Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis

Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on... Clinical Kidney Journal, 2018, 1–10 doi: 10.1093/ckj/sfy014 Original Article OR I G I N AL A R T I C L E Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis 1 2,3 1,8 2 Amy M. Meadowcroft , Borut Cizman , Louis Holdstock , Nandita Biswas , 4 5 6 2 Brendan M. Johnson , Delyth Jones , A. Kaldun Nossuli , John J. Lepore , 7 2 Michael Aarup and Alexander R. Cobitz Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, NC, USA, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 4 5 Philadelphia, PA, USA, Clinical Pharmacology, Roivant Sciences, Durham, NC, USA, Clinical Statistics, 6 7 GlaxoSmithKline, Stevenage, UK, Nossuli Research, Greenbelt, MD, USA, Department of Nephrology, Odense University Hospital, Odense, Denmark and Present address: United Therapeutics, Research Triangle Park, NC, USA Correspondence and offprint requests to: Borut Cizman; E-mail: borut.x.cizman@gsk.com ABSTRACT Background: This study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease. Methods: Participants (n¼ 216) with baseline hemoglobin levels of 9–11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10–11.5 g/dL. The primary outcome was characterization of the dose–response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks. Results: Over the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from 0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and 0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were 14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population. Received: 20.7.2017. Editorial decision: 9.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| A.M. Meadowcroft et al. Conclusions: Daprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks. Keywords: anemia, chronic kidney disease, daprodustat, hemodialysis, recombinant human erythropoietin stable rhEPO doses for 8 weeks before randomization and had INTRODUCTION stable hemoglobin levels between 9 and 11.5 g/dL based on the Anemia is a common complication in patients with chronic kid- average of three values obtained during the screening phase. ney disease (CKD) who receive maintenance hemodialysis (HD) Maintenance oral or IV iron supplementation was allowed, but [1, 2]. The standard of care for treating this anemia uses participants were excluded if ferritin was <100 ng/mL and/or recombinant human erythropoietin (rhEPO) and its analogs, transferrin saturation (TSAT) was <12% or>57%. The complete supplemented with intravenous (IV) iron administration [3]. inclusion, exclusion and study medication stopping criteria and Well-controlled clinical outcomes trials have demonstrated that prohibited drugs can be found in the Supplementary data, Item rhEPO and its analogs increase the risk of cardiovascular events, S1, and the iron protocol is shown in Supplementary data, Table stroke and death when targeting higher hemoglobin levels S1 in Item S2. (>13 g/dL) [4–7]. These findings led the US Food and Drug Administration to modify safety language in labeling for rhEPO and its analogs in 2007 and 2011 to limit their initiation in HD Study design patients until the hemoglobin level is<10 g/dL and to reduce or This global study (ClinicalTrials.gov identifier NCT01977482; interrupt treatment if the hemoglobin level approaches or EudraCT number 2013-002682-19) was conducted from 15 exceeds 11 g/dL [8, 9]. November 2013 to 18 March 2015 at 107 sites in 16 countries (67 Given the safety concerns with rhEPO and its analogs, sites in 15 countries randomized participants), performed in hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors adherence with the Declaration of Helsinki and approved by rel- (PHIs) including daprodustat (previously GSK1278863) are being evant institutional review boards or ethics committees. The developed to treat anemia of CKD [10–14]. These agents stimu- investigators or study site staff were responsible for detecting, late erythropoiesis by inhibiting the HIF-prolyl hydroxylase documenting and reporting adverse events (AEs). An internal (PHD) enzymes PHD1, PHD2 and PHD3. This leads to stabiliza- GlaxoSmithKline Safety Review Team reviewed blinded safety tion of HIF-a transcription factors and induction of HIF- data in stream and an independent data monitoring committee responsive genes involved in adaptation to hypoxia—including periodically reviewed the same safety data but unblinded. erythropoietin (EPO), vascular endothelial growth factor (VEGF) The study consisted of a 4-week screening phase, 24-week and genes that regulate iron uptake, mobilization and treatment phase and a follow-up visit 4 weeks after complet- transport—resulting in decreased hepcidin production [15, 16]. ing treatment. Participants who discontinued study medication Potential advantages of HIF-PHI agents over rhEPO and its ana- or withdrew early from the study attended an early withdrawal logs, which are being tested in long-term studies, include (EW) visit, a follow-up visit after 4 weeks, phone assessments increasing hemoglobin without exposing the patient to the aligned with the remaining key study visits as required and an supraphysiologic EPO levels associated with rhEPO and its ana- EW final visit at Week 24. Study investigators or staff were logs, improving iron availability for erythropoiesis and correc- responsible for monitoring and recording AEs. AEs were col- tion of anemia in patients who do not respond to rhEPO and its lected from the start of study treatment and until the follow-up analogs and treating anemia without producing hypertension. contact. (Additional information regarding the study design is It is postulated, for these reasons, that daprodustat may be included in the Supplementary data, Item S3 and Figure S1.) associated with fewer cardiovascular events than rhEPO and its Eligible participants were stratified by region (Japan versus non- analogs. Japan) and prior rhEPO dose and then randomized 2:2:2:2:1:2 to A previous 4-week study with daprodustat demonstrated its receive blinded daprodustat tablets once daily at starting doses ability to maintain hemoglobin levels in HD patients who of 4, 6, 8, 10 or 12 mg or placebo tablets (control group). switched from rhEPO [13]. The effects of daprodustat on hemo- At Week 4, the daprodustat and control groups were to have globin were achieved with small increases in circulating EPO doses adjusted in order to achieve and maintain hemoglobin levels that averaged 17-fold lower than in the rhEPO control within the prespecified target range (10–11.5 g/dL). Participants group [17]. We report the results of a trial designed to further randomized to daprodustat had automatic dose adjustments evaluate the dose–response relationship between daprodustat through an interactive voice/web response system based on a and hemoglobin levels over the first 4 weeks of treatment prespecified dose-adjustment algorithm, with the dose of dap- (primary endpoint) and to evaluate the safety and efficacy of rodustat continually being blinded. Control participants daprodustat over 24 weeks in achieving and maintaining hemo- received open-label rhEPO (epoetins or their biosimilars, or dar- globin levels within a prespecified target range (10–11.5 g/dL) in bepoetin), with the rhEPO type, dose and route of administra- HD participants switched to daprodustat from a stable dose of tion being determined by the investigator. Study medications rhEPO. were permanently discontinued if hemoglobin levels were <7.5 g/dL, and participants were managed per standard of care (e.g. rhEPO and its analogs and/or iron). (A complete description MATERIALS AND METHODS of the primary and secondary endpoints and associated study assessments are listed in Table 1.) Details of the study assess- Study population ments performed, including laboratory assessments, AE report- Informed consent was obtained from all participants. Eligible ing, echocardiology and ophthalmology exams, are listed in participants were on adequate HD three to five times weekly, on Supplementary data, Item S4. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 3 Table 1. Study objectives and endpoints Objectives Endpoints Primary Characterize the dose–response relationship Hemoglobin change from baseline at Week 4 between daprodustat and hemoglobin at Week 4 Secondary Characterize the ability of daprodustat to Hemoglobin concentration at Week 24 achieve hemoglobin within the target Percentage of time within, below and above target range between Weeks 20 range (10.0–11.5 g/dL) and 24 Number (%) of participants with hemoglobin in the target range at Week 24 Number (%) of participants reaching predefined hemoglobin stopping criteria Characterize the effect of daprodustat on Change from baseline in hepcidin, ferritin, transferrin, TSAT, total iron, TIBC measures of iron metabolism and utiliza- and CHr at Week 24 tion, on indices of hematopoiesis and EPO Change from baseline in hematocrit, RBCs and reticulocyte number at Week 24 and on VEGF Maximum observed change from baseline in EPO Maximum observed change from baseline in VEGF Safety Assess the safety and tolerability of daprodu- Incidence and severity of AEs and SAEs stat following QD administration for 24 Reasons for discontinuation of study medication weeks Discontinuation for safety-related reasons, e.g. prespecified stopping criteria or AE Absolute values and changes from baseline in laboratory parameters, sPAP, LVEF, ophthalmology assessments and vital signs Preliminary assessment of MACE and other CV events AE, adverse event; CHr, reticulocyte hemoglobin content; CV, cardiovascular; EPO, erythropoietin; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; QD, once daily; RBC, red blood cell; SAE, severe adverse event; sPAP, systolic pulmonary artery pressure; TIBC, total iron-binding capacity; TSAT, transferrin saturation; VEGF, vascular endothelial growth factor. (Figure 1). The predominant reason in both groups for partici- Statistical analyses pants not completing the study was withdrawal by the partici- Analyses were performed on the intent-to-treat (ITT) popula- pant (withdrew consent): 8% in the combined daprodustat tion. All analyses were estimation based; no formal hypothesis group and 5% in the control group. For those randomized to testing was planned. Results are expressed using descriptive daprodustat, the highest rates of noncompleters were in groups statistics. with a starting dose of daprodustat of 4 or 12 mg. For the primary analysis, a Bayesian approach was used to Baseline and demographic characteristics are shown for the characterize the relationship between daprodustat dose and daprodustat and control groups (Table 2). In the ITT population, hemoglobin using an E model (details are described in the max mean age (57.9 and 61.6 years), percentage of males (65% and Supplementary data, Item S5). For the secondary analysis, time 60%), mean weight (80.3 and 84.8 kg) and mean body mass index (days) spent with hemoglobin within the target range while on (28.2 and 30.1 kg/m ) were well balanced in the combined dapro- treatment between Weeks 20 and 24 was calculated using the dustat and control groups, respectively. method of Rosendaal et al. [18] and percentage of time within, above, and below hemoglobin target range between Weeks 20 and 24 was reported. The number of participants within, above Hemoglobin dose–response and below the hemoglobin target range was determined at At baseline, mean hemoglobin across the daprodustat and con- Week 24. Safety data were summarized by treatment group. trol groups was 10.4 g/dL (individual group means ranged from This study was designed as a dose-ranging study and, as such, 10.3 to 10.6 g/dL). Over the 4-week fixed-dose treatment phase, was not designed to make any formal comparisons between the daprodustat doses up to 10 mg once daily produced a dose- daprodustat and control arms. dependent change in hemoglobin from baseline (12 mg produced The sample size for daprodustat was sufficient to estimate similar responses to 10 mg), with changes evident at Week 2; the dose–response relationship and to provide data on at least hemoglobin decreased in the control group receiving placebo 100 participants exposed to daprodustat for 24 weeks (see (Figure 2, Supplementary data, Table S2, Item S6). Supplementary data, Item S5 for complete justification). The dose–response model-based analysis estimated that a dose of 4.4 mg of daprodustat would produce a 0 mg/dL change in hemoglobin over 4 weeks after switching from rhEPO and RESULTS that a dose of 0.42 mg would be the minimally effective dose Participant disposition and baseline characteristics (i.e. 0.5 g/dL change from baseline). (Additional outputs of the model are provided in the Supplementary data, Item S6.) The study included 177 participants randomized to one of the daprodustat dose groups and 39 participants randomized to the control group. Of those randomized, all were included in the Change in hemoglobin levels over time safety population and 171 (97%) in the ITT population. The over- all study completion rate was 87%, with 85% of participants in After the fixed-dosing phase, when doses were titrated to the daprodustat and 92% in the control groups completing the achieve the hemoglobin target range (10–11.5 g/dL), hemoglobin study, i.e. the participant completed all study visits or the levels for those receiving daprodustat (combining all starting abbreviated schedule if study medication was discontinued doses) converged toward the hemoglobin target. In the control Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| A.M. Meadowcroft et al. Randomized (N=216) (4.5:1 daprodustat:control) Randomized to daprodustat Randomized to control (N=177) (N=39) 26 Discontinued 3 Discontinued All received study medication All received study medication � 5 died before end � 0 died before end of treatment of treatment � 21 Withdrew from the � 3 Withdrew from the study (reason per PI) study (reason per PI) a a � 14 Withdrawal by Completed the study Completed the study � 2 Withdrawal by participant (N=151/177) 85% (N=36/39) 92% participant � 0 Lost to follow-up � 1 Lost to follow-up � 7 Other – not protocol- � 0 Other – not protocol- specified specified Discontinued study medication Discontinued study medication – 1 physician decision early (N=66/177) 37% early (N=8/39) 21% – 1 protocol deviation b b Reasons Reasons – 5 met the IP stopping � 10 Adverse events � 3 Adverse events criteria � 34 Met protocol-defined � 3 Met protocol-defined stopping criteria stopping criteria � 19 Withdrawal from study � 2 Withdrawal from study medication by subject medication by subject � 3 Other reasons – not protocol-specified a b FIGURE 1: Study flow diagram. Completed all study visits or abbreviated schedule if study medication was discontinued. Twenty-two participants discontinued study medi- cation because of AEs; however, 12 of these participants had AEs that were actually protocol-defined stopping criteria and are presented here in the stopping criteria category rather than the AE category. Protocol-defined stopping criteria are detailed in the Supplementary data, Item S1. IP, investigational product; PI, principal investigator. group, hemoglobin levels returned to baseline by Week 14 after Measures of iron metabolism and IV iron use restarting rhEPO at Week 4 (Figure 3). Mean baseline levels in hepcidin and other iron parameters At Week 24, the mean6 standard deviation (SD) hemoglobin were similar across the treatment and control groups (Table 4). change from baseline was 0.036 1.05 g/dL for the daprodustat Hepcidin levels decreased for participants in the daprodustat group and 0.116 1.43 g/dL for the control group, with 58% of group over the first 4 weeks and remained below baseline for participants in each group having hemoglobin values within the the combined daprodustat group throughout the treatment target range. The median percentage of time within the hemo- phase (Figure 4, Table 4). Participants in the control group had globin target range over the last 4 study weeks was 60% for the an initial increase in hepcidin while on placebo, and once rhEPO daprodustat group and 66% for the control group. A sensitivity was restarted at Week 4, mean hepcidin levels decreased over analysis of the percentage of time within, above and below the time and approached baseline by the end of treatment. (Results hemoglobin target range between Weeks 20 and 24 is shown in for other iron parameters are provided in Table 4 and Supplementary data, Table S3, Item S6. The median final dose Supplementary data, Figure S2, Item S8.) of daprodustat was 6 mg and the median final rhEPO dose, Approximately 67% of participants in both the treatment standardized to IV epoetin, was 55.8 U/kg/week. and control groups were receiving IV iron at baseline. During Two (1%) participants in the combined daprodustat group the treatment phase, the median IV iron dose, adjusted by expo- met protocol-defined hemoglobin stopping criteria (<7.5 g/dL). sure, was similar (44.1 versus 42.7 mg/week) for the daprodustat Hemoglobin levels 13 g/dL were observed in 17 (10%) partici- and control groups, respectively. pants in the combined daprodustat group, with 82% occurring in those randomized to starting doses 8 mg. Hemoglobin levels Safety 13 g/dL were observed in one (3%) participant in the control group. Few participants in either group received red blood cell The overall incidence of any AEs through the 24-week treat- (RBC) transfusions during the study [7 (4%) combined daprodu- ment phase was similar in the combined daprodustat and con- stat; 2 (5%) control], with acute bleeding being the most com- trol groups (Table 5). Of the AEs most frequently reported, mon reason. diarrhea, nausea, hypertension and hyperkalemia were The changes in hemoglobin were associated with expected reported more often in the combined daprodustat group, while changes in hematocrit, RBC count and absolute reticulocyte nasopharyngitis and back pain were reported more often in the count (Supplementary data, Table S4, Item S7). control group. While hyperkalemia was reported as an AE more frequently in the daprodustat group than in the control group (Table 5), the proportion of hyperkalemia events of potential Erythropoietin and VEGF levels clinical importance (potassium >6.3 mmol/L) was slightly Baseline plasma EPO levels were similar across the daprodustat higher in the control group (17%) than in the daprodustat group and control groups. The median maximum observed EPO level (14%). was 36.5 IU/L for the combined daprodustat group and 522.9 IU/L Serious AEs (SAEs) were reported in 31 (18%) participants in for the control group (Table 3). the combined daprodustat group and in 10 (26%) participants in Across the treatment and control groups, plasma VEGF the control group. The most common SAEs in the combined levels were similar at baseline (Table 3). VEGF levels were highly daprodustat group were acute myocardial infarction (MI) and variable at all time points, with no clear signal for a change in cardiac arrest, in three participants each, followed by unstable any treatment group (Table 3). angina, cardiac failure, hypertensive crisis, lobar pneumonia Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 5 Table 2. Baseline and demographic characteristics (ITT population (sPAP) were similar for the daprodustat and control groups and safety population where indicated) (Supplementary data, Table S5, Item S9). An increase of >20 mmHg from baseline in estimated sPAP was observed in Combined eight (7%) participants in the combined daprodustat group and daprodustat Control in no participants in the control group. (n¼ 171) (n¼ 39) Mean changes from baseline in blood pressure (BP) for the combined daprodustat and control groups are presented in Age , years Table 6. Although the mean change from baseline in systolic BP n 171 39 mean (SD) 59.6 (13.3) 59.7 (18.7) was greater in the control group than the combined daprodustat Sex group by 5 mmHg, more participants in the combined dapro- n 171 39 dustat group [22 (12%)] had an increase in the number of antihy- male, n (%) 108 (63) 26 (67) pertensive medications relative to the control group [2 (5%)]. Weight (kg) No adverse trends were noted for clinical laboratory values n 171 39 and electrocardiogram parameters. Furthermore, no changes mean (SD) 77.8 (23.0) 76.3 (19.8) were seen in visual acuity or intraocular pressure based on the a 2 BMI (kg/m ) protocol-specified ophthalmology exams (data not shown). n 170 39 mean (SD) 27.7 (7.5) 27.2 (5.8) Race , n (%) DISCUSSION n 171 39 This study is the largest and longest completed to date in White 124 (73) 23 (59) the HD population switched from rhEPO to treatment with the African American 18 (11) 7 (18) HIF-PHI, daprodustat. Over the first 4 weeks, daprodustat Asian 27 (16) 7 (18) produced dose-dependent changes in hemoglobin up to the Other 2 (1) 2 (5) 10-mg dose, with dose separation noted as early as the first Geographical region , n (%) assessment at 2 weeks. These increases in hemoglobin were n 171 39 associated with the expected increase in absolute reticulocyte Japan 19 (11) 5 (13) North America 44 (26) 13 (33) count, thus supporting increased erythropoiesis as the main Russia 37 (22) 9 (23) driver for daprodustat’s effect on hemoglobin. Rest of the world 71 (42) 12 (31) Over the 24-week treatment phase, daprodustat maintained Mode of dialysis , n (%) hemoglobin levels, with 2 (1%) participants requiring permanent n 177 39 discontinuation of study medication (hemoglobin <7.5 g/dL). Hemodiafiltration 51 (29) 5 (13) Although 17 (10%) participants on daprodustat required a dose HD 120 (68) 33 (85) interruption for hemoglobin 13 g/dL, this was influenced by the Hemofiltration 6 (3) 2 (5) random starting dose allocation, as most excursions occurred a,c Prior rhEPO dose stratification , n (%) with starting doses 8 mg. The proportion of participants on dap- n 171 39 rodustat who were within the hemoglobin target range (58%) at Low rhEPO dose 143 (84) 33 (85) Week 24 is lower than that observed in a recently conducted High rhEPO dose 28 (16) 6 (15) 24-week study in participants with CKD and could be due to par- Baseline hemoglobin level (g/dL) ticipants in this study being assigned to random starting doses n 171 39 (2–12 mg). In the CKD study, starting doses were assigned based mean (SD) 10.4 (0.66) 10.6 (0.94) b on salient baseline parameters (74% in the target range at Week CV risk factors , n (%) 24; [31]). n 177 39 In the daprodustat group, hemoglobin was maintained with Any CV risk factor 166 (94) 38 (97) postdose plasma EPO levels similar to those observed during Hypertension 160 (90) 37 (95) acclimatization to high altitude [19]. In contrast, maximum Hyperlipidemia 85 (48) 20 (51) observed postdose EPO levels in the control group were 14-fold Diabetes mellitus 62 (35) 18 (46) Angina pectoris 13 (7) 2 (5) higher than in the daprodustat group, a finding consistent with prior daprodustat clinical studies [13]. If higher EPO levels Intent-to-treat population. contribute to the cardiovascular risk associated with rhEPO [20], Safety population. then daprodustat may provide a safer cardiovascular risk Low rhEPO dose: <100 IU/kg/week epoetin or <0.5 lg/kg/week darbepoetin; high profile. rhEPO dose: 100 IU/kg/week epoetin or 0.5 lg/kg/week darbepoetin. Consistent with findings from prior trials with daprodustat BMI, body mass index; CV, cardiovascular; ITT, intent-to-treat; IU, international and vadadustat [13, 14, 21], in this 24-week study, daprodustat, unit; rhEPO, recombinant human erythropoietin; SD, standard deviation. as well as the control, had minimal if any effect on VEGF, a known target gene of HIF [22–24]. This is consistent with pre- and pulmonary edema in two participants each. All other clinical work demonstrating that VEGF expression is less sensi- SAEs were reported in one participant each. In the control tive to HIF activation than is EPO expression (GlaxoSmithKline, group, no specific SAE was reported in more than one partici- unpublished data) [25]. pant. A summary of cardiovascular events, including major Participants were iron replete at baseline and an iron proto- adverse cardiovascular events (MACEs) and component end- col provided thresholds for IV iron use to ensure participants points, are summarized in Table 5. Other preidentified AEs of remained replete. Decreases in hepcidin, ferritin and TSAT and interest are described in the Supplementary data, Item S9. increases in total iron-binding capacity (TIBC) during the initial Mean baseline and absolute changes in left ventricular ejec- 4-week, fixed-dose phase corresponded with the increases in tion fraction and estimated systolic pulmonary artery pressure hemoglobin observed across the daprodustat doses studied, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| A.M. Meadowcroft et al. FIGURE 2: Mean change in hemoglobin levels from baseline to Week 4 by treatment group [intent-to-treat (ITT) population]. FIGURE 3: Mean hemoglobin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population]. BL, baseline. Table 3. Levels and change from baseline for EPO and VEGF (ITT population) Combined daprodustat Control (n¼ 171) (n¼ 39) EPO levels (IU/L) Baseline n 163 36 Median (minimum, maximum) 9.2 (2.5, 755.8) 9.3 (2.6, 54.6) Maximum observed EPO level , median (minimum, maximum) 36.5 (5.2, 1379.3) 522.9 (19.0, 51 200.0) Maximum observed CFB in EPO level , median (minimum, maximum) 27.1 (724.5, 1371.6) 512.9 (5.3, 51 195.4) VEGF levels (ng/L) Baseline n 163 36 Median (minimum, maximum) 186.9 (64.3, 1142.6) 220.0 (78.2, 595.7) Maximum observed VEGF median (minimum, maximum) 270.0 (81.8, 808.3) 269.4 (98.7, 924.0) Baseline is the last predose value. Measurements in the daprodustat group were done predose and postdose 6–15 h after dosing; measurement in the control group was performed 5–15 min after dos- ing with rhEPO. CFB, change from baseline; EPO, erythropoietin; ITT, intent-to-treat; IU, international units; rhEPO, recombinant human erythropoietin; VEGF, vascular endothelial growth factor. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 7 Table 4. Changes from baseline for markers of iron metabolism (ITT population) Combined daprodustat (n¼ 171) Control (n¼ 39) Baseline % CFB at Week 24 Baseline % CFB at Week 24 Hepcidin (mg/L) n 171 114 38 32 Geometric mean 388.2 –20.6 334.4 3.6 95% CI 352.9, 427.1 –29.9, –10.0 274.7, 407.1 –20.4, 34.9 TSAT (%) n 171 115 39 32 Geometric mean 29.6 –4.4 30.7 –9.0 95% CI 27.9, 31.5 –11.2, 2.8 27.0, 35.0 –27.3, 13.9 Baseline CFB at Week 24 Baseline CFB at Week 24 Ferritin (mg/L) n 171 115 39 33 Mean 585.1 59.9 459.0 56.8 SD 429.7 331.8 261.0 214.3 TIBC (mmol/L) n 171 115 39 32 Mean 41.6 5.5 41.2 2.0 SD 6.6 6.6 7.2 4.5 Total iron (mmol/L) n 171 115 39 33 Mean 13.4 0.9 13.4 0.8 SD 6.1 6.1 4.9 7.6 CFB, change from baseline; CI, confidence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation. FIGURE 4: Mean hepcidin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population]. which is similar to findings reported with other HIF-PHIs the prespecified iron protocol stopping thresholds, and the [10, 26]. The decrease in ferritin and TSAT and increase in TIBC study duration may have been insufficient to deplete iron stores are consistent with iron utilization due to increased erythropoi- to the point of elucidating a difference between treatments. esis, and the decreased hepcidin could be an effect of the resul- Further work remains to understand the effects of daprodustat tant decreased iron availability. The continued suppression of on iron metabolism and the resultant effects on IV iron require- hepcidin and ferritin observed for the remainder of the trial in ments; these are being tested in a current Phase 3 trial participants on daprodustat may reflect iron stores that (NCT03029208). remained lower than baseline with daprodustat [27]. Although Treatment with daprodustat for up to 24 weeks demon- no difference in IV iron administration between treatment strated an AE profile consistent with the complex medical his- groups was observed, the interpretation of data is confounded tories and cardiovascular comorbidities typical of this patient since many participants continued IV iron despite exceeding population. MACEs occurred more frequently in the daprodustat Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| A.M. Meadowcroft et al. Table 5. AEs and frequency of MACE and component end points in An imbalance was also reported for the number of partici- the combined daprodustat and control groups (safety population) pants with a >20 mmHg increase from baseline in estimated sPAP for the daprodustat group relative to controls, despite Combined mean absolute changes from baseline in estimated sPAP daprodustat Control being similar for both groups. This finding was not dose (n¼ 177) (n¼ 39) related. Changes in fluid status could not be ruled out as a confounder, given that the timing of echocardiograms AEs occurring in 5% of participants (ECHOs) relative to dialysis day was inconsistent both within Any event, n (%) 129 (73) 31 (79) Diarrhea 16 (9) 2 (5) a given participant and between participants in the daprodu- Nasopharyngitis 15 (8) 5 (13) stat and control groups. In a 24-week study in participants Nausea 13 (7) 0 with CKD, who are less prone to fluid shifts as compared with Headache 9 (5) 2 (5) participants on HD, there was no difference in estimated sPAP Hypertension 9 (5) 1 (3) elevations >20 mmHg in those receiving daprodustat com- Hyperkalemia 8 (5) 0 pared with controls [31]. Additionally, dedicated preclinical Back pain 7 (4) 4 (10) data (GlaxoSmithKline, unpublished data) and a clinical study MACE composite in healthy volunteers [28] demonstrated no effect of daprodu- endpoints , n (%) stat on peak right ventricular pressure or sPAP, respectively, Any MACE 7 (4) 0 even in the setting of a hypoxic challenge. Any MACEþ 10 (6) 1 (3) Treatment with daprodustat did not raise BP. Consistent Components of composite with the known AEs of rhEPO [29], the control group had an endpoints , n (%) increase in systolic BP at Week 24. Interpretation of the collec- All-cause mortality 5 (3) 0 tive BP data is complicated by a greater proportion of partici- MI (fatal or nonfatal) 3 (2) 0 pants on daprodustat reporting AEs of hypertension and having Stroke (fatal or nonfatal) 0 0 an increase in the number of antihypertensive medications rel- Hospitalization due to 5 (3) 1 (3) ative to control. These imbalances may be due to more careful heart failure monitoring of BP in the combined daprodustat group, given it is Cardiovascular events, including MACEs, defined as MI, stroke or death, were an investigational drug, and underreporting of events in the collected but were not formally adjudicated. control arm, given the known AE of hypertension with rhEPO. A MACE is defined as a first occurrence of all-cause mortality, a nonfatal MI or a Limitations of this trial include an uneven randomization nonfatal stroke. ratio (4.5:1) resulting in a relatively small control group (n¼ 39) A MACEþ is defined as a first occurrence of a MACE or hospitalization due to and the open-label design from Week 4 onward. Additionally, heart failure. d the tight eligibility criteria limit the generalizability of the find- Includes all events. MACE, major adverse cardiovascular event; MI, myocardial infarction. ings, and the degree of noncompletion and large number of sec- ondary outcomes complicates interpretation of the results. The open-label design could potentially influence how AEs are Table 6. Summary of SBP and DBP at Week 24 (ITT population) reported by participants or recorded by study staff for an inves- tigational medication as compared with the standard of care. Combined For example, more AEs of hyperkalemia were reported in the daprodustat Control daprodustat group than in the control group, despite the fact (n¼ 171) (n¼ 39) that more hyperkalemia events of potential clinical importance SBP (mmHg) were reported in the control group. This kind of bias may also Baseline have been true for the excess reports of nausea with daprodu- n 163 36 stat compared with controls. Nausea is common in patients on Mean (SD) 141.5 (17.4) 139.5 (18.7) dialysis [30]. More AEs of nausea reported in the daprodustat Change from baseline at Week 24 group could have been influenced by daprodustat being an n 112 31 investigational medication or the oral route of daprodustat Mean (SD) 0.7 (18.0) 5.6 (19.3) administration. Cardiovascular events were not formally adju- DBP (mmHg) dicated and the study was not powered for any formal assess- Baseline ment of cardiovascular events. Lastly, the timing of the ECHO n 163 36 assessment relative to HD was not standardized and specific Mean (SD) 74.9 (12.6) 75.5 (11.9) data to determine fluid shifts and estimated dry weight were Change from baseline at Week 24 not collected. n 112 31 Overall, these data demonstrate that daprodustat produced Mean (SD) 0.3 (9.7) 1.3 (11.5) dose-dependent changes from baseline in hemoglobin over the first 4 weeks and, with the dose-adjustment rules applied in Baseline is the last predose value. this trial, daprodustat effectively achieves and maintains hemo- DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation. globin target levels after switching from a stable dose of rhEPO. This efficacy was achieved while maintaining effective plasma group, but these events were underpowered and not adjudi- EPO levels and an AE profile consistent with that of the patient cated, so definitive conclusions cannot be made. A long-term population. These data support continued development of dap- cardiovascular outcome study is ongoing to conclusively assess rodustat to treat anemia of CKD in patients receiving dialysis, these associations. No emerging safety concerns based on the including an ongoing large-scale cardiovascular outcomes trial collective safety data, nor safety signals for any preidentified AE (ASCEND-D) in patients receiving maintenance dialysis who are of interest, were identified for daprodustat. switching from rhEPO and its analogs (NCT02879305) and a trial Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 9 in patients who are initiating dialysis (NCT03029208) to assess 3. Locatelli F, Del Vecchio L. New strategies for anaemia man- the safety and efficacy of daprodustat. agement in chronic kidney disease. Contrib Nephrol 2017; 189: 184–188 4. Besarab A, Bolton WK, Browne JK et al. The effects of normal SUPPLEMENTARY DATA as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. Supplementary data are available at ckj online. N Engl J Med 1998; 339: 584–590 5. Dru ¨ eke TB, Locatelli F, Clyne N et al. Normalization of hemo- ACKNOWLEDGEMENTS globin level in patients with chronic kidney disease and ane- mia. N Engl J Med 2006; 355: 2071–2084 The authors thank the investigators and their staff for their 6. Pfeffer MA, Burdmann EA, Chen C-Y et al. A trial of darbepoe- contributions (see ClinicalTrials.gov NCT01977482 for the site tin alfa in type 2 diabetes and chronic kidney disease. N Engl list). The authors acknowledge the following GlaxoSmithKline J Med 2009; 361: 2019–2032 (GSK) employees for their assistance with study management 7. Singh AK, Szczech L, Tang KL et al. Correction of anemia with and critical review: Deborah Kelly, MD, and Douglas Wicks, epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: MPH, CMPP. Authors meet the authorship criteria set forth by 2085–2098 the International Committee of Medical Journal Editors. 8. Jenkins J. Statement regarding erythropoiesis-stimulating Medical editorial support (Nancy Price, PhD, Gautam Bijur, agents (ESA) before the Committee on Ways and Means PhD, and Sarah Hummasti, PhD) and graphic services were Subcommittee on Health, US House of Respresentatives. provided by AOI Communications and were funded by GSK. Washington, DC: US Government Printing Office. https:// B.M.J. was previously affiliated with Clinical Pharmacology www.gpo.gov/fdsys/pkg/CHRG-110hhrg49981/pdf/CHRG- Modeling and Simulation, GlaxoSmithKline, Research Triangle 110hhrg49981.pdf. Published 26 June 2007 (20 December 2017, Park, NC, USA. date last accessed) 9. US Food and Drug Administration. FDA drug safety commu- nication: modified dosing recommendations to improve the FUNDING safe use of erythropoiesis-stimulating agents (ESAs) in Funding for this study (ClinicalTrials.gov: NCT01977482; chronic kidney disease. https://www.fda.gov/Drugs/ EudraCT: 2013-002682-19; GSK PHI113633) was provided by DrugSafety/ucm259639.htm. Published 24 June 2011 (21 GlaxoSmithKline. March 2017, date last accessed) 10. Besarab A, Chernyavskaya E, Motylev I et al. Roxadustat (FG- 4592): correction of anemia in incident dialysis patients. AUTHORS’ CONTRIBUTIONS J Am Soc Nephrol 2016; 27: 1225–1233 The concept and study were designed by A.M.M., B.C., L.H., 11. Provenzano R, Besarab A, Sun CH et al. Oral hypoxia- inducible factor prolyl hydroxylase inhibitor roxadustat (FG- N.B., B.M.J., J.J.L. and A.R.C. A.K.N. and M.A. were in charge 4592) for the treatment of anemia in patients with CKD. Clin J of data acquisition. Statistical analysis was conduted by N.B. Am Soc Nephrol 2016; 11: 982–991 and D.J. All authors reviewed the analysis and interpreted 12. Brigandi RA, Johnson B, Oei C et al. PHI: a novel hypoxia- the data. A.M.M. wrote the initial draft and each author con- inducible factor-prolyl hydroxylase inhibitor (GSK1278863) tributed important intellectual content during manuscript for anemia in CKD: a 28-day, phase 2A randomized trial. Am development and revision. All authors agree to be account- J Kidney Dis 2016; 67: 861–871 able for all aspects of the work. 13. Holdstock L, Meadowcroft AM, Maier R et al. Four-week stud- ies of oral hypoxia-inducible factor-prolyl hydroxylase CONFLICT OF INTEREST STATEMENT inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016; 27: 1234–1244 A.M.M., B.C., N.B., D.J., J.J.L. and A.R.C. are employees of and 14. Pergola PE, Spinowitz BS, Hartman CS et al. Vadadustat, a hold stock in GlaxoSmithKline (GSK). L.H. and B.M.J. are for- novel oral HIF stabilizer, provides effective anemia treat- mer employees of GSK and hold stock options in GSK. A.K.N. ment in nondialysis-dependent chronic kidney disease. received research grants from GSK and research sponsor- Kidney Int 2016; 90: 1115–1122 ship from Affymax. M.A. has no potential conflicts of inter- 15. Mastrogiannaki M, Matak P, Keith B et al. HIF-2a, but not HIF- est to report. This manuscript is not under consideration for 1a, promotes iron absorption in mice. J Clin Invest 2009; 119: publication elsewhere. The results presented in this article 1159–1166 have not been published previously in whole or part, except 16. Liu Q, Davidoff O, Niss K et al. Hypoxia-inducible factor regu- in abstract form. Some of the data included in the present lates hepcidin via erythropoietin-induced erythropoiesis. article were presented at the American Society of J Clin Invest 2012; 122: 4635–4644 17. Mason-Garcia M, Beckman BS, Brookins JW et al. Nephrology meeting in Chicago, IL, USA, 15–20 November Development of a new radioimmunoassay for erythropoie- tin using recombinant erythropoietin. Kidney Int 1990; 38: 969–975 REFERENCES 18. Rosendaal FR, Cannegieter SC, van der Meer FJ et al. 1. United States Renal Data System. 2013 Atlas of CKD and ESRD. A method to determine the optimal intensity of oral anticoa- Clinical indicators and preventive care. https://www.usrds.org/ gulant therapy. Thromb Haemost 1993; 69: 236–239 2013/pdf/v2_ch2_13.pdf (3 February 2017, date last accessed) 19. Milledge JS, Cotes PM. Serum erythropoietin in humans at 2. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc high altitude and its relation to plasma renin. J Appl Physiol Nephrol 2012; 23: 1631–1634 1985; 59: 360–364 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 10 | A.M. 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Hypoxia-inducible factor in healthy volunteers following administration of the HIF- prolyl hydroxylase inhibition: robust new target or another prolyl hydroxylase inhibitor, GSK1278863. Pharmacotherapy big bust for stroke therapeutics? J Cereb Blood Flow Metab 2014; 34: e222 2012; 32: 1347–1361 29. Krapf R, Hulter HN. Arterial hypertension induced by eryth- 24. Nitta K, Uchida K, Kimata N et al. Recombinant human erythro- ropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol 2009; 4: 470–480 poietin stimulates vascular endothelial growth factor release by glomerular endothelial cells. Eur J Pharmacol 1999; 373: 121–124 30. Asgari MR, Asghari F, Ghods AA et al. Incidence and severity 25. Flamme I, Oehme F, Ellinghaus P et al. Mimicking hypoxia to of nausea and vomiting in a group of maintenance hemo- treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimu- dialysis patients. J Renal Inj Prev 2017; 6: 49–55 lates erythropoietin production without hypertensive 31. Holdstock L, Cizman B, Meadowcroft AM et al. Daprodustat effects. PLoS One 2014; 9: e111838 for anemia: a 24-week, open-label, randomized controlled 26. Provenzano R, Besarab A, Wright S et al. Roxadustat (FG- trial in participants with chronic kidney disease. Clin Kidney J 4592) versus epoetin alfa for anemia in patients receiving 2018; doi: 10.1093/ckj/sfy013 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis

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Abstract

Clinical Kidney Journal, 2018, 1–10 doi: 10.1093/ckj/sfy014 Original Article OR I G I N AL A R T I C L E Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis 1 2,3 1,8 2 Amy M. Meadowcroft , Borut Cizman , Louis Holdstock , Nandita Biswas , 4 5 6 2 Brendan M. Johnson , Delyth Jones , A. Kaldun Nossuli , John J. Lepore , 7 2 Michael Aarup and Alexander R. Cobitz Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, NC, USA, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 4 5 Philadelphia, PA, USA, Clinical Pharmacology, Roivant Sciences, Durham, NC, USA, Clinical Statistics, 6 7 GlaxoSmithKline, Stevenage, UK, Nossuli Research, Greenbelt, MD, USA, Department of Nephrology, Odense University Hospital, Odense, Denmark and Present address: United Therapeutics, Research Triangle Park, NC, USA Correspondence and offprint requests to: Borut Cizman; E-mail: borut.x.cizman@gsk.com ABSTRACT Background: This study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease. Methods: Participants (n¼ 216) with baseline hemoglobin levels of 9–11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10–11.5 g/dL. The primary outcome was characterization of the dose–response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks. Results: Over the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from 0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and 0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were 14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population. Received: 20.7.2017. Editorial decision: 9.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| A.M. Meadowcroft et al. Conclusions: Daprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks. Keywords: anemia, chronic kidney disease, daprodustat, hemodialysis, recombinant human erythropoietin stable rhEPO doses for 8 weeks before randomization and had INTRODUCTION stable hemoglobin levels between 9 and 11.5 g/dL based on the Anemia is a common complication in patients with chronic kid- average of three values obtained during the screening phase. ney disease (CKD) who receive maintenance hemodialysis (HD) Maintenance oral or IV iron supplementation was allowed, but [1, 2]. The standard of care for treating this anemia uses participants were excluded if ferritin was <100 ng/mL and/or recombinant human erythropoietin (rhEPO) and its analogs, transferrin saturation (TSAT) was <12% or>57%. The complete supplemented with intravenous (IV) iron administration [3]. inclusion, exclusion and study medication stopping criteria and Well-controlled clinical outcomes trials have demonstrated that prohibited drugs can be found in the Supplementary data, Item rhEPO and its analogs increase the risk of cardiovascular events, S1, and the iron protocol is shown in Supplementary data, Table stroke and death when targeting higher hemoglobin levels S1 in Item S2. (>13 g/dL) [4–7]. These findings led the US Food and Drug Administration to modify safety language in labeling for rhEPO and its analogs in 2007 and 2011 to limit their initiation in HD Study design patients until the hemoglobin level is<10 g/dL and to reduce or This global study (ClinicalTrials.gov identifier NCT01977482; interrupt treatment if the hemoglobin level approaches or EudraCT number 2013-002682-19) was conducted from 15 exceeds 11 g/dL [8, 9]. November 2013 to 18 March 2015 at 107 sites in 16 countries (67 Given the safety concerns with rhEPO and its analogs, sites in 15 countries randomized participants), performed in hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors adherence with the Declaration of Helsinki and approved by rel- (PHIs) including daprodustat (previously GSK1278863) are being evant institutional review boards or ethics committees. The developed to treat anemia of CKD [10–14]. These agents stimu- investigators or study site staff were responsible for detecting, late erythropoiesis by inhibiting the HIF-prolyl hydroxylase documenting and reporting adverse events (AEs). An internal (PHD) enzymes PHD1, PHD2 and PHD3. This leads to stabiliza- GlaxoSmithKline Safety Review Team reviewed blinded safety tion of HIF-a transcription factors and induction of HIF- data in stream and an independent data monitoring committee responsive genes involved in adaptation to hypoxia—including periodically reviewed the same safety data but unblinded. erythropoietin (EPO), vascular endothelial growth factor (VEGF) The study consisted of a 4-week screening phase, 24-week and genes that regulate iron uptake, mobilization and treatment phase and a follow-up visit 4 weeks after complet- transport—resulting in decreased hepcidin production [15, 16]. ing treatment. Participants who discontinued study medication Potential advantages of HIF-PHI agents over rhEPO and its ana- or withdrew early from the study attended an early withdrawal logs, which are being tested in long-term studies, include (EW) visit, a follow-up visit after 4 weeks, phone assessments increasing hemoglobin without exposing the patient to the aligned with the remaining key study visits as required and an supraphysiologic EPO levels associated with rhEPO and its ana- EW final visit at Week 24. Study investigators or staff were logs, improving iron availability for erythropoiesis and correc- responsible for monitoring and recording AEs. AEs were col- tion of anemia in patients who do not respond to rhEPO and its lected from the start of study treatment and until the follow-up analogs and treating anemia without producing hypertension. contact. (Additional information regarding the study design is It is postulated, for these reasons, that daprodustat may be included in the Supplementary data, Item S3 and Figure S1.) associated with fewer cardiovascular events than rhEPO and its Eligible participants were stratified by region (Japan versus non- analogs. Japan) and prior rhEPO dose and then randomized 2:2:2:2:1:2 to A previous 4-week study with daprodustat demonstrated its receive blinded daprodustat tablets once daily at starting doses ability to maintain hemoglobin levels in HD patients who of 4, 6, 8, 10 or 12 mg or placebo tablets (control group). switched from rhEPO [13]. The effects of daprodustat on hemo- At Week 4, the daprodustat and control groups were to have globin were achieved with small increases in circulating EPO doses adjusted in order to achieve and maintain hemoglobin levels that averaged 17-fold lower than in the rhEPO control within the prespecified target range (10–11.5 g/dL). Participants group [17]. We report the results of a trial designed to further randomized to daprodustat had automatic dose adjustments evaluate the dose–response relationship between daprodustat through an interactive voice/web response system based on a and hemoglobin levels over the first 4 weeks of treatment prespecified dose-adjustment algorithm, with the dose of dap- (primary endpoint) and to evaluate the safety and efficacy of rodustat continually being blinded. Control participants daprodustat over 24 weeks in achieving and maintaining hemo- received open-label rhEPO (epoetins or their biosimilars, or dar- globin levels within a prespecified target range (10–11.5 g/dL) in bepoetin), with the rhEPO type, dose and route of administra- HD participants switched to daprodustat from a stable dose of tion being determined by the investigator. Study medications rhEPO. were permanently discontinued if hemoglobin levels were <7.5 g/dL, and participants were managed per standard of care (e.g. rhEPO and its analogs and/or iron). (A complete description MATERIALS AND METHODS of the primary and secondary endpoints and associated study assessments are listed in Table 1.) Details of the study assess- Study population ments performed, including laboratory assessments, AE report- Informed consent was obtained from all participants. Eligible ing, echocardiology and ophthalmology exams, are listed in participants were on adequate HD three to five times weekly, on Supplementary data, Item S4. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 3 Table 1. Study objectives and endpoints Objectives Endpoints Primary Characterize the dose–response relationship Hemoglobin change from baseline at Week 4 between daprodustat and hemoglobin at Week 4 Secondary Characterize the ability of daprodustat to Hemoglobin concentration at Week 24 achieve hemoglobin within the target Percentage of time within, below and above target range between Weeks 20 range (10.0–11.5 g/dL) and 24 Number (%) of participants with hemoglobin in the target range at Week 24 Number (%) of participants reaching predefined hemoglobin stopping criteria Characterize the effect of daprodustat on Change from baseline in hepcidin, ferritin, transferrin, TSAT, total iron, TIBC measures of iron metabolism and utiliza- and CHr at Week 24 tion, on indices of hematopoiesis and EPO Change from baseline in hematocrit, RBCs and reticulocyte number at Week 24 and on VEGF Maximum observed change from baseline in EPO Maximum observed change from baseline in VEGF Safety Assess the safety and tolerability of daprodu- Incidence and severity of AEs and SAEs stat following QD administration for 24 Reasons for discontinuation of study medication weeks Discontinuation for safety-related reasons, e.g. prespecified stopping criteria or AE Absolute values and changes from baseline in laboratory parameters, sPAP, LVEF, ophthalmology assessments and vital signs Preliminary assessment of MACE and other CV events AE, adverse event; CHr, reticulocyte hemoglobin content; CV, cardiovascular; EPO, erythropoietin; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; QD, once daily; RBC, red blood cell; SAE, severe adverse event; sPAP, systolic pulmonary artery pressure; TIBC, total iron-binding capacity; TSAT, transferrin saturation; VEGF, vascular endothelial growth factor. (Figure 1). The predominant reason in both groups for partici- Statistical analyses pants not completing the study was withdrawal by the partici- Analyses were performed on the intent-to-treat (ITT) popula- pant (withdrew consent): 8% in the combined daprodustat tion. All analyses were estimation based; no formal hypothesis group and 5% in the control group. For those randomized to testing was planned. Results are expressed using descriptive daprodustat, the highest rates of noncompleters were in groups statistics. with a starting dose of daprodustat of 4 or 12 mg. For the primary analysis, a Bayesian approach was used to Baseline and demographic characteristics are shown for the characterize the relationship between daprodustat dose and daprodustat and control groups (Table 2). In the ITT population, hemoglobin using an E model (details are described in the max mean age (57.9 and 61.6 years), percentage of males (65% and Supplementary data, Item S5). For the secondary analysis, time 60%), mean weight (80.3 and 84.8 kg) and mean body mass index (days) spent with hemoglobin within the target range while on (28.2 and 30.1 kg/m ) were well balanced in the combined dapro- treatment between Weeks 20 and 24 was calculated using the dustat and control groups, respectively. method of Rosendaal et al. [18] and percentage of time within, above, and below hemoglobin target range between Weeks 20 and 24 was reported. The number of participants within, above Hemoglobin dose–response and below the hemoglobin target range was determined at At baseline, mean hemoglobin across the daprodustat and con- Week 24. Safety data were summarized by treatment group. trol groups was 10.4 g/dL (individual group means ranged from This study was designed as a dose-ranging study and, as such, 10.3 to 10.6 g/dL). Over the 4-week fixed-dose treatment phase, was not designed to make any formal comparisons between the daprodustat doses up to 10 mg once daily produced a dose- daprodustat and control arms. dependent change in hemoglobin from baseline (12 mg produced The sample size for daprodustat was sufficient to estimate similar responses to 10 mg), with changes evident at Week 2; the dose–response relationship and to provide data on at least hemoglobin decreased in the control group receiving placebo 100 participants exposed to daprodustat for 24 weeks (see (Figure 2, Supplementary data, Table S2, Item S6). Supplementary data, Item S5 for complete justification). The dose–response model-based analysis estimated that a dose of 4.4 mg of daprodustat would produce a 0 mg/dL change in hemoglobin over 4 weeks after switching from rhEPO and RESULTS that a dose of 0.42 mg would be the minimally effective dose Participant disposition and baseline characteristics (i.e. 0.5 g/dL change from baseline). (Additional outputs of the model are provided in the Supplementary data, Item S6.) The study included 177 participants randomized to one of the daprodustat dose groups and 39 participants randomized to the control group. Of those randomized, all were included in the Change in hemoglobin levels over time safety population and 171 (97%) in the ITT population. The over- all study completion rate was 87%, with 85% of participants in After the fixed-dosing phase, when doses were titrated to the daprodustat and 92% in the control groups completing the achieve the hemoglobin target range (10–11.5 g/dL), hemoglobin study, i.e. the participant completed all study visits or the levels for those receiving daprodustat (combining all starting abbreviated schedule if study medication was discontinued doses) converged toward the hemoglobin target. In the control Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| A.M. Meadowcroft et al. Randomized (N=216) (4.5:1 daprodustat:control) Randomized to daprodustat Randomized to control (N=177) (N=39) 26 Discontinued 3 Discontinued All received study medication All received study medication � 5 died before end � 0 died before end of treatment of treatment � 21 Withdrew from the � 3 Withdrew from the study (reason per PI) study (reason per PI) a a � 14 Withdrawal by Completed the study Completed the study � 2 Withdrawal by participant (N=151/177) 85% (N=36/39) 92% participant � 0 Lost to follow-up � 1 Lost to follow-up � 7 Other – not protocol- � 0 Other – not protocol- specified specified Discontinued study medication Discontinued study medication – 1 physician decision early (N=66/177) 37% early (N=8/39) 21% – 1 protocol deviation b b Reasons Reasons – 5 met the IP stopping � 10 Adverse events � 3 Adverse events criteria � 34 Met protocol-defined � 3 Met protocol-defined stopping criteria stopping criteria � 19 Withdrawal from study � 2 Withdrawal from study medication by subject medication by subject � 3 Other reasons – not protocol-specified a b FIGURE 1: Study flow diagram. Completed all study visits or abbreviated schedule if study medication was discontinued. Twenty-two participants discontinued study medi- cation because of AEs; however, 12 of these participants had AEs that were actually protocol-defined stopping criteria and are presented here in the stopping criteria category rather than the AE category. Protocol-defined stopping criteria are detailed in the Supplementary data, Item S1. IP, investigational product; PI, principal investigator. group, hemoglobin levels returned to baseline by Week 14 after Measures of iron metabolism and IV iron use restarting rhEPO at Week 4 (Figure 3). Mean baseline levels in hepcidin and other iron parameters At Week 24, the mean6 standard deviation (SD) hemoglobin were similar across the treatment and control groups (Table 4). change from baseline was 0.036 1.05 g/dL for the daprodustat Hepcidin levels decreased for participants in the daprodustat group and 0.116 1.43 g/dL for the control group, with 58% of group over the first 4 weeks and remained below baseline for participants in each group having hemoglobin values within the the combined daprodustat group throughout the treatment target range. The median percentage of time within the hemo- phase (Figure 4, Table 4). Participants in the control group had globin target range over the last 4 study weeks was 60% for the an initial increase in hepcidin while on placebo, and once rhEPO daprodustat group and 66% for the control group. A sensitivity was restarted at Week 4, mean hepcidin levels decreased over analysis of the percentage of time within, above and below the time and approached baseline by the end of treatment. (Results hemoglobin target range between Weeks 20 and 24 is shown in for other iron parameters are provided in Table 4 and Supplementary data, Table S3, Item S6. The median final dose Supplementary data, Figure S2, Item S8.) of daprodustat was 6 mg and the median final rhEPO dose, Approximately 67% of participants in both the treatment standardized to IV epoetin, was 55.8 U/kg/week. and control groups were receiving IV iron at baseline. During Two (1%) participants in the combined daprodustat group the treatment phase, the median IV iron dose, adjusted by expo- met protocol-defined hemoglobin stopping criteria (<7.5 g/dL). sure, was similar (44.1 versus 42.7 mg/week) for the daprodustat Hemoglobin levels 13 g/dL were observed in 17 (10%) partici- and control groups, respectively. pants in the combined daprodustat group, with 82% occurring in those randomized to starting doses 8 mg. Hemoglobin levels Safety 13 g/dL were observed in one (3%) participant in the control group. Few participants in either group received red blood cell The overall incidence of any AEs through the 24-week treat- (RBC) transfusions during the study [7 (4%) combined daprodu- ment phase was similar in the combined daprodustat and con- stat; 2 (5%) control], with acute bleeding being the most com- trol groups (Table 5). Of the AEs most frequently reported, mon reason. diarrhea, nausea, hypertension and hyperkalemia were The changes in hemoglobin were associated with expected reported more often in the combined daprodustat group, while changes in hematocrit, RBC count and absolute reticulocyte nasopharyngitis and back pain were reported more often in the count (Supplementary data, Table S4, Item S7). control group. While hyperkalemia was reported as an AE more frequently in the daprodustat group than in the control group (Table 5), the proportion of hyperkalemia events of potential Erythropoietin and VEGF levels clinical importance (potassium >6.3 mmol/L) was slightly Baseline plasma EPO levels were similar across the daprodustat higher in the control group (17%) than in the daprodustat group and control groups. The median maximum observed EPO level (14%). was 36.5 IU/L for the combined daprodustat group and 522.9 IU/L Serious AEs (SAEs) were reported in 31 (18%) participants in for the control group (Table 3). the combined daprodustat group and in 10 (26%) participants in Across the treatment and control groups, plasma VEGF the control group. The most common SAEs in the combined levels were similar at baseline (Table 3). VEGF levels were highly daprodustat group were acute myocardial infarction (MI) and variable at all time points, with no clear signal for a change in cardiac arrest, in three participants each, followed by unstable any treatment group (Table 3). angina, cardiac failure, hypertensive crisis, lobar pneumonia Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 5 Table 2. Baseline and demographic characteristics (ITT population (sPAP) were similar for the daprodustat and control groups and safety population where indicated) (Supplementary data, Table S5, Item S9). An increase of >20 mmHg from baseline in estimated sPAP was observed in Combined eight (7%) participants in the combined daprodustat group and daprodustat Control in no participants in the control group. (n¼ 171) (n¼ 39) Mean changes from baseline in blood pressure (BP) for the combined daprodustat and control groups are presented in Age , years Table 6. Although the mean change from baseline in systolic BP n 171 39 mean (SD) 59.6 (13.3) 59.7 (18.7) was greater in the control group than the combined daprodustat Sex group by 5 mmHg, more participants in the combined dapro- n 171 39 dustat group [22 (12%)] had an increase in the number of antihy- male, n (%) 108 (63) 26 (67) pertensive medications relative to the control group [2 (5%)]. Weight (kg) No adverse trends were noted for clinical laboratory values n 171 39 and electrocardiogram parameters. Furthermore, no changes mean (SD) 77.8 (23.0) 76.3 (19.8) were seen in visual acuity or intraocular pressure based on the a 2 BMI (kg/m ) protocol-specified ophthalmology exams (data not shown). n 170 39 mean (SD) 27.7 (7.5) 27.2 (5.8) Race , n (%) DISCUSSION n 171 39 This study is the largest and longest completed to date in White 124 (73) 23 (59) the HD population switched from rhEPO to treatment with the African American 18 (11) 7 (18) HIF-PHI, daprodustat. Over the first 4 weeks, daprodustat Asian 27 (16) 7 (18) produced dose-dependent changes in hemoglobin up to the Other 2 (1) 2 (5) 10-mg dose, with dose separation noted as early as the first Geographical region , n (%) assessment at 2 weeks. These increases in hemoglobin were n 171 39 associated with the expected increase in absolute reticulocyte Japan 19 (11) 5 (13) North America 44 (26) 13 (33) count, thus supporting increased erythropoiesis as the main Russia 37 (22) 9 (23) driver for daprodustat’s effect on hemoglobin. Rest of the world 71 (42) 12 (31) Over the 24-week treatment phase, daprodustat maintained Mode of dialysis , n (%) hemoglobin levels, with 2 (1%) participants requiring permanent n 177 39 discontinuation of study medication (hemoglobin <7.5 g/dL). Hemodiafiltration 51 (29) 5 (13) Although 17 (10%) participants on daprodustat required a dose HD 120 (68) 33 (85) interruption for hemoglobin 13 g/dL, this was influenced by the Hemofiltration 6 (3) 2 (5) random starting dose allocation, as most excursions occurred a,c Prior rhEPO dose stratification , n (%) with starting doses 8 mg. The proportion of participants on dap- n 171 39 rodustat who were within the hemoglobin target range (58%) at Low rhEPO dose 143 (84) 33 (85) Week 24 is lower than that observed in a recently conducted High rhEPO dose 28 (16) 6 (15) 24-week study in participants with CKD and could be due to par- Baseline hemoglobin level (g/dL) ticipants in this study being assigned to random starting doses n 171 39 (2–12 mg). In the CKD study, starting doses were assigned based mean (SD) 10.4 (0.66) 10.6 (0.94) b on salient baseline parameters (74% in the target range at Week CV risk factors , n (%) 24; [31]). n 177 39 In the daprodustat group, hemoglobin was maintained with Any CV risk factor 166 (94) 38 (97) postdose plasma EPO levels similar to those observed during Hypertension 160 (90) 37 (95) acclimatization to high altitude [19]. In contrast, maximum Hyperlipidemia 85 (48) 20 (51) observed postdose EPO levels in the control group were 14-fold Diabetes mellitus 62 (35) 18 (46) Angina pectoris 13 (7) 2 (5) higher than in the daprodustat group, a finding consistent with prior daprodustat clinical studies [13]. If higher EPO levels Intent-to-treat population. contribute to the cardiovascular risk associated with rhEPO [20], Safety population. then daprodustat may provide a safer cardiovascular risk Low rhEPO dose: <100 IU/kg/week epoetin or <0.5 lg/kg/week darbepoetin; high profile. rhEPO dose: 100 IU/kg/week epoetin or 0.5 lg/kg/week darbepoetin. Consistent with findings from prior trials with daprodustat BMI, body mass index; CV, cardiovascular; ITT, intent-to-treat; IU, international and vadadustat [13, 14, 21], in this 24-week study, daprodustat, unit; rhEPO, recombinant human erythropoietin; SD, standard deviation. as well as the control, had minimal if any effect on VEGF, a known target gene of HIF [22–24]. This is consistent with pre- and pulmonary edema in two participants each. All other clinical work demonstrating that VEGF expression is less sensi- SAEs were reported in one participant each. In the control tive to HIF activation than is EPO expression (GlaxoSmithKline, group, no specific SAE was reported in more than one partici- unpublished data) [25]. pant. A summary of cardiovascular events, including major Participants were iron replete at baseline and an iron proto- adverse cardiovascular events (MACEs) and component end- col provided thresholds for IV iron use to ensure participants points, are summarized in Table 5. Other preidentified AEs of remained replete. Decreases in hepcidin, ferritin and TSAT and interest are described in the Supplementary data, Item S9. increases in total iron-binding capacity (TIBC) during the initial Mean baseline and absolute changes in left ventricular ejec- 4-week, fixed-dose phase corresponded with the increases in tion fraction and estimated systolic pulmonary artery pressure hemoglobin observed across the daprodustat doses studied, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| A.M. Meadowcroft et al. FIGURE 2: Mean change in hemoglobin levels from baseline to Week 4 by treatment group [intent-to-treat (ITT) population]. FIGURE 3: Mean hemoglobin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population]. BL, baseline. Table 3. Levels and change from baseline for EPO and VEGF (ITT population) Combined daprodustat Control (n¼ 171) (n¼ 39) EPO levels (IU/L) Baseline n 163 36 Median (minimum, maximum) 9.2 (2.5, 755.8) 9.3 (2.6, 54.6) Maximum observed EPO level , median (minimum, maximum) 36.5 (5.2, 1379.3) 522.9 (19.0, 51 200.0) Maximum observed CFB in EPO level , median (minimum, maximum) 27.1 (724.5, 1371.6) 512.9 (5.3, 51 195.4) VEGF levels (ng/L) Baseline n 163 36 Median (minimum, maximum) 186.9 (64.3, 1142.6) 220.0 (78.2, 595.7) Maximum observed VEGF median (minimum, maximum) 270.0 (81.8, 808.3) 269.4 (98.7, 924.0) Baseline is the last predose value. Measurements in the daprodustat group were done predose and postdose 6–15 h after dosing; measurement in the control group was performed 5–15 min after dos- ing with rhEPO. CFB, change from baseline; EPO, erythropoietin; ITT, intent-to-treat; IU, international units; rhEPO, recombinant human erythropoietin; VEGF, vascular endothelial growth factor. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 7 Table 4. Changes from baseline for markers of iron metabolism (ITT population) Combined daprodustat (n¼ 171) Control (n¼ 39) Baseline % CFB at Week 24 Baseline % CFB at Week 24 Hepcidin (mg/L) n 171 114 38 32 Geometric mean 388.2 –20.6 334.4 3.6 95% CI 352.9, 427.1 –29.9, –10.0 274.7, 407.1 –20.4, 34.9 TSAT (%) n 171 115 39 32 Geometric mean 29.6 –4.4 30.7 –9.0 95% CI 27.9, 31.5 –11.2, 2.8 27.0, 35.0 –27.3, 13.9 Baseline CFB at Week 24 Baseline CFB at Week 24 Ferritin (mg/L) n 171 115 39 33 Mean 585.1 59.9 459.0 56.8 SD 429.7 331.8 261.0 214.3 TIBC (mmol/L) n 171 115 39 32 Mean 41.6 5.5 41.2 2.0 SD 6.6 6.6 7.2 4.5 Total iron (mmol/L) n 171 115 39 33 Mean 13.4 0.9 13.4 0.8 SD 6.1 6.1 4.9 7.6 CFB, change from baseline; CI, confidence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation. FIGURE 4: Mean hepcidin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population]. which is similar to findings reported with other HIF-PHIs the prespecified iron protocol stopping thresholds, and the [10, 26]. The decrease in ferritin and TSAT and increase in TIBC study duration may have been insufficient to deplete iron stores are consistent with iron utilization due to increased erythropoi- to the point of elucidating a difference between treatments. esis, and the decreased hepcidin could be an effect of the resul- Further work remains to understand the effects of daprodustat tant decreased iron availability. The continued suppression of on iron metabolism and the resultant effects on IV iron require- hepcidin and ferritin observed for the remainder of the trial in ments; these are being tested in a current Phase 3 trial participants on daprodustat may reflect iron stores that (NCT03029208). remained lower than baseline with daprodustat [27]. Although Treatment with daprodustat for up to 24 weeks demon- no difference in IV iron administration between treatment strated an AE profile consistent with the complex medical his- groups was observed, the interpretation of data is confounded tories and cardiovascular comorbidities typical of this patient since many participants continued IV iron despite exceeding population. MACEs occurred more frequently in the daprodustat Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| A.M. Meadowcroft et al. Table 5. AEs and frequency of MACE and component end points in An imbalance was also reported for the number of partici- the combined daprodustat and control groups (safety population) pants with a >20 mmHg increase from baseline in estimated sPAP for the daprodustat group relative to controls, despite Combined mean absolute changes from baseline in estimated sPAP daprodustat Control being similar for both groups. This finding was not dose (n¼ 177) (n¼ 39) related. Changes in fluid status could not be ruled out as a confounder, given that the timing of echocardiograms AEs occurring in 5% of participants (ECHOs) relative to dialysis day was inconsistent both within Any event, n (%) 129 (73) 31 (79) Diarrhea 16 (9) 2 (5) a given participant and between participants in the daprodu- Nasopharyngitis 15 (8) 5 (13) stat and control groups. In a 24-week study in participants Nausea 13 (7) 0 with CKD, who are less prone to fluid shifts as compared with Headache 9 (5) 2 (5) participants on HD, there was no difference in estimated sPAP Hypertension 9 (5) 1 (3) elevations >20 mmHg in those receiving daprodustat com- Hyperkalemia 8 (5) 0 pared with controls [31]. Additionally, dedicated preclinical Back pain 7 (4) 4 (10) data (GlaxoSmithKline, unpublished data) and a clinical study MACE composite in healthy volunteers [28] demonstrated no effect of daprodu- endpoints , n (%) stat on peak right ventricular pressure or sPAP, respectively, Any MACE 7 (4) 0 even in the setting of a hypoxic challenge. Any MACEþ 10 (6) 1 (3) Treatment with daprodustat did not raise BP. Consistent Components of composite with the known AEs of rhEPO [29], the control group had an endpoints , n (%) increase in systolic BP at Week 24. Interpretation of the collec- All-cause mortality 5 (3) 0 tive BP data is complicated by a greater proportion of partici- MI (fatal or nonfatal) 3 (2) 0 pants on daprodustat reporting AEs of hypertension and having Stroke (fatal or nonfatal) 0 0 an increase in the number of antihypertensive medications rel- Hospitalization due to 5 (3) 1 (3) ative to control. These imbalances may be due to more careful heart failure monitoring of BP in the combined daprodustat group, given it is Cardiovascular events, including MACEs, defined as MI, stroke or death, were an investigational drug, and underreporting of events in the collected but were not formally adjudicated. control arm, given the known AE of hypertension with rhEPO. A MACE is defined as a first occurrence of all-cause mortality, a nonfatal MI or a Limitations of this trial include an uneven randomization nonfatal stroke. ratio (4.5:1) resulting in a relatively small control group (n¼ 39) A MACEþ is defined as a first occurrence of a MACE or hospitalization due to and the open-label design from Week 4 onward. Additionally, heart failure. d the tight eligibility criteria limit the generalizability of the find- Includes all events. MACE, major adverse cardiovascular event; MI, myocardial infarction. ings, and the degree of noncompletion and large number of sec- ondary outcomes complicates interpretation of the results. The open-label design could potentially influence how AEs are Table 6. Summary of SBP and DBP at Week 24 (ITT population) reported by participants or recorded by study staff for an inves- tigational medication as compared with the standard of care. Combined For example, more AEs of hyperkalemia were reported in the daprodustat Control daprodustat group than in the control group, despite the fact (n¼ 171) (n¼ 39) that more hyperkalemia events of potential clinical importance SBP (mmHg) were reported in the control group. This kind of bias may also Baseline have been true for the excess reports of nausea with daprodu- n 163 36 stat compared with controls. Nausea is common in patients on Mean (SD) 141.5 (17.4) 139.5 (18.7) dialysis [30]. More AEs of nausea reported in the daprodustat Change from baseline at Week 24 group could have been influenced by daprodustat being an n 112 31 investigational medication or the oral route of daprodustat Mean (SD) 0.7 (18.0) 5.6 (19.3) administration. Cardiovascular events were not formally adju- DBP (mmHg) dicated and the study was not powered for any formal assess- Baseline ment of cardiovascular events. Lastly, the timing of the ECHO n 163 36 assessment relative to HD was not standardized and specific Mean (SD) 74.9 (12.6) 75.5 (11.9) data to determine fluid shifts and estimated dry weight were Change from baseline at Week 24 not collected. n 112 31 Overall, these data demonstrate that daprodustat produced Mean (SD) 0.3 (9.7) 1.3 (11.5) dose-dependent changes from baseline in hemoglobin over the first 4 weeks and, with the dose-adjustment rules applied in Baseline is the last predose value. this trial, daprodustat effectively achieves and maintains hemo- DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation. globin target levels after switching from a stable dose of rhEPO. This efficacy was achieved while maintaining effective plasma group, but these events were underpowered and not adjudi- EPO levels and an AE profile consistent with that of the patient cated, so definitive conclusions cannot be made. A long-term population. These data support continued development of dap- cardiovascular outcome study is ongoing to conclusively assess rodustat to treat anemia of CKD in patients receiving dialysis, these associations. No emerging safety concerns based on the including an ongoing large-scale cardiovascular outcomes trial collective safety data, nor safety signals for any preidentified AE (ASCEND-D) in patients receiving maintenance dialysis who are of interest, were identified for daprodustat. switching from rhEPO and its analogs (NCT02879305) and a trial Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Daprodustat for anemia in HD | 9 in patients who are initiating dialysis (NCT03029208) to assess 3. Locatelli F, Del Vecchio L. New strategies for anaemia man- the safety and efficacy of daprodustat. agement in chronic kidney disease. Contrib Nephrol 2017; 189: 184–188 4. Besarab A, Bolton WK, Browne JK et al. The effects of normal SUPPLEMENTARY DATA as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. Supplementary data are available at ckj online. N Engl J Med 1998; 339: 584–590 5. Dru ¨ eke TB, Locatelli F, Clyne N et al. Normalization of hemo- ACKNOWLEDGEMENTS globin level in patients with chronic kidney disease and ane- mia. N Engl J Med 2006; 355: 2071–2084 The authors thank the investigators and their staff for their 6. Pfeffer MA, Burdmann EA, Chen C-Y et al. A trial of darbepoe- contributions (see ClinicalTrials.gov NCT01977482 for the site tin alfa in type 2 diabetes and chronic kidney disease. N Engl list). The authors acknowledge the following GlaxoSmithKline J Med 2009; 361: 2019–2032 (GSK) employees for their assistance with study management 7. Singh AK, Szczech L, Tang KL et al. Correction of anemia with and critical review: Deborah Kelly, MD, and Douglas Wicks, epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: MPH, CMPP. Authors meet the authorship criteria set forth by 2085–2098 the International Committee of Medical Journal Editors. 8. Jenkins J. Statement regarding erythropoiesis-stimulating Medical editorial support (Nancy Price, PhD, Gautam Bijur, agents (ESA) before the Committee on Ways and Means PhD, and Sarah Hummasti, PhD) and graphic services were Subcommittee on Health, US House of Respresentatives. provided by AOI Communications and were funded by GSK. Washington, DC: US Government Printing Office. https:// B.M.J. was previously affiliated with Clinical Pharmacology www.gpo.gov/fdsys/pkg/CHRG-110hhrg49981/pdf/CHRG- Modeling and Simulation, GlaxoSmithKline, Research Triangle 110hhrg49981.pdf. Published 26 June 2007 (20 December 2017, Park, NC, USA. date last accessed) 9. US Food and Drug Administration. FDA drug safety commu- nication: modified dosing recommendations to improve the FUNDING safe use of erythropoiesis-stimulating agents (ESAs) in Funding for this study (ClinicalTrials.gov: NCT01977482; chronic kidney disease. https://www.fda.gov/Drugs/ EudraCT: 2013-002682-19; GSK PHI113633) was provided by DrugSafety/ucm259639.htm. Published 24 June 2011 (21 GlaxoSmithKline. March 2017, date last accessed) 10. Besarab A, Chernyavskaya E, Motylev I et al. Roxadustat (FG- 4592): correction of anemia in incident dialysis patients. AUTHORS’ CONTRIBUTIONS J Am Soc Nephrol 2016; 27: 1225–1233 The concept and study were designed by A.M.M., B.C., L.H., 11. Provenzano R, Besarab A, Sun CH et al. Oral hypoxia- inducible factor prolyl hydroxylase inhibitor roxadustat (FG- N.B., B.M.J., J.J.L. and A.R.C. A.K.N. and M.A. were in charge 4592) for the treatment of anemia in patients with CKD. Clin J of data acquisition. Statistical analysis was conduted by N.B. Am Soc Nephrol 2016; 11: 982–991 and D.J. All authors reviewed the analysis and interpreted 12. Brigandi RA, Johnson B, Oei C et al. PHI: a novel hypoxia- the data. A.M.M. wrote the initial draft and each author con- inducible factor-prolyl hydroxylase inhibitor (GSK1278863) tributed important intellectual content during manuscript for anemia in CKD: a 28-day, phase 2A randomized trial. Am development and revision. All authors agree to be account- J Kidney Dis 2016; 67: 861–871 able for all aspects of the work. 13. Holdstock L, Meadowcroft AM, Maier R et al. Four-week stud- ies of oral hypoxia-inducible factor-prolyl hydroxylase CONFLICT OF INTEREST STATEMENT inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016; 27: 1234–1244 A.M.M., B.C., N.B., D.J., J.J.L. and A.R.C. are employees of and 14. Pergola PE, Spinowitz BS, Hartman CS et al. Vadadustat, a hold stock in GlaxoSmithKline (GSK). L.H. and B.M.J. are for- novel oral HIF stabilizer, provides effective anemia treat- mer employees of GSK and hold stock options in GSK. A.K.N. ment in nondialysis-dependent chronic kidney disease. received research grants from GSK and research sponsor- Kidney Int 2016; 90: 1115–1122 ship from Affymax. M.A. has no potential conflicts of inter- 15. Mastrogiannaki M, Matak P, Keith B et al. HIF-2a, but not HIF- est to report. This manuscript is not under consideration for 1a, promotes iron absorption in mice. J Clin Invest 2009; 119: publication elsewhere. The results presented in this article 1159–1166 have not been published previously in whole or part, except 16. Liu Q, Davidoff O, Niss K et al. Hypoxia-inducible factor regu- in abstract form. Some of the data included in the present lates hepcidin via erythropoietin-induced erythropoiesis. article were presented at the American Society of J Clin Invest 2012; 122: 4635–4644 17. Mason-Garcia M, Beckman BS, Brookins JW et al. 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J Renal Inj Prev 2017; 6: 49–55 lates erythropoietin production without hypertensive 31. Holdstock L, Cizman B, Meadowcroft AM et al. Daprodustat effects. PLoS One 2014; 9: e111838 for anemia: a 24-week, open-label, randomized controlled 26. Provenzano R, Besarab A, Wright S et al. Roxadustat (FG- trial in participants with chronic kidney disease. Clin Kidney J 4592) versus epoetin alfa for anemia in patients receiving 2018; doi: 10.1093/ckj/sfy013 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy014/4944172 by Ed 'DeepDyve' Gillespie user on 12 July 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Mar 19, 2018

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