Daprodustat

Abstract

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Generic Name: DAPRODUSTAT

Proprietary Name: Jesduvroq (GlaxoSmithKline)

Approval Rating: 1S

Therapeutic Class: Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Similar Drugs: Roxadustat, Vadadustat

Sound-/Look-Alike Names: Daprolin, Daprox, Daypro

Indications

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least 4 months. Daprodustat is not indicated for use as a substitute for red blood cell transfusion in patients requiring immediate correction of anemia, or for treatment of anemia due to CKD in patients not on dialysis. ¹

Anemia associated with CKD has been previously treated with erythropoiesis-stimulating agents (ESAs), including darbepoetin alfa, epoetin alfa, epoetin beta, epoetin omega, epoetin delta, and methoxy polyethylene glycol-epoetin beta. ² However, all these drugs are given by injection. Daprodustat and the other HIF-PH inhibitors pending approval (eg, roxadustat, vadadustat) are given orally and may be an alternative to ESAs.^3,4

AstraZeneca received a Complete Response Letter (CRL) from the FDA in August 2021 regarding its New Drug Application (NDA) for use of roxadustat in the treatment of adults with anemia due to CKD, in both non–dialysis-dependent and dialysis-dependent patients. The reason for issuing the CRL was the need for additional clinical studies regarding the safety of roxadustat in both non–dialysis-dependent and dialysis-dependent populations. ⁵

Akebia Therapeutics received a CRL from the FDA in March 2022 regarding its NDA for use of vadadustat in the treatment of anemia due to CKD. The FDA expressed safety concerns regarding the following: failure to meet noninferiority in major adverse cardiovascular event (MACE) in the non–dialysis-dependent patient population, an increased risk of thromboembolic events (driven by vascular access thrombosis in dialysis patients), and risk of drug-induced liver injury. The CRL recommended new clinical trials to address these issues. ⁶

Clinical Pharmacology

Daprodustat is an oral HIF-PH inhibitor; it has activity against PH1, PH2, and PH3.^{1 -4,7} The oxygen sensors (prolyl hydroxylases) help regulate HIF activity through oxygen-dependent proteasomal degradation. When hypoxia is observed, HIF (a transcription factor) stimulates endogenous erythropoietin production by the liver and kidneys and ultimately erythropoiesis.^8-10 Daprodustat stabilizes intracellular HIF1α and HIF2α and is thought to induce a transient pseudo-hypoxic state that results in the stimulation of erythropoiesis in CKD patients with anemia.^1,2,7 Daprodustat may also influence iron hemostasis through effects on ferritin levels, transferrin saturation, transferrin receptor expression, hepcidin concentrations, and other iron-related proteins.^{2 -4,7}

Daprodustat’s mechanism of action is different from previously used ESAs (eg, epoetin alfa, epoetin beta, rh-epoetin, darbepoetin alfa).^{10 -12} Daprodustat appears to have 1000-fold or higher selectivity for the 3 prolyl hydroxylase domains (PHD1, PHD2, PHD3), with a preference for PHD1 and PHD3.^2,7,10 Roxadustat appears to equally inhibit all 3 enzymes, and vadadustat may have more selective activity against PHD3 and PHD1 than PHD2. ¹⁰ There are other HIF-PH inhibitors (eg, desidustat, enarodustat, molidustat, roxadustat, vadadustat) in development.^{10 -12}

Daprodustat’s impact on plasma hemoglobin concentration, serum total iron-binding capacity, and ferritin concentrations is dose related, with higher doses associated with a higher impact on these outcomes.^1,13 An increase in endogenous erythropoietin occurred within 6 to 8 hours after administration. With continued administration, weak increases in reticulocyte counts occur between 7 and 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks after initial administration (approximately 4 weeks with ESA use and 16-20 weeks in those not using ESAs). Improvements in serum transferrin and total iron-binding capacity as well as decreases in serum ferritin, transferrin saturation, and hepcidin were observed over 52 weeks of treatment in adults on dialysis with anemia due to CKD. ¹

Single doses of daprodustat 75 and 500 mg did not produce clinically meaningful changes in QT/QTc interval.^1,14

Pharmacokinetics

Absolute oral bioavailability is 65%.^1,15 Median T_max following oral administration is 1 to 2 hours. T_max for the 6 predominant metabolites is slower, with a median C_max occurring between 2 and 8 hours. ¹⁶ Administration with a high-fat/high-calorie meal did not significantly alter daprodustat exposure compared with administration in the fasted state. ¹

The terminal half-life of daprodustat was approximately 1 to 4 hours in healthy participants and 7 hours in patients with CKD.^1,2,15,16 Daprodustat’s half-life was similar among patients with CKD stage 3 to 4, patients on hemodialysis (when received on dialysis day), and patients on peritoneal dialysis, while in dialysis patients receiving daprodustat on nondialysis days, mean half-life was 18.9 hours.^2,16 Daprodustat is mainly metabolized by CYP2C8 (with minor contribution of CYP3A4); therefore, CYP2C8 inhibitors or inducers may alter the plasma concentration of daprodustat when used concomitantly.^1,2,15 The percentage excreted unchanged was 0.05% for subjects with normal renal function and 0.04% in those with CKD stage 3 to 4. ¹⁶

Following IV administration in healthy adults, volume of distribution is 14.3 L.1 Daprodustat is highly bound to protein (mainly albumin); therefore, the drug is not significantly removed by hemodialysis.^1,2

Mean clearance from plasma was 18.9 L/hour, which correlates to blood clearance of 15 L/hour and equates to a hepatic extraction of approximately 18%. Within 7 days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the rest accounted for by daprodustat. ¹

The steady-state exposure of daprodustat is similar in patients with normal renal function and in those with varying degrees of renal impairment; daprodustat exposure is not significantly impacted by hemodialysis or peritoneal dialysis. The systemic exposure of daprodustat metabolites was higher in patients with stage 3 to 5 CKD compared to those with normal renal function. Exposures of metabolites were higher on nondialysis days compared to dialysis days. ¹

Clearance was 0.2 mL/minute in healthy subjects and 0.17 mL/minute in patients with CKD stage 3 to 4. Dialysis clearance was −8.5 mL/minute during hemodialysis and 10.61 mL/minute during peritoneal dialysis. Dialysis clearance of the metabolites was higher in patients on hemodialysis and lower in patients on peritoneal dialysis. ¹⁶

Daprodustat C_max and AUC were increased 2-fold in participants with moderate (Child-Pugh class B) hepatic impairment versus healthy controls; in participants with mild hepatic impairment, C_max was comparable with controls and AUC was increased 1.5-fold.^1,17

Comparative Efficacy

Indication: Anemia in Patients With Chronic Kidney Disease Undergoing Dialysis (FDA-Approved Use)

These studies confirm the results in phase 2 studies.^7,18,19

Separate phase 3 studies conducted in Japanese patients undergoing hemodialysis and peritoneal dialysis showed comparable results for daprodustat efficacy and safety.^20-22

Studies

• Drug: Daprodustat vs ESA (Darbepoetin Alfa or Epoetin Alfa)

• Reference: Singh AK, et al, 2021 (ASCEND-D trial; NCT02879305)^4,23

• Study Design: Phase 3, randomized, open-label, multicenter, noninferiority study

• Study Funding: GlaxoSmithKline

• Patients: 2964 adults with CKD who were undergoing dialysis for at least 90 days, had received an ESA for at least 6 weeks, and had a hemoglobin level of 8 to 11 g/dL. Exclusion criteria included anemia unrelated to CKD; planned kidney transplant within 52 weeks of study start; ferritin 100 ng/mL or less; transferrin saturation 20% or less; aplasias; GI bleeding; myocardial infarction (MI), acute coronary syndrome, or stroke or transient ischemic attack within 4 weeks prior to screening; New York Heart Association (NYHA) class IV heart failure; uncontrolled hypertension; prolonged QTc interval; liver disease; malignancy (within 2 years prior to screening through to randomization); treatment with a strong CYP2C8 inhibitor or inducer; prior treatment with daprodustat; and pregnancy or breastfeeding.

• Respective baseline characteristics in the daprodustat and ESA groups were as follows: Median patient age was 58 and 59 years; 42.8% and 42.7% were female; 66.9% and 66.5% were White, 15.3% and 15.8% were Black, and 11.8% and 12.3% were Asian; median body mass index (BMI) was 26.8 and 26.8 kg/m²; ESA hyporesponsiveness was 12.3% and 12.2%; percent receiving hemodialysis was 88.5% and 88.6%, and percent receiving peritoneal dialysis was 11.5% and 11.4%; and the duration of dialysis was 0 to less than 2 years in 30.5% and 30.5%, respectively, 2 to less than 5 years in 36% and 35.8%, and 5 or more years in 33.6% and 33.6%. Mean baseline hemoglobin was 10.35 g/dL in the daprodustat group and 10.39 g/dL in the ESA group. About 29% of patients were from the United States.

• Intervention: After a 4-week placebo run-in period, eligible patients (N = 2964) were randomized (1:1 using balanced blocks) to oral daprodustat or an injectable ESA (intravenous [IV] epoetin alfa among patients receiving hemodialysis and subcutaneous darbepoetin alfa among patients receiving peritoneal dialysis). Randomization was stratified according to type of dialysis, geographic region, and enrollment in the ambulatory blood pressure monitoring substudy. The initial daprodustat dosage was 4 to 12 mg once daily, based on previous ESA dose. The maintenance daprodustat dosage could range from 1 to 24 mg daily. The initial ESA dosage was based on previous ESA dosage and hemoglobin level. Dosages of both study drugs were adjusted using a preset modification schedule to achieve and maintain hemoglobin in the target range of 10 to 11 g/dL. If rescue therapy was necessary, the patient could receive IV iron or a red blood cell transfusion.

• Results:

• Primary End Point(s):

• ● Mean change in hemoglobin level from baseline to the primary evaluation period (weeks 28 through 52) was 0.28 g/dL in the daprodustat group and 0.1 g/dL in the ESA group; mean adjusted difference was 0.18 g/dL (95% CI, 0.12-0.24; P < .001), meeting the prespecified noninferiority margin; the prespecified subgroup analysis showed comparable results.

• ● Occurrence of adjudicated MACE (composite of death from any cause, nonfatal MI, or nonfatal stroke) was 25.2% in the daprodustat group and 26.7% in the ESA group; hazard ratio (HR) was 0.93 (95% CI, 0.81-1.07; P < .001), which was less than the prespecified noninferiority margin.

• Secondary End Point(s):

• ● Incidence of MACE (on treatment analysis) was 25.2% in the daprodustat group and 26.7% in the ESA group.

• ● Superiority testing results for the first occurrence of various secondary cardiovascular outcomes were not significant: MACE (HR, 0.93; 95% CI, 0.81-1.07), MACE or a thromboembolic event (HR, 0.88; 95% CI, 0.78-1), and MACE or hospitalization for heart failure (HR, 0.97; 95% CI, 0.85-1.11).

• ● Adjusted mean monthly IV iron dose from baseline to week 52 was 90.8 mg in the daprodustat group and 99.9 mg in the ESA group; mean difference was −9.1 mg (95% CI, −18.4 to 0.2).

• ● Incidence of all-cause mortality (primary safety analysis) was 16.4% in the daprodustat group and 15.8% in the ESA group.

• Comments: The study was conducted at 431 centers in 35 countries and used an open-label design; the investigator and patients were aware of the treatment assignment, but the sponsor and steering committee were unaware of treatment assignments. The primary end points were evaluated for noninferiority, while the key secondary end points were evaluated for superiority. The original noninferiority margin for MACE was 1.2, but was changed because of COVID-19 to 1.25 to accelerate closeout of the study. The noninferiority margin for change in hemoglobin level from baseline to the primary evaluation period was left unchanged at −0.75 g/dL. These end points were evaluated using the intention-to-treat (ITT) population and in parallel using a 1-sided alpha of 0.025. The primary end point regarding change in hemoglobin from baseline to the evaluation period was assessed using an analysis of covariance model after adjustment for baseline hemoglobin level and variables used in the MACE model; missing hemoglobin values were imputed using multiple imputation under a “missing at random” assumption. The secondary end points were only assessed if noninferiority was established for both primary end points (hierarchical testing). The secondary MACE analysis used an on-treatment analysis restricted to events that had occurred between the initiation of study drug and 28 days after the last dose, the date of study completion, or withdrawal, whichever occurred first.

• Rescue therapy was required by 3.6% in both groups; the percentage that required at least one red blood cell or whole blood transfusion during the treatment period was 15.7% in the daprodustat group and 18.3% in the ESA group (HR, 0.86; 95% CI, 0.72-1.02). Median duration of follow-up for evaluation of cardiovascular events was 2.5 years and provided 7,028 total person-years of follow-up.

• Limitations: The open-label design and difference in dosing frequency may have influenced adverse event reporting. Because HIF activates the transcription of many cytokines, some of which have oncogenic or other potential long-term adverse effects, the observation time for this trial (although extended) may be insufficient to characterize the full risks. Epoetin alfa was used as the comparator for patients undergoing hemodialysis in this trial, which may limit the generalizability of the authors’ conclusions about the noninferiority of daprodustat to other ESAs.

• Drug: Daprodustat vs Darbepoetin Alfa

• Reference: Singh AK, et al, 2022 (ASCEND-ID trial; NCT03029208)^24,25

• Study Design: Phase 3, randomized, open-label, multicenter, noninferiority study

• Study Funding: GlaxoSmithKline

• Patients: 312 adults (18-99 years of age) with advanced CKD with planned (within 6 weeks of screening) or recent (within 90 days of randomization) initiation of hemodialysis or peritoneal dialysis. Patients had a screening hemoglobin concentration of 8 to 10.5 g/dL, a randomization hemoglobin concentration of 8 to 11 g/dL, and were iron-replete (serum ferritin levels greater than 100 ng/mL and transferrin saturation greater than 20%). Exclusion criteria included use of any ESA treatment within 8 weeks before screening (except for limited use as part of dialysis initiation); planned kidney transplantation; vitamin B₁₂ level below the lower limit at screening or after vitamin B₁₂ supplementation; folate less than 2 ng/mL; history of bone marrow aplasia or pure red cell aplasia; untreated anemias; evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease, or clinically significant GI bleeding (within 10 weeks prior to screening through randomization); acute cardiovascular events (eg, MI, stroke or transient ischemic attack) within 10 weeks of screening to randomization; NYHA class IV heart failure; uncontrolled hypertension; prolonged QTc interval; liver disease; history of malignancy (within 2 years prior to screening through to randomization); severe allergic or anaphylactic reactions to study drugs or their excipients; required treatment with a strong CYP2C8 inhibitor inducer; and pregnancy or breastfeeding, or of reproductive potential and refusal to follow one of the contraceptive options.

• In the daprodustat ITT cohort, median patient age was 52 years; 61% were male; and 70% were White, 17% were Asian, and 10% were Black or African American. In the darbepoetin alfa ITT cohort, median patient age was 56 years; 63% were male; and 69% were White, 20% were Asian, and 8% were Black or African American. The majority of patients were undergoing hemolysis (80% and 81%, respectively), with dialysis planned in 69% in both groups; baseline mean hemoglobin was 9.5 g/dL in both groups; median transferrin saturation was 28% and 30%, respectively; ferritin was 365 and 373 ng/mL, respectively; oral iron was used by 16% and 14% and IV iron was used by 67% and 70%, respectively (median standardized IV iron dose at baseline was 87 and 130 mg/month, respectively).

• Intervention: After 2 weeks of screening, patients were randomly assigned (1:1) to treatment with daprodustat (n = 157) or darbepoetin alfa (n = 155) for 52 weeks. Patients were stratified by type of dialysis and by planned versus unplanned or urgent dialysis start. The first half of the treatment period (day 1 to week 28) was the stabilization period, which was followed by the evaluation period (weeks 28-52) and then a follow-up period (weeks 56-58). Randomized patients were evaluated every 2 weeks up to week 8 and then every 4 weeks up to week 52. All patients completed a posttreatment follow-up visit between weeks 56 and 58. The starting dose of oral daprodustat was based on baseline hemoglobin level: 4 mg/day if hemoglobin was 8 to less than 9 g/mL, 2 mg/day if hemoglobin was 9 to 10 g/dL, and 1 mg/day if hemoglobin was greater than 10 g/dL. The dose of darbepoetin alfa was 40 or 60 µg every 2 or 4 weeks (based on weight); drug was given by subcutaneous injection for peritoneal dialysis patients and IV for hemodialysis patients. Dosages were then adjusted to achieve a hemoglobin concentration of 10 to 11 g/mL. The median daily dose of daprodustat was 2 mg, and the typical darbepoetin alfa dose was 60 µg every 4 weeks. Supplemental iron therapy was used if ferritin level was 100 ng/mL or less or transferrin saturation was 20% or less. Rescue treatment with IV iron and/or transfusion of packed red blood cells was allowed if hemoglobin criteria were not achieved.

• Results:

• Primary End Point(s):

• ● Mean hemoglobin concentration during the evaluation period was 10.5 g/dL in the daprodustat arm and 10.6 g/dL in the darbepoetin alfa arm. Mean hemoglobin concentration for both arms remained in the analysis range of 10 to 11.5 g/dL. Adjusted mean change from baseline in hemoglobin level was 1.02 and 1.12 g/dL, respectively; treatment difference was −0.1 g/dL (95% CI, −0.34 to 0.14), which met noninferiority criteria.

• ● Secondary End Point(s):

• ● Reduction in mean monthly IV iron dose from baseline to week 52 was similar for the 2 treatment groups (adjusted mean treatment difference was 19.4 mg/month [95% CI, −11 to 49.9]); mean monthly IV iron use was 142 mg in the daprodustat group and 137 mg in the darbepoetin alfa group.

• ● Adjudicated MACE-type adverse reactions: MACE occurred in 12% of the daprodustat group and 10% of the darbepoetin alfa group; all-cause mortality occurred in 9% and 6%, respectively. The incidence rate per 100 patient-years was 11.65 and 9.24; absolute rate difference per 100 patient-years was 2.41 (−4.61 to 9.43).

• Comments: This study was conducted at 90 centers in 14 countries. The first 90 days after initiating dialysis is a period of high risk, with mortality being twice as high as mortality in the subsequent 9-month period. Therefore, the incident dialysis period has been arbitrarily defined as the period within 90 to 120 days of starting dialysis. During this time, the patient’s body is undergoing abrupt physiological (eg, metabolic flux from clearances of uremic mediators; correction of anemia; changes in parameters of metabolic bone disease, blood pressure, and extracellular volume) and psychological changes. This study focused on the efficacy and safety of daprodustat and darbepoetin alfa in patients with CKD that were starting dialysis. Premature discontinuation of treatment occurred in 29% of patients receiving daprodustat and 25% receiving darbepoetin alfa.

• Subgroup analysis (based on hemodialysis and peritoneal dialysis and planned and unplanned dialysis start) for the primary hemoglobin outcome showed similar results. Noninferiority of daprodustat compared with darbepoetin alfa was declared if the lower bound of the 2-sided 95% CI of the difference in hemoglobin concentration between treatments exceeded −0.75 g/dL.

• The efficacy analysis was evaluated in the ITT cohort, with missing hemoglobin values being imputed using multiple imputation under a “missing at random” assumption. Rescue therapy was only required by 3% of patients in both groups.

• Limitations: The study was relatively short and included a small sample size, limiting evaluation of safety outcomes. The open-label study design could be criticized for biased adverse reaction reporting.

• Drug: Daprodustat vs Epoetin Alfa

• Reference: Coyne DW, et al, 2021 (ASCEND-TD trial; NCT03400033)^26,27

• Study Design: Phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority study

• Study Funding: GlaxoSmithKline

• Patients: 407 adults (18-99 years of age) with CKD requiring hemodialysis. Patients had baseline hemoglobin of 8 to 11.5 g/dL and were already receiving epoetin alfa or analog for at least 8 weeks. Exclusion criteria included planned kidney transplantation within 52 weeks after randomization, ferritin level less than 100 ng/mL, transferrin saturation less than 20%, aplasias, other conditions other than anemia of CKD that can affect erythropoiesis, acute cardiovascular events (MI, acute coronary syndrome, stroke or transient ischemic attack) within 8 weeks, chronic NYHA class IV heart failure, uncontrolled hypertension, prolonged QTc interval, liver disease, active GI bleeding within 8 weeks, history of malignancy (within 2 years prior to screening through randomization), required treatment with a strong CYP2C8 inhibitor or inducer, history of severe allergic or anaphylactic reaction to drugs or excipients, and prior use of daprodustat. The percentage of patients 19 to 64 years of age was 64.6%, and the other 35.4% were 65 years and older; 56.5% were male; and 69.5% were White and 19.9% were Black or African American.

• Intervention: In-center prevalent hemodialysis patients were randomized (2:1) to receive daprodustat administered 3 times weekly (n = 270) or epoetin alfa (n = 137). All patients received an oral tablet (daprodustat or placebo) 3 times weekly and an IV infusion (epoetin alfa or placebo) once weekly or 3 times weekly (depending on dose level) for 52 weeks. Doses of both drugs were adjusted using a dosing algorithm to maintain hemoglobin between 10 and 11 g/dL. The daprodustat dosage ranged from 2 to 48 mg orally 3 times weekly. Total weekly epoetin alfa dosage ranged from 1500 to 60 000 units.

• Results:

• Primary End Point(s):

• ● Treatment difference in mean change in hemoglobin during the evaluation period (weeks 28-52) was −0.05 g/dL (95% CI, −0.21 to 0.1), which met criteria for noninferiority. Mean hemoglobin level during the evaluation period was 10.45 g/dL in the daprodustat group and 10.41 g/dL in the epoetin alfa group.

• Secondary End Point(s):

• ● Average monthly IV iron requirements were not statistically significantly different between the 2 groups: 98.11 mg in the daprodustat group and 106.23 mg in the epoetin alfa group; treatment difference was −8.12 mg (95% CI, −45.66 to 29.41).

• ● Proportion of responders (in hemoglobin analysis range 10-11.5 g/dL) over evaluation period: 80% of the daprodustat group were classified as responders compared with 63.6% of the epoetin alfa group; treatment difference was 16.5% (1-sided nominal P < .001 after adjustment for region).

• ● Fewer blood pressure elevations occurred in the daprodustat group than in the epoetin alfa group (1-sided nominal P = .009), and the overall effect on blood pressure was similar with both drugs.

• Comments: The study was conducted in Argentina, Australia, Brazil, Canada, France, Italy, the Republic of Korea, Poland, Romania, the Russian Federation, Spain, the United Kingdom, and the United States. Noninferiority for the change in hemoglobin during the evaluation period end point was established if the lower limit of the 2-sided 95% CI for treatment difference was greater than the prespecified noninferiority margin (−0.75 g/dL).

• The manufacturer is required to conduct 2 observational studies comparing daprodustat and an ESA comparator arm. A prospective observational study (at least 5-year follow-up) in the United States is being conducted to characterize the long-term safety (eg, MACE, hospitalization for heart failure, serious GI bleeds, eye disorders, hepatic injury) of daprodustat in adults with dialysis-dependent CKD treated with the approved dosing regimen; an interim report is due in July 2028 and the study must be completed by July 2031, with the final report submitted by July 2032. An observational study (at least 5-year follow-up) is being conducted to assess the risk of malignancy in adults with dialysis-dependent CKD; the study must be completed by October 2031, with the final report submitted by October 2032. ²⁸

• Limitations: Study results and details are only available via a meeting abstract and on ClinicalTrials.gov.

Indication: Anemia in Patients With Chronic Kidney Disease Not Undergoing Dialysis (Non–FDA-Approved Use)

These studies confirm results in phase 2 studies.^7,29

A separate phase 3 study conducted in Japanese patients not on dialysis showed comparable results regarding daprodustat efficacy and safety compared with epoetin beta pegol. ³⁰

Network meta-analyses of the efficacy and safety of HIF-PH inhibitors, epoetin, and darbepoetin for anemia of CKD in patients not undergoing dialysis determined there was no difference between the various drugs regarding elevation of hemoglobin levels; compared with placebo, there was no significant association between the various drugs and all-cause mortality.^11,12,31

Studies

• Drug: Daprodustat vs Darbepoetin Alfa

• Reference: Singh AK, et al, 2021 (ASCEND-ND trial; NCT02876835)^3,32,33

• Study Design: Phase 3, randomized, open-label, multicenter, noninferiority study

• Study Funding: GlaxoSmithKline

• Patients: 3872 adults (18-99 years of age) with stage 3 to 5 CKD who were neither receiving dialysis nor scheduled to start dialysis within 90 days. Patients were required to have hemoglobulin of 8 to 10 g/dL (if not receiving an ESA) or 8 to 12 g/dL (if receiving an ESA), serum ferritin level greater than 100 ng/mL, and transferrin saturation above 20%. Exclusion criteria included anemia unrelated to CKD; dialysis; planned kidney transplant within 52 weeks after study start; ferritin 100 ng/mL or less; transferrin saturation 20% or less; aplasias; GI bleeding; MI, acute coronary syndrome, or stroke or transient ischemic attack within 4 weeks of screening; NYHA class IV heart failure; uncontrolled hypertension; prolonged QTc interval; liver disease; malignancy (within 2 years prior to screening through to randomization); treatment with a strong CYP2C8 inhibitor or inducer; prior treatment with daprodustat; and pregnancy or breastfeeding.

• Median patient age was 67 years in both the daprodustat and darbepoetin alfa groups; 56.9% and 55.3%, respectively, were female; 56.7% and 54.5% were White, 27.1% and 27.8% were Asian, and 9.4% and 9.6% were Black; median BMI was 26.9 and 26.6 kg/m²; proportion not using an ESA was 53.2% and 53.3%; and 82.2% and 80.8% had stage 4 or 5 CKD. Mean baseline hemoglobulin was 9.9 g/dL in the daprodustat group and 9.8 g/dL in the darbepoetin alfa group. About 25% of patients were from the United States.

• Intervention: After a placebo run-in period, eligible patients (N = 3872) were randomized (1:1 using balanced blocks) to treatment with oral daprodustat or subcutaneous darbepoetin alfa. Randomization was stratified according to use of ESA, geographic region, and enrollment in the ambulatory blood pressure monitoring substudy. The initial dosage of daprodustat was 1 to 4 mg orally once daily, based on baseline hemoglobulin level if the patient was not receiving an ESA or based on ESA dose if the patient was receiving an ESA; stepped changes ranging from 1 to 24 mg daily were available for dosage adjustments. The initial dose of darbepoetin alfa was based on patient body weight and hemoglobin level at baseline for those not receiving an ESA or based on previous ESA dose if the patient was receiving an ESA; stepped changes in dose were predefined, with most steps increasing the dose by 25% to 33%. Doses of both study drugs were adjusted using a preset modification schedule to achieve and maintain hemoglobin in the target range of 10 to 11 g/dL. If rescue therapy was necessary, the patient could receive IV iron, a red blood cell transfusion, or both.

• Results:

• Primary End Point(s):

• ● Mean change in hemoglobin level from baseline to the primary evaluation period (weeks 28 through 52) was 0.74 g/dL in the daprodustat group and 0.66 g/dL in the darbepoetin alfa group; mean adjusted difference was 0.08 g/dL (95% CI, 0.03-0.13; P < .001), which met the prespecified noninferiority margin; the prespecified subgroup analysis showed comparable results.

• ● Proportion of patients with occurrence of MACE (composite of death from any cause, nonfatal MI, or nonfatal stroke) was 19.5% in the daprodustat group and 19.2% in the darbepoetin alfa group; HR was 1.03 (95% CI, 0.89-1.19; P = .005), which was less than the prespecified noninferiority margin.

• Secondary End Point(s):

• ● Incidence of MACE (on treatment analysis, which censored data on patients at 28 days after the date of the last dose) was 14.1% in the daprodustat group and 10.5% in the darbepoetin alfa group; HR was 1.4 (95% CI, 1.17-1.68). This analysis did not consider the different dosing intervals between the 2 treatment groups or the impact of the observation periods. Therefore, post hoc analyses were conducted to explore the effect of the different dosing frequencies; results were more consistent with the results of the primary analysis.

• ● Superiority testing results for the first occurrence of various secondary cardiovascular outcomes were not significant: MACE (HR, 1.03; 95% CI, 0.89-1.19), MACE or a thromboembolic event (HR, 1.06; 95% CI, 0.93-1.22), MACE or hospitalization for heart failure (HR, 1.09; 95% CI, 0.95-1.24), and CKD progression (HR, 0.98; 95% CI, 0.84-1.13).

• ● Incidence of all-cause mortality was similar between treatment groups; HR was 1.03 (95% CI, 0.87-1.2).

• Comments: The study was conducted at 506 centers in 39 countries. The study used an open-label design; the investigator and patients were aware of the treatment assignment, but the sponsor and steering committee were unaware of treatment assignments. The primary end points were evaluated for noninferiority, while the key secondary end points were evaluated for superiority. The original noninferiority margin for MACE was 1.2, but was changed because of COVID-19 to 1.25 to accelerate closeout of the trial. The noninferiority margin for the change in hemoglobin level from baseline to the primary evaluation period was left unchanged at −0.75 g/dL. These end points were evaluated using the ITT population and in parallel using a 1-sided alpha of 0.025. The primary end point regarding change in hemoglobin from baseline to the evaluation period was assessed using an analysis of covariance model after adjustment for baseline hemoglobin level and variables used in the MACE model; missing hemoglobin values were imputed using multiple imputation under the “missing at random” assumption. The secondary end points were only assessed if noninferiority was established for both primary end points (hierarchical testing). The secondary MACE analysis used an on-treatment analysis restricted to events that had occurred between initiation of the study drug and 28 days after the last dose, the date of study completion, or withdrawal, whichever occurred first.

• Adherence to the assigned therapy was 97% in the daprodustat group and 98% in the darbepoetin alfa group. Rescue therapy was required by 2% of the daprodustat group and 3.3% of the darbepoetin alfa group; the percentage that required at least 1 red blood cell or whole blood transfusion during the treatment period was 12.8% in the daprodustat group and 13.5% in the darbepoetin alfa group (HR, 0.96; 95% CI, 0.81-1.14). Discontinuation of treatment for reasons other than death occurred in 29.5% of the daprodustat group and 28.9% of the darbepoetin alfa group. Median duration of follow-up for evaluation of cardiovascular events was 1.9 years, which provided 7,210 total person-years of follow-up.

• Limitations: The open-label design and difference in dosing frequency may have influenced adverse event reporting. Because HIF activates transcription of many cytokines, which may have oncogenic or other potential long-term adverse effects, the observation time for this trial (although extended) may still be insufficient to characterize the full risks. Darbepoetin alfa was used as the ESA comparator, which might limit conclusions about noninferiority to other ESAs.

• Drug: Daprodustat vs Placebo

• Reference: Johansen KL, et al, 2021 (ASCEND-NHQ trial; NCT03409107)^34,35

• Study Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter study

• Study Funding: GlaxoSmithKline

• Patients: 614 non–dialysis-dependent adults (18 years of age and older) with anemia of CKD (stage 3-5) without recent ESA therapy. Patients were required to have hemoglobin of 8.5 to 10.5 g/dL at the screening visit and 8.5 to 10 g/dL at randomization, transferrin saturation of 15% or higher, and ferritin of 50 ng/mL or higher. IV iron could have been administered within the 8 weeks prior to screening only; no IV iron could be received between screening and randomization. If the patient was receiving oral iron, change in overall dose had to be less than 50% with no change in type of iron prescribed in the 4 weeks prior to randomization. Exclusion criteria included dialysis or impending need for dialysis within 180 days after randomization, planned kidney transplantation within 28 weeks after randomization, transferrin saturation less than 15% at screening, ferritin less than 50 ng/mL at screening, history of ESA use within 8 weeks prior to screening or randomization, history of transfusion within 8 weeks prior to screening or between screening and randomization, bone marrow aplasia, pure red cell aplasia, other types of anemia, active GI bleeding or clinically significant GI bleed within 8 weeks prior to screening through to randomization, history of severe allergic or anaphylactic reaction to drug or excipients, required treatment with a strong CYP2C8 inhibitor or inducer, ferric citrate use within 4 weeks of randomization, prior exposure to daprodustat, acute cardiovascular events within 8 weeks, NYHA class IV heart failure, QT interval prolongation, liver disease, history of malignancy (within 2 years prior to screening through randomization), and uncontrolled hypertension.

• Mean patient age was 65.9 years; 57.7% were female; and 63.8% were White, 14.8% were Black or African American, and 11.1% were American Indian or Alaska Native.

• Intervention: Patients were randomly assigned (1:1) to treatment with oral daprodustat or placebo tablets for 28 weeks. All patients received iron therapy if ferritin level was less than 50 ng/mL and/or transferrin saturation was less than 15%. Dosage was adjusted to maintain a hemoglobin of 11 to 12 g/dL.

• Results:

• Primary End Point(s):

• ● Mean change in hemoglobin between baseline and the evaluation period (mean value over week 24-28) was 1.58 g/dL with daprodustat and 0.19 g/dL with placebo; adjusted mean difference in hemoglobin was 1.4 g/dL (95% CI, 1.23-1.56; P < .001).

• Secondary End Point(s):

• ● Proportion of patients with a 1 g/dL or more increase in hemoglobin was 77% with daprodustat and 18% with placebo (P < .001); estimated difference in response rate was 0.56 (95% CI, 0.49-0.63).

• ● Mean change in SF-36 vitality (fatigue) score from baseline to week 28 was 7.3 points with daprodustat and 1.9 points with placebo (P < .001); mean difference was 5.36 (95% CI, 2.17-8.56).

• ● Percentage of patients with hemoglobin response (achievement of hemoglobin of 11-12 g/dL) during the evaluation period (weeks 24-28) was 52% with daprodustat and 8% with placebo; estimated value for difference in response rate was 0.45 (95% CI, 0.37-0.52).

• ● Proportion of patients who were SF-36 vitality responders (6-point or more increase) was 58% with daprodustat and 40% with placebo; treatment difference was 13% (95% CI, 4% to 22%).

• ● Blood pressure elevations occurred more often with daprodustat (32%) than placebo (26%) (P = .07); however, the overall effect of daprodustat therapy on blood pressure was similar to placebo.

• Comments: The study was conducted in Argentina, Australia, Brazil, Canada, France, Italy, the Republic of Korea, Mexico, Poland, Romania, the Russian Federation, Spain, the United Kingdom, and the United States.

• Limitations: Study results and details are available only via a meeting abstract and on ClinicalTrials.gov.

Contraindications, Warnings, and Precautions

Contraindications

Daprodustat is contraindicated in patients requiring treatment with strong CYP2C8 inhibitors (eg, gemfibrozil). ¹

Daprodustat is contraindicated in patients with uncontrolled hypertension. ¹

Though not stated in the daprodustat product labeling, a potential contraindication to use is hypersensitivity reactions to daprodustat or to any of the product ingredients (ie, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, titanium dioxide). ¹

Warnings and Precautions

Daprodustat labeling includes a boxed warning regarding the risk of death, MI, stroke, venous thromboembolism, and thrombosis of vascular access during treatment with daprodustat. The risk of potentially fatal thrombotic vascular events, including MACE, is increased during treatment with daprodustat. Daprodustat use should be avoided in patients with a history of MI, cerebrovascular events, or acute coronary syndrome within the past 3 months. ¹

A rise in hemoglobin greater than 1 g/dL over 2 weeks may contribute to these risks. Also, a target hemoglobin level greater than 11 g/dL may increase the risk of death and arterial venous thrombotic events, a risk that is also associated with the use of ESAs. It is unknown if adjustments to the hemoglobin target level, dose, or dosing strategy can decrease these risks. Therefore, the lowest dose of daprodustat sufficient to reduce the need for red blood cell transfusions should be prescribed, and adherence to dosing and hemoglobin monitoring is recommended to avoid excessive erythropoiesis. ¹

Risk of hospitalization for heart failure may be higher with daprodustat therapy. In the ASCEND-D trial, hospitalization for heart failure occurred in 7.5% (3.3 per 100 person-years) of patients on dialysis receiving daprodustat and 6.8% (3 per 100 person-years) of patients receiving recombinant human erythropoietin (rhEPO). Patients with preexisting heart failure were at increased risk of hospitalization for heart failure with daprodustat (14.5%; 6.8 per 100 person-years) compared with rhEPO (11.3%; 5.1 per 100 person-years). ¹

Uncontrolled hypertension is a contraindication to daprodustat therapy. In the ASCEND-D trial, worsening of hypertension occurred in 24% (12 per 100 person-years) of patients receiving daprodustat and 24% (12 per 100 person-years) of patients receiving rhEPO. Serious worsening of hypertension occurred in 3.1% of patients receiving daprodustat and 3.1% of patients receiving rhEPO. Cases of hypertensive crisis, including hypertensive encephalopathy and seizures, have also been reported. Periodically monitor blood pressure and adjust or initiate antihypertensive therapy as needed. ¹

GI erosion may occur during daprodustat therapy. In the ASCEND-D trial, gastric or esophageal erosions occurred in 5.7% (2.5 per 100 person-years) of patients receiving daprodustat and 6.6% (2.9 per 100 person-years) of rhEPO-treated patients. Serious erosions, including GI bleeding and the need for red blood cell transfusions, were reported in 3.6% and 3.1% of patients receiving daprodustat and rhEPO, respectively. Consider this risk particularly in patients at increased risk for GI erosions, such as those with a history of GI erosion, peptic ulcer disease, use of concomitant medications that increase the risk of GI erosion, and current tobacco and alcohol use. ¹

The safety of daprodustat has not been sufficiently established for the treatment of anemia due to CKD in adults not on dialysis, and this use is not FDA approved. In ASCEND-ND, an increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious GI erosions was observed in patients treated with daprodustat compared with rhEPO. ¹

The safety of daprodustat in patients with malignancy has not been established. Based on its mechanism of action (increased HIF-1 levels), daprodustat may have an unfavorable effect on cancer growth and therefore should be avoided in patients with active malignancies. Malignancies were observed in 4.4% (1.9 per 100 person-years) of patients treated with daprodustat and 5.2% (2.3 per 100 person-years) of patients treated with rhEPO. ¹

There are no adequate and well-controlled studies of daprodustat use during pregnancy. CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low–birth weight infants, and polyhydramnios. Daprodustat in animal studies was associated with adverse fetal outcomes. Pregnant patients should be advised of the potential risk to the fetus. ¹ A prospective and retrospective evaluation of data from patients exposed to daprodustat during pregnancy is required to assess the risk of pregnancy and maternal complications, adverse effects on the developing fetus and neonate, and adverse effects on the infant. An interim report is due by September 2027 and the study must be completed by August 2029, with the final report submitted by September 2030. ²⁸

Caution should be used when administering daprodustat during breastfeeding. No studies have been conducted to assess the presence of daprodustat in human milk or its effects on breastfeeding infants or milk production. Daprodustat is present in the milk of lactating rats and, therefore, would likely be present in human milk. Because of the potential for serious adverse reactions (eg, thrombotic vascular events), patients should be advised not to breastfeed during daprodustat therapy and for 1 week after the final dose. ¹

Safety and effectiveness of daprodustat have not been established in pediatric patients. ¹ A study is required to evaluate the pharmacokinetics, pharmacodynamics, and safety of daprodustat for the treatment of anemia associated with CKD in children and adolescents aged 3 months to younger than 18 years requiring dialysis. The study must be completed by August 2029, with the final report submitted by February 2030. ²⁸

No overall differences in safety and efficacy were observed in patients 65 years and older and younger adults treated with daprodustat. ¹

Adverse Reactions

The most common adverse reactions associated with daprodustat (incidence at least 10%) are hypertension, thrombotic vascular events, and abdominal pain. ¹

See Table 1 for adverse reactions reported in patients with anemia undergoing dialysis (ASCEND-D study). ⁴ See Table 2 for adverse reactions reported in patients with anemia not undergoing dialysis (ASCEND-ND study). ³ See Table 3 for a summary of key adverse effects highlighted in the prescribing information. ¹

Table 1.

Common Adverse Reactions and Adverse Reactions of Special Interest ^a (According to Investigators) With Daprodustat in the ASCEND-D Study. ⁴

Adverse reaction	Daprodustat (n = 1482)	ESA (n = 1474)	Relative risk	P value
Anemia	5%	7%
Arteriovenous fistula–site complication	5%	6%
Arteriovenous fistula thrombosis	6%	7%
Atrial fibrillation	4%	5%
Back pain	4%	6%
Bronchitis	6%	7%
Cancer-related death or tumor progression or recurrence	3.2%	3.5%	0.92 (95% CI, 0.62-1.35)	.66
Cardiomyopathy	1%	1.1%	0.93 (95% CI, 0.46-1.88)	.85
Cough	7%	7%
Dialysis hypotension	10%	7%
Diarrhea	11%	12%
Dyspnea	5%	6%
Esophageal or gastric erosions	4%	5.5%	0.74 (95% CI, 0.53-1.02)	.06
Exacerbation of rheumatoid arthritis	0.1%	0.1%	1.99 (95% CI, 0.18-21.91)	.57
Fall	6%	6%
Fluid overload	6%	7%
Headache	8%	9%
Hyperkalemia	6%	6%
Hypertension	16%	16%
Hypotension	8%	7%
Nasopharyngitis	8%	7%
Nausea	6%	6%
Pain in extremity	6%	5%
Pneumonia	8%	8%
Proliferative retinopathy, macular edema, or choroidal neovascularization	2.6%	2.4%	1.08 (95% CI, 0.69-1.7)	.74
Pulmonary artery hypertension	0.6%	0.8%	0.75 (95% CI, 0.32-1.77)	.5
Pyrexia	4%	5%
Thrombosis or tissue ischemia due to excessive erythropoiesis	1.3%	0.7%	1.18 (95% CI, 0.87-3.76)	.11
Upper respiratory tract infection	7%	7%
Urinary tract infection	6%	6%
Vomiting	6%	5%
Worsening of hypertension	19.8%	20.5%	0.96 (95% CI, 0.84-1.11)	.63

^aAdverse reactions of special interest are those with a relative risk value and P value.

Table 2.

Common Adverse Reactions and Adverse Reactions of Special Interest ^a (According to Investigators) With Daprodustat in the ASCEND-ND Study. ³

Adverse reaction	Daprodustat (n = 1937)	Darbepoetin alfa (n = 1933)	Relative risk	P value
Worsening of hypertension	17.8%	18.8%	0.95 (95% CI, 0.83-1.08)	.41
Hypertension	13%	14%
Urinary tract infection	10%	9%
Edema, peripheral	10%	9%
Hyperkalemia	8%	7%
Diarrhea	8%	7%
CKD	7%	6%
Constipation	7%	5%
Nasopharyngitis	6%	7%
Pneumonia	6%	6%
Fall	6%	5%
Anemia	6%	4%
Upper respiratory tract infection	5%	5%
Nausea	5%	4%
Acute kidney injury	5%	4%
Back pain	4%	6%
Cancer-related death or tumor progression or recurrence	3.7%	2.5%	1.47 (95% CI, 1.03-2.1)	.04
Esophageal or gastric erosions	3.6%	2.1%	1.7 (95% CI, 1.16-2.49)	.005
Proliferative retinopathy, macular edema, or choroidal neovascularization	2.8%	2.3%	1.22 (95% CI, 0.83-1.18)	.31
Pulmonary artery hypertension	0.8%	0.5%	1.66 (95% CI, 0.73-3.79)	.22
Thrombosis or tissue ischemia due to excessive erythropoiesis	0.3%	0.2%	1.66 (95% CI, 0.4-60.95)	.48
Cardiomyopathy	0.3%	0.4%	0.86 (95% CI, 0.29-2.54)	.78
Exacerbation of rheumatoid arthritis	0.1%	0.2%	0.5 (95% CI, 0.09-2.72)	.41

^aAdverse reactions of special interest are those with a relative risk value and P value.

Table 3.

Adverse Reactions Highlighted in the Daprodustat Prescribing Information (ASCEND-D Study). ¹

Adverse reaction	Daprodustat (n = 1482)	rhEPO (n = 1474)
Abdominal pain	11%	8%
Dizziness	7%	6%
Hypersensitivity	7%	7%
Hypertension	24%	24%
Adjudicated thrombotic vascular events (fatal and nonfatal)
Vascular access thrombosis	5 per 100 person-years	6.3 per 100 person-years
MI	3.4 per 100 person-years	4.1 per 100 person-years
Stroke	1.2 per 100 person-years	1.5 per 100 person-years
Deep vein thrombosis	0.7 per 100 person-years	0.6 per 100 person-years
Pulmonary embolism	0.3 per 100 person-years	0.4 per 100 person-years

The manufacturer is required to complete a pharmacovigilance analysis of all serious adverse events of GI erosion and hypertensive crisis. The periodic adverse drug experience report is due quarterly during the first 3 years post approval and annually thereafter, through the fifth year following the initial US approval date. The manufacturer must also submit daprodustat utilization reports, including use in non–dialysis-dependent patients and in females of reproductive potential (ie, 15-50 years of age), calculated cumulatively from the initial approval date; utilization reports must be submitted annually through the fifth year following the initial US approval date. ²⁸

Drug Interactions

Daprodustat is a CYP2C8 substrate; inhibitors (eg, clopidogrel, trimethoprim) or inducers (eg, rifampicin) of this enzyme may alter daprodustat plasma concentration.^1,2,36

Concomitant administration of moderate CYP2C8 inhibitors (eg, clopidogrel) increases daprodustat exposure. The starting daprodustat dose should be reduced by half, except in patients whose starting dose is already 1 mg, when initiating treatment in patients receiving clopidogrel or a moderate CYP2C8 inhibitor. Hemoglobin should be monitored and dose adjusted when initiating or stopping therapy with clopidogrel or a moderate CYP2C8 inhibitor during treatment with daprodustat. ¹

Concomitant use of a CYP2C8 inducer (eg, rifampin) may decrease daprodustat exposure; hemoglobin levels need to be monitored and the dose of daprodustat adjusted when initiating or stopping therapy with CYP2C8 inducers. ¹

Recommended Monitoring

Hemoglobulin levels should be obtained at baseline and periodically throughout therapy. ¹

Blood pressure should be monitored throughout therapy. ¹

Patients should be advised to report any signs or symptoms of MACE, heart failure, or gastric or esophageal erosions and GI bleeding. ¹

Dosing

Prior to starting daprodustat treatment, the cause of the anemia needs to be determined (eg, vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) and corrected, and iron status needs to be established. If serum ferritin is less than 100 µg/mL or serum transferrin saturation is less than 20%, supplemental iron therapy should be initiated; the majority of patients require supplemental iron during the course of therapy. Liver function tests should also be obtained (eg, ALT, AST, alkaline phosphatase, total bilirubin). If the patient develops signs or symptoms consistent with liver disease during daprodustat treatment, the tests should be repeated. ¹

The dose of daprodustat needs to be individualized to reduce the need for red blood cell transfusions and to maintain a hemoglobin level of less than or equal to 11 g/dL.1

The starting dose of daprodustat for adults with anemia due to CKD receiving dialysis for at least 4 months is based on hemoglobin level and previous ESA use (see Tables 4 and 5). Dose modifications are needed for patients receiving concomitant treatment with a moderate CYP2C8 inhibitor or who have moderate hepatic impairment. ¹

Table 4.

Starting Daprodustat Dose for Adults on Dialysis Not Receiving an ESA. ¹

Pretreatment hemoglobin level	Starting dose of daprodustat (once-daily dosing)
<9 g/dL	4 mg
9 to ≤10 g/dL	2 mg
>10 g/dL	1 mg

Table 5.

Starting Daprodustat Dose for Adults on Dialysis Switching From an ESA. ¹

Current dose of ESA			Daprodustat dose
Epoetin alfa IV	Darbepoetin alfa subcutaneous/IV	Methoxy PEG-epoetin beta subcutaneous/IV	Once-daily oral dose
≤2000 units/week	20-30 µg per 4 weeks	30-40 µg/month	4 mg
>2000 to <10 000 units/week	>30-150 µg per 4 weeks	>40-180 µg/month	6 mg
10 000 to <20 000 units/week	>150-300 µg per 4 weeks	>180-360 µg/month	8 mg
≥20 000 units/week	>300 µg per 4 weeks	>360 µg/month	12 mg

Hemoglobin levels should be obtained every 2 weeks after initiation of treatment and after each dose adjustment for the first month and then every 4 weeks thereafter. Dosage adjustments should be based on the hemoglobin rate of rise, rate of decline, and hemoglobin variability, but increases in dose should be no more frequent than once every 4 weeks. If a dose adjustment is necessary, the dose should be increased or decreased by one dose level at a time (1, 2, 4, 6, 8, 12, 16, and 24 mg). The maximum recommended daily dose of daprodustat is 24 mg. The dose of daprodustat should be decreased if hemoglobin increases rapidly (eg, greater than 1 g/dL over 2 weeks or greater than 2 g/dL over 4 weeks) or if hemoglobin exceeds 11 g/dL. If hemoglobin exceeds 12 g/dL, interrupt treatment with daprodustat. Treatment can be restarted at one dose level lower when hemoglobin returns to within the target range. If no clinically meaningful increase in hemoglobin level is achieved within 24 weeks, treatment with daprodustat should not be continued; instead, alternative explanations for an inadequate response should be sought and treated before restarting daprodustat treatment. ¹

Patients with moderate hepatic impairment (Child-Pugh class B) should receive a lower daily dose of daprodustat; the starting dose should be reduced by 50% except in patients whose starting dose is already 1 mg. Daprodustat therapy is not recommended in patients with severe hepatic impairment (Child-Pugh class C). ¹

Concomitant treatment with moderate CYP2C8 inhibitors or clopidogrel requires a 50% reduction in the starting dose of daprodustat, except for patients whose starting dose is already 1 mg. If the CYP2C8 inhibitor or clopidogrel therapy is discontinued, the hemoglobin level should be monitored and the dose of daprodustat adjusted accordingly. ¹

Daprodustat tablets should be swallowed whole once daily; do not cut, crush, or chew. ¹

Daprodustat can be administered without regard to timing or type of dialysis. ¹

If a dose is missed, it should be taken as soon as possible, unless it is the same day as the next dose. In this case, the missed dose should be skipped, and the next dose should be taken at the usual time; do not double a dose to make up for a missed dose. ¹

Product Availability and Storage

The NDA for daprodustat (for treatment of anemia associated with CKD in adults receiving dialysis) was accepted by the FDA in April 2022, with a Prescription Drug User Fee Act date of February 1, 2023. ³⁷ Daprodustat was approved by the FDA on February 1, 2023. ²⁸

Daprodustat is available as 1, 2, 4, 6, and 8 mg tablets in bottles of 30. ¹

The tablets should be stored at 20°C to 25°C (68°F-77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). ¹

Drug Safety/REMS

No REMS is required for daprodustat. ¹

Conclusion

Daprodustat is a HIF-PH inhibitor FDA approved for the treatment of anemia associated with CKD in adults receiving dialysis for at least 4 months. Its mechanism of action is different from the ESAs, which may make it a useful alternative in patients unable to tolerate ESAs or with an inadequate response to an ESA plus adequate iron supplementation. Based on results from phase 3 clinical trials, daprodustat is capable of improving and maintaining hemoglobin concentrations and other hematopoietic indicators in both non–dialysis-dependent and dialysis-dependent patients; however, FDA approval is only for use in the treatment of anemia due to CKD in adults receiving dialysis.