate use and dosing, and repeat liver tests should take place if patients develop signs or symptoms consistent with liver disease. Patients with Child-Pugh class B (moderate) liver disease should be initiated on a lower dose of daprodustat, and daprodustat is not recommended for use in patients with Child-Pugh class C (severe disease). Daprodustat should not be continued for longer than 24 weeks if a clinically meaningful increase in Hgb levels is not observed.⁸

Interactions

As daprodustat is primarily metabolized through CYP450 isoenzyme 2C8 and is a CYP2C8 substrate, most drug interactions occur with CYP2C8 inducers and inhibitors. It is recommended to reduce the starting dose of daprodustat when concomitantly administering with moderate CYP2C8 inhibitors. Serum Hgb levels should be monitored closely with CYP2C8 inducers, and daprodustat doses should be adjusted accordingly.⁸

Contraindications

Daprodustat is contraindicated in concomitant use with strong CYP2C8 inhibitors such as gemfibrozil. Similar to ESAs, daprodustat is also contraindicated in uncontrolled hypertension due to the risk of thrombotic vascular events and major adverse cardiovascular events (MACEs). Daprodustat may cause fetal harm and should be avoided in pregnancy, and breastfeeding is not recommended until after 1 week from the final dose.⁸

Warnings and precautions

Daprodustat carries the Boxed Warning of increased risk of arterial and venous thrombotic events, including myocardial infarction (MI), stroke, venous thromboembolism (VTE), and vascular access thrombosis. Thus, treatment should be avoided in patients with a history of acute coronary syndrome, MI, or cerebrovascular event in the preceding 3 months as patients with CV disease are at increased risk of these events.⁸

Clinical Trials

The study population, design, and outcome results for the trials collected from the literature search evaluating daprodustat are detailed in Table 1.

Table 1.

Literature Evaluating Daprodustat in Anemia of Chronic Kidney Disease.

Trial and study population	Study design	Efficacy outcomes	Safety outcomes
ASCEND-D (2021) Inclusion: ESRD on iHD or PD for prior 90 days Received ESA for at least 6 weeks Hgb 8-12 g/dL Ferritin > 100 ng/mL, TSat > 20% Mean baseline Hgb: 10.4 +/- 1.0 g/dL	Randomized, open-label, phase 3 trial Interventions: daprodustat vs injectable ESA (epoetin alfa if on iHD, darbepoetin alfa if on PD) to maintain Hgb 10-11 g/dL	Mean change in Hgb from baseline to weeks 28-52: daprodustat 0.28 +/- 0.2 g/dL vs ESA 0.10 +/- 0.02 g/dL (difference 0.18 g/dL, 0.12-0.24, met prespecified non-inferiority margin of -0.75 g/dL)	First occurrence of MACE (composite of death from any cause, nonfatal MI, or nonfatal stroke): daprodustat 374/1487 patients (25.2%) vs ESA 394/1477 patients (26.7%) (HR 0.93, 0.81-1.07, met prespecified non-inferiority margin of 1.25)
ASCEND-ND (2021) Inclusion: CKD stages 3-5 not receiving dialysis Hgb 8-12 g/dL Ferritin >100 ng/mL; TSat > 20% Mean baseline Hgb: 9.9 +/- 0.9 g/dL	Randomized, open-label, phase 3 trial Interventions: daprodustat vs subcutaneous darbepoetin alfa to maintain Hgb 10-11 g/dL	Mean change in Hgb from baseline to weeks 28-52: daprodustat 0.74 +/- 0.2 g/dL vs darbepoetin alfa 0.66 +/- 0.02 g/dL (difference 0.08 g/dL, 0.03-0.13, met prespecified non-inferiority margin of -0.75 g/dL)	First occurrence of MACE (composite of death from any cause, nonfatal MI, or nonfatal stroke): daprodustat 378/1937 patients (19.5%) vs ESA 371/1935 patients (19.2%) (HR 1.03 0.89-1.19, met prespecified non-inferiority margin of 1.25) On-treatment first occurrence of MACE: daprodustat 14.1% vs darbepoetin alfa 10.5% (HR 1.40, 1.17-1.68)
ASCEND-TD (2022) Inclusion: ESRD on iHD for prior 90 days Received ESA for at least 8 weeks Hgb 8-11.5 g/dL Ferritin > 100 ng/mL, TSat > 20% Median (IQR) baseline Hgb: 10.6 g/dL (10.0-11.1)	Randomized, double-blind, double-dummy, phase 3 trial Interventions: daprodustat 3 times weekly and intravenous saline vs intravenous epoetin once weekly or 3 times weekly and placebo tablets to maintain Hgb 10-11.5 g/dL	Mean change in Hgb from baseline to weeks 28-52: model-adjusted mean treatment difference (daprodustat vs epoetin) -0.05 (95% CI, -0.21 to 0.01, meeting non-inferiority margin) Mean Hgb in range of 10-11.5 g/dL: daprodustat 80% vs epoetin 64%	Treatment-emergent adverse effects similar with daprodustat (75%) vs epoetin (79%) Effects on blood pressure similar between daprodustat and epoetin
Meadowcroft et al¹² Inclusion: ESRD on iHD Received ESA for at least 8 weeks Hgb 9-11.5 g/dL Ferritin > 100 ng/mL and/or TSat < 12% or > 57% Mean baseline Hgb: 10.4 g/dL	Randomized, blinded through week 4 and open-label thereafter, dose-range, efficacy, and safety trial Interventions: daprodustat (dose-ranging) vs placebo tablets in 2:2:2:2:1:2 ratio to maintain Hgb 10-11.5 g/dL	Mean change in Hgb from baseline to week 24: combined daprodustat group 0.03 g/dL vs placebo -0.11 g/dL Mean change in baseline Hgb to week 24: increased dose-dependently with daprodustat from -0.29 g/dL (4 mg tablets) to 0.69 g/dL (10 and 12 mg tablets)	Treatment-emergent adverse events similar in combined daprodustat group vs placebo Serious adverse events occurred in 31 (18%) participants in combined daprodustat group vs 10 (26%) placebo Increased need for additional blood pressure medications in combined daprodustat group (n = 22, 12%) vs placebo (n = 2, 5%)
ASCEND-NHQ (2023) Inclusion: CKD stages 3-5 not receiving dialysis No recent ESA use in prior 8 weeks Hgb 8.5-10.5 g/dL Ferritin ≥ 50 ng/mL, TSat ≥ 15% Median baseline Hgb: 9.75 g/dL	Randomized, multicenter, double-blind, placebo-controlled trial Interventions: daprodustat vs placebo to maintain Hgb 11-12 g/dL	Mean change in Hgb from baseline to weeks 24-28: daprodustat 1.58 g/dL vs placebo 0.19 g/dL Adjusted mean change in Hgb from baseline 1.40 g/dL (95% CI, 1.23 to 1.56) with daprodustat vs placebo Mean Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality (fatigue) score (0-100) increased by 7.3 points with daprodustat and 1.9 points with placebo (5.4 point 28-week difference)	Treatment-emergent adverse events similar with daprodustat (69%) vs placebo (71%) (RR 0.98, 95% CI, 0.88 to 1.09) Serious adverse events similar with daprodustat (20%) vs placebo (22%)
ASCEND-ID (2022) Inclusion: ESRD and planned to initiate dialysis within 6 weeks from screening or initiated and received dialysis within 90 days prior to screening No recent ESA use or ESA-naive Ferritin > 100 ng/mL, TSat > 20% Mean baseline Hgb: 9.5 g/dL	Randomized, open-label, phase 3 trial Interventions: daprodustat vs darbepoetin alfa to maintain goal Hgb of 10-11 g/dL	Mean change in Hgb levels from baseline to weeks 28-52: daprodustat 1.02 g/dL (0.09) vs darbepoetin alfa 1.12 g/dL (0.09) (adjusted mean treatment difference -0.10 g/dL, 95% CI, -0.34 to 0.14 g/dL, meeting non-inferiority margin of -0.75 g/dL)	Treatment-emergent adverse events similar with daprodustat (76%) vs darbepoetin alfa (72%) Rates of MACE and thromboembolic events similar with daprodustat vs darbepoetin alfa
Kanai et al¹³ Inclusion: ESRD on PD Hgb 8-11 g/dL Ferritin > 100 ng/mL, TSat >20% Mean (SD) baseline Hgb: 10.9 g/dL (0.96)	Randomized, multicenter, open-label, phase 3 trial Interventions: daprodustat in either ESA-naive or ESA-experienced (no control group) to maintain Hgb 11-13 g/dL	Mean Hgb level at week 12: 11.36 g/dL Median (SD) time spent in Hgb target range during weeks 40-52: 10.3 weeks (2.70)	Treatment-emergent adverse events similar with daprodustat vs darbepoetin alfa (96%) Serious adverse events similar with daprodustat vs darbepoetin alfa (46%)

Abbreviations: CI, confidence interval; CKD, chronic kidney disease; ESA, erythropoiesis stimulating agents; ESRD, end-stage renal disease; HD, hemodialysis; Hgb, hemoglobin; HR, hazard ratio; IQR, interquartile range; MACE, major cardiovascular adverse events; MI, myocardial infarction; PD, peritoneal dialysis; SD, standard deviation; TSat, transferrin saturation.

Daprodustat

Anemia Study in Chronic Kidney Disease: Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis (ASCEND-D) Trial

The ASCEND-D trial evaluated daprodustat compared with injectable ESAs in patients undergoing hemodialysis and peritoneal dialysis. The phase 3, open-label, non-inferiority trial included those receiving dialysis for the last 90 days and an ESA for the previous 6 weeks with Hgb levels of 8 to 12 g/dL, ferritin level <100 ng/mL, and TSat <20%. Patients were randomized to oral daprodustat or injectable ESA (intravenous epoetin alfa in patients receiving hemodialysis, and subcutaneous darbepoetin alfa in patients receiving peritoneal dialysis) after successful completion of a 4-week adherence run-in period. Initial doses of daprodustat ranged from 4 to 12 mg daily and were dependent on previous ESA doses, whereas ESA doses were based on previous doses and Hgb levels. Dose adjustments of daprodustat were made based on prespecified criteria.

Of the ASCEND-D study participants, 88.5% were receiving hemodialysis, and the mean Hgb level of participants was 10.4 ± 1.0 g/dL. The primary efficacy outcome of mean change in Hgb from baseline to weeks 28 to 52 was 0.28 ± 0.2 g/dL with daprodustat vs 0.10 ± 0.02 g/dL with ESAs (difference = 0.18 g/dL, confidence interval [CI] = 0.12 to 0.24) which met the prespecified non-inferiority margin of −0.75 g/dL. The primary safety outcome of first occurrence of MACE, which was a composite outcome of death from any cause, non-fatal MI, or non-fatal stroke, occurred in 374/1487 patients (25.2%) receiving daprodustat vs 394/1477 patients (26.7%) receiving an ESA (hazard ratio [HR] = 0.93, 95% CI = 0.81 to 1.07), which met the prespecified non-inferiority margin. The secondary outcomes of first occurrence of MACE, first occurrence of MACE or a thromboembolic event, and first occurrence of MACE or hospitalization for heart failure that were tested for superiority did not significantly differ between groups.

Adverse effects did not significantly differ between the treatment groups. Although a rapid increase in serum Hgb levels, defined as an increase of greater than 2 mg/dL in 4-week period, occurred in 50/1218 patients (4.1%) receiving daprodustat and 20/1247 patients (1.6%) receiving an ESA during the first 4 weeks of the study, it decreased to less than 2% thereafter. The percentage of patients requiring blood transfusions also did not differ significantly between the 2 treatment groups. (HR = 0.85, 95% CI = 0.72 to 1.02).⁹

As ASCEND-D’s study population comprised mostly hemodialysis patients receiving epoetin alfa, the results of this study cannot be extrapolated to other modalities of dialysis or other ESAs. In addition, the open-label trial design could have introduced reporting bias to the study, and the short study duration may not have been adequate to notice additional efficacy or safety parameters.

Anemia Study in Chronic Kidney Disease: Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis (ASCEND-ND) Trial

The ASCEND-ND was a phase 3, open-label non-inferiority trial that evaluated daprodustat compared with subcutaneous darbepoetin alfa in patients with CKD stages 3 to 5 who were not receiving dialysis. Patients were required to meet Hgb level criteria of 8 to 10 g/dL in patients not receiving ESAs and 8 to 12 g/dL in patients receiving ESAs, with ferritin and transferrin levels greater than 100 ng/mL, and 20%, respectively. Patients were randomized after successful completion of a 4-week adherence run-in period to oral daprodustat or darbepoetin alfa in a 1:1 fashion. Daprodustat dose adjustments were made based on prespecified trial criteria.

Baseline criteria of mean Hgb levels of study participants, serum iron levels, and exogenous iron requirements were similar between treatment groups at baseline. The primary efficacy outcome of mean change in Hgb from baseline to weeks 28 to 52 was 0.74 ± 0.02 g/dL with daprodustat vs 0.66 ± 0.02 g/dL with ESAs (difference = 0.08 g/dL, CI = 0.03 to 0.13) which met the prespecified non-inferiority margin of −0.75 g/dL. The primary safety outcome in the primary intention-to-treat analysis of first occurrence of MACE, which was a composite outcome of death from any cause, non-fatal MI, or non-fatal stroke, occurred in 378/1937 patients (19.5%) receiving daprodustat vs 371/1395 patients (19.2%) receiving darbepoetin alfa (HR = 1.03, 95% CI = 0.89 to 1.19), which met the prespecified non-inferiority margin of 1.25. However, the on-treatment analysis, which evaluated patients 28 days post-last dose of study medication, revealed a higher rate of first MACE in those receiving daprodustat vs darbepoetin alfa during the treatment period (14.1% vs 10.5%, HR = 1.40, 95% CI = 1.17 to 1.68). The secondary outcomes of first occurrence of MACE, MACE or thromboembolic events, MACE or hospitalization for heart failure, and CKD progression did not significantly differ between groups. However, 2 adverse events of special interest, cancer-related death or tumor progression or recurrence and esophageal and gastric erosions, were significantly increased in those receiving daprodustat.

Rates of any adverse event experienced did not significantly differ between treatment groups, but serious adverse events, including infections (eg, pneumonia, COVID-19, urinary tract infection), renal-related events (eg, CKD, acute kidney injury, azotemia, ESRD), and CV events (eg, acute MI) were numerically greater in the daprodustat group (43.9%) vs the darbepoetin alfa group (36.4%). During the trial period, a similar number of patients receiving daprodustat required blood transfusions compared with those receiving ESA therapy (12.8% vs 13.5%, HR = 0.96, 95% CI = 0.81 to 1.14).¹⁴

Similar to ASCEND-D, the open-label trial design of ASCEND-ND may have introduced reporting bias of adverse effects, and the study duration may not have been sufficient time to notice all potential safety concerns. The use of darbepoetin alfa as the only ESA may also make these results less generalizable to use of other ESAs; however, in the non–dialysis-dependent population, darbepoetin’s less frequent administration frequency may be more desirable than others’.

Clinical Review of Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors

Cochrane Review

A Cochrane review sought to evaluate the benefits and harms of HIF-PHIs in the treatment of anemia of CKD. Fifty-one studies including over 30 000 patients were included in the analysis. Studies were included if they evaluated HIF-PHIs for treatment in comparison with placebo, standard of care, ESAs, or iron supplementations.

When compared directly with placebo, daprodustat exhibited beneficial effects on the percentage of patients whose Hgb was increased and probable effects on the reduction on blood transfusions (8 studies, 4329 participants): risk ratio (RR) = 0.51, 95% CI = 0.44 to 0.60; heterogeneity (I²) = 0%; moderate certainty evidence and uncertain effects on CV death (10 studies, 1114 participants): RR = 3.68, 95% CI = 0.19 to 70.21; very low certainty evidence. Daprodustat also demonstrated uncertain effects on non-fatal MI and uncertain effects on stroke incidence as well as peripheral arterial disease; however, it appeared to increase thrombosis risk when compared with placebo. When compared directly with ESAs, HIF-PHIs had probable effects on decreasing the proportion of patients requiring blood transfusion (11 studies, 10 786 participants): RR = 0.87, 95% CI = 0.76 to 1.00; I² = 25%; moderate certainty evidence. However, they did not exhibit benefits in the proportion of patients who reached target Hgb (14 studies, 4601 participants): RR = 1.00, 95% CI = 0.93 to 1.07; I² = 70%; low certainty evidence, compared with ESA. Hypoxia-inducible factor–prolyl hydroxylase inhibitors did not exhibit differences in CV outcomes such as CV death, non-fatal MI, and non-fatal stroke when compared with daprodustat.

Several outcomes remained uncertain at the conclusion of the review including the effects of the agents on fatigue, heart failure hospitalizations, peripheral arterial events, and others. The authors concluded that although HIF-PHIs had uncertain effects on CV and renal outcomes, fatigue, and death, they did likely reduce the proportion of patients requiring blood transfusions and likely increased the proportion of patients who met serum Hgb goals. Adverse events were rarely reported and did not differ significantly between treatment groups.¹⁵

Meta-analysis by Yang and Colleagues

A meta-analysis of HIF-PHIs in patients who are not dialysis-dependent was conducted to determine the benefits of these agents against traditional iron-repleting therapies given that patients not on dialysis typically have a lower risk of inflammatory states when compared with traditional dialysis populations. Data were utilized from 15 studies including over 3000 patients. Compared with placebo, all HIF-PHIs and ESAs had greater ability to raise Hgb, as expected, with an HIF-PHI, desidustat (not currently available in the United States), demonstrating the highest potential for increasing Hgb. Furthermore, when comparing HIF-PHIs to ESAs, total iron binding capacity and transferrin were increased, whereas other iron markers, including hepcidin, ferritin, and TSat, reflected decreases. Of note, in this meta-analysis, daprodustat, in comparison to all other agents, had the highest potential to lower hepcidin levels, further supporting its benefits in all patients presenting with iron-depleted states.¹⁶

Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs

Efficacy

Daprodustat is a promising treatment for promoting endogenous erythropoietin production for treatment of anemia in CKD and offers the benefit of an oral dosage form not seen with traditional ESAs. The ASCEND-D trial showed that daprodustat can be used in patients with CKD on dialysis to further increase serum Hgb levels without increasing the risk of first occurrence of MACE. However, the overall increases in Hgb seen in ASCEND-D and other previous studies may not be clinically significant in the dialysis population due to the relatively small improvements in laboratory parameters as well as some instances of increased serious adverse events.

Prior to the ASCEND-D trial’s publication, daprodustat was found to increase mean Hgb levels from baseline compared with placebo in dialysis-dependent patients who were receiving ESAs 8 weeks prior in a 24-week randomized, dose-ranging trial without significantly increasing rates of adverse events. There were also less serious adverse events numerically with daprodustat (18%) compared with placebo (26%). More patients receiving daprodustat in this study had Hgb levels that exceeded 13 g/dL (n = 17, 10%) vs placebo (n = 1, 3%); however, 82% of patients with Hgb levels greater than 13 g/dL were randomized to starting doses of daprodustat of at least 8 mg daily. Need for additional blood pressure medications was also greater with daprodustat (n = 22, 12%) vs placebo (n = 2, 5%). Minimal changes in intravenous iron doses were required in both study groups, and decreases in hepcidin, ferritin, and TSat were noted in those receiving daprodustat, alluding to HIF-PHIs causing increased iron utilization due to increased erythropoeisis.¹² Of note, a combined 171 study participants received varying doses of daprodustat in this 24-week trial, whereas 39 participants were in the control group. Thus, some benefits and risks noted with daprodustat may have been dose-dependent and may not be reflected in the overall study results.

Effects on Iron Panel

Hypoxia-inducible factor–prolyl hydroxylase inhibitors have been found to reduce hepcidin levels which can enhance iron metabolism and increase transferrin levels and total iron binding capacity.⁷ When compared with ESAs in a large meta-analysis, HIF-PHIs increased total iron binding capacity and transferrin levels.¹⁷ These results were confirmed by the ASCEND-D and ASCEND-ND trials where it was observed that patients receiving daprodustat had numerically increased total iron binding capacity in comparison to those receiving ESAs. For dialysis-dependent patients in ASCEND-D, TSat levels were not numerically different between groups in dialysis-dependent patients, whereas serum iron levels were seen to be higher. In patients who were non–dialysis-dependent patients in ASCEND-ND, TSat levels were numerically higher, serum iron levels were similar, and hepcidin was decreased in comparison to the control population.^9,14 Thus, daprodustat’s enhancement of iron utilization due to increased erythropoiesis and potential ability to improve serum iron panel levels warrants further exploration. It is currently unable to be determined whether exogenous iron supplementation can be reduced with long-term daprodustat administration.

Safety

Common adverse effects that were noted in trials evaluating daprodustat were hypertension, diarrhea, headache, nausea, and nasopharyngitis, which were similar to those experienced by patients receiving ESAs.⁹ In trials evaluating other HIF-PHIs, headache, emesis, and thrombosis were observed more frequently compared with ESAs.¹⁸ Although no significant differences were noted in changes in blood pressure and thrombotic events between patients receiving daprodustat and ESAs in the ASCEND-D and ASCEND-ND trials, the median follow-up times in the trials may not have been long enough to observe the development of these adverse effects.^9,14 In addition, in the current literature, more adverse effects were experienced at higher initial starting doses and escalated doses of daprodustat, so dosing based on current Hgb levels and titrating slowly to effect and tolerability is warranted.

The ASCEND trials evaluated treatment-emergent serious adverse events which mostly consisted of acute infections and CV events but also consisted of renal-related events (eg, CKD, acute kidney injury, azotemia, and ESRD) that could have been representative of progression of renal disease as opposed to a true adverse effect of daprodustat. A primary concern with administration of ESAs is MACE, and daprodustat had a similar rate of MACE in clinical trials in dialysis-dependent patients.^9,12,19 Multiple clinical trials suggest that non–dialysis-dependent patients experienced a higher rate of first occurrence of MACE with daprodustat and other HIF-PHIs.^14,20 Due to this safety issue as well as a lack of data for other serious adverse events, daprodustat is not FDA-approved in non–dialysis-dependent patients.²¹

Quality of Life

Treatment of anemia of CKD can positively impact quality of life through reduction of bothersome symptoms including fatigue, shortness of breath, weakness, body ache, or dizziness and fainting. In the ASCEND-D trial, although treatment with daprodustat conferred a comparable increase in Hgb to treatment with traditional ESA therapy, it was not shown to improve fatigue or overall well-being or quality of life in dialysis-dependent patients.⁹ However, the ASCEND-NHQ trial evaluated changes in fatigue in non–dialysis-dependent CKD stages 3 to 5 patients and found notable increases in Vitality scores, indicating decreased fatigue.²² Notably, 40% of patients receiving daprodustat in the ASCEND-NHQ study had increases in Vitality scores of greater than or equal to 6, which was determined to be clinically significant by study investigators.²² Non-serious adverse event rates were overall similar in both trials with daprodustat vs comparators, and efficacy parameters reflected overall increases in serum Hgb over placebo as well as fewer blood transfusions with active treatment in comparison to placebo.

Further analysis of effects on fatigue with daprodustat treatment in dialysis- and non–dialysis-dependent patients through treatment of anemia of CKD is warranted in order to better assess its impact on quality of life. The oral dosage form could be advantageous and lead to improved patient satisfaction, especially with a lower pill burden as was investigated in the ASCEND-TD trial. In this trial, patients were randomized to receive either daprodustat 3 times weekly or conventional epoetin and were followed for 52 weeks. The primary endpoint, mean change in Hgb from baseline to weeks 28 to 52, met criteria for non-inferiority against epoetin (model-adjusted mean treatment difference [daprodustat-epoetin], −0.05; 95% CI = −0.21 to 0.10). Fewer participants in the ASCEND-TD trial receiving daprodustat had Hgb values below 10 g/dL or above 11 g/dL during the evaluation period, and intravenous iron usage, effects on blood pressure, and percentage of treatment-emergent adverse events were similar between daprodustat and epoetin also, suggesting that decreased dosing intervals can be efficacious.¹⁹

Peritoneal Dialysis and Newly Initiated Dialysis

The majority of patients evaluated in the ASCEND-D trial were receiving hemodialysis (88.5%), with only 11.5% receiving peritoneal dialysis. In subgroup analyses of ASCEND-D, mean changes in Hgb from baseline were similar with daprodustat, regardless of dialysis modality, and patients receiving peritoneal dialysis could be more appropriate targets for oral erythropoiesis stimulating therapy, especially given that they do not have permanent accessible lines to receive intravenous ESAs.⁹ Daprodustat was evaluated in peritoneal dialysis patients in a small, non-comparator trial conducted mostly in patients who had previously received ESAs to maintain Hgb levels of 11 to 13 g/dL. In this study by Kanai and colleagues, baseline Hgb levels in the study population were 10.9 g/dL, and mean time on peritoneal dialysis was 2.7 years. Serum Hgb levels in study participants increased to a mean of 11.36 g/dL after 12 weeks of therapy and was maintained through weeks 40 to 52. Ninety-six percent of patients in this study experienced an adverse event, with the most common adverse effects (occurring in greater than 5% of patients) being nasopharyngitis, catheter-site infections, peritonitis, diarrhea, and nausea. In the trial, 46% of patients experienced a serious adverse event, including heart failure and peritonitis. The mean daprodustat dose during the final 12 weeks of the study was 5.7 mg daily.¹³

Similar efficacy was shown in the ASCEND-ID trial, both in patients who were either newly receiving dialysis within 90 days prior to screening or were planning to initiate dialysis in the upcoming 6 weeks from the study screening period. In this study, 20% of patients received peritoneal dialysis, and as was shown in ASCEND-D, mean Hgb changes from baseline were similar with daprodustat vs darbepoetin alfa with similar rates of adverse events between all study groups.²³ In addition, the rate of first occurrence of blood transfusions during treatment were 12% with daprodustat vs 14% with darbepoetin alfa (HR = 0.88, 95% CI = 0.47 to 1.66), and less patients receiving daprodustat had blood pressure elevations compared with darbepoetin alfa. Therefore, further prospective exploration of daprodustat vs traditional ESA therapy in peritoneal dialysis and those who are new to dialysis, regardless of modality, is warranted to determine its efficacy and safety in these patient populations.^22,23

Non-Dialysis Chronic Kidney Disease Patients

As patients receiving hemodialysis can more readily receive ESAs at dialysis centers, daprodustat and other HIF-PHIs may be a more preferred medication in those with CKD stage 3 to 5 not receiving dialysis for treatment of anemia of CKD. A randomized, open-label, 52-week, phase 3 trial conducted in Japan assessed daprodustat vs epoetin beta pegol. The mean Hgb level at baseline in the daprodustat group was 10.5 and 10.7 g/dL in the epoetin beta group. The primary endpoint of mean Hgb levels during weeks 40 to 52 of the study did not significantly differ between groups (difference = 0.1 g/dL, CI = 11.8 to 12.1) with mean Hgb levels in those in the daprodustat group of 12.0 and 11.9 g/dL in the epoetin beta group. The majority of patients in each treatment group had either CKD stage 4 or stage 5 at baseline, and approximately one-half of participants were ESA-naive. Ninety-two percent of patients receiving daprodustat and 89% of those receiving epoetin beta experienced at least 1 adverse effect of therapy, with nasopharyngitis and constipation being most common, and rates of serious adverse events were lower and similar between groups. The authors noted that the study duration did not allow for analysis of either medication’s effect on CV outcomes. The mean dose of daprodustat in ESA-naive patients was 4 mg per day and 5.3 mg daily in ESA-experienced patients.²⁴ Until more data emerge on daprodustat’s influence on MACE in comparison to ESAs in non–dialysis-dependent CKD, it is unclear whether daprodustat and other HIF-PHIs can be safely used in this population.

Literature Evaluating Other Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors

Daprodustat has not been studied head-to-head to other HIF-PHIs in clinical trials, but there are studies evaluating other HIF-PHIs compared with ESAs or placebo. Vadadustat has been evaluated in dialysis-dependent and non–dialysis-dependent CKD patients and has shown comparable efficacy in increasing serum Hgb levels from baseline in comparison to ESAs.^19,25 Although it did not increase the risk of MACE in comparison to darbepoetin alfa in dialysis-dependent patients in 2 large, randomized, phase 3 trials, vadadustat did not meet non-inferiority criteria for CV safety in 2 large trials comparing it to darbepoetin alfa in non–dialysis-dependent patients.^19,25 Roxadustat has also shown similar increases in serum Hgb levels in dialysis-dependent patients compared with darbepoetin alfa and was superior in increasing Hgb in non–dialysis-dependent patients compared with placebo.^26,27 Current literature evaluating roxadustat has not been powered to detect differences in CV safety, but no numerical differences in CV events between roxadustat and ESAs have been noted in dialysis-dependent patients.²⁶

Feasibility and Accessibility

The HIF-PHIs’ place in therapy has not been fully determined upon writing this review. However, the oral dosage form and the change in the Centers for Medicare & Medicaid (CMS) ESRD Prospective Payment System (PPS) bundle in 2023 could make it a favorable option for patients and dialysis centers alike. The PPS was updated to include oral medications in drug classes that are indicated in ESRD patients, such as calcimimetics, and could extend to treatments for anemia of CKD in the future.²⁸ In addition, the Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat–Pediatric (ASCEND-P) trial, an observational study that is currently ongoing, is evaluating daprodustat in pediatric patients ages 3 to 17 years old in 2 cohorts, non-dialysis and dialysis, with a primary safety endpoint which could further determine daprodustat’s place in therapy.²⁹ The oral dosage form could also be advantageous for patients receiving peritoneal dialysis and/or in those who are planned to initiate dialysis in upcoming weeks, but more data in these populations are warranted before definitive conclusions can be made.

Recommendations are provided in the daprodustat package insert regarding how to convert doses of an injectable ESA to oral daprodustat therapy.⁸ Importantly, similar to ESAs, daprodustat’s approval in dialysis-dependent CKD was conducted in patients who were considered to be iron-replete, so appropriate iron supplementation must be addressed before initiation of daprodustat.⁹ As new data emerge, daprodustat may gain new dosing recommendations and indications in other populations, such as non–dialysis-dependent patients or those receiving peritoneal dialysis, and recommendations for iron status prior to initiation and during treatment could be made.

Conclusions

Daprodustat is a promising option for anemia of CKD treatment that enhances production of endogenous erythropoietin and is indicated in dialysis-dependent patients who have been receiving dialysis for at least 4 months. Several studies have demonstrated the agent’s ability to significantly increase Hgb levels and decrease the need for transfusions while not increasing the risk of MACE in the dialysis population. However, the mean increases in Hgb may not be clinically relevant in comparison to ESAs in patients who are able to easily access and receive ESAs such as those receiving hemodialysis. It also has the propensity to enhance patients’ quality of life by decreasing fatigue and anemia of CKD symptoms through a convenient oral dosing option. Long-term efficacy and safety data beyond 2 years are pending and may ultimately determine daprodustat’s place in therapy in the treatment of anemia of CKD.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Haley N. Johnson

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