Effects of Molidustat in the Treatment of Anemia in Chronic Kidney Disease

CJASN ePress. Published on December 17, 2018 as doi: 10.2215/CJN.02510218 Article

Iain C. Macdougall,1 Tadao Akizawa,2 Jeffrey S. Berns,3 Thomas Bernhardt,4 and Thilo Krueger5

Abstract Background and objectives The efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on 1Department of Renal dialysis (DaIly orAL treatment increasing endOGenoUs Erythropoietin [DIALOGUE] 1 and 2) and in those who Medicine, King’s are on dialysis (DIALOGUE 4). College Hospital, London, UK; 2Division Design, setting, participants, & measurements DIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and of Nephrology, 75 mg once daily; 25 and 50 mg twice daily). DIALOGUE 2 and 4 were open-label, variable-dose trials, in which Department of Medicine, Showa treatment was switched from darbepoetin (DIAGLOGUE 2) or epoetin (DIALOGUE 4) to molidustat or continued University School of with the original agents. Starting molidustat ranged between 25–75 and 25–150 mg daily in DIAGLOGUE 2 and 4, Medicine, Tokyo, respectively, and could be titrated to maintain hemoglobin levels within predefined target ranges. The primary Japan; 3Perelman end point was the change in hemoglobin level between baseline and the mean value from the last 4 weeks of the School of Medicine at the University of treatment period. Pennsylvania, Hospitalofthe Results In DIAGLOGUE 1 (n=121), molidustat treatment was associated with estimated increases in mean University of hemoglobin levels of 1.4–2.0 g/dl. In DIAGLOGUE 2 (n=124), hemoglobin levels were maintained within the Pennsylvania, target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels Philadelphia, Pennsylvania; between molidustat and darbepoetin treatments of up to 0.6 g/dl. In DIAGLOGUE 4 (n=199), hemoglobin levels 4Departments of were maintained within the target range after switching to molidustat 75 and 150 mg, with estimated differences in Pharmaceutials mean change between molidustat and epoetin treatment of 20.1 and 0.4 g/dl. Molidustat was generally well Development, and TA tolerated, and most adverse events were mild or moderate in severity. Cardiology and Nephrology, Bayer AG,Berlin,Germany; Conclusions The overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables and 5Departments of the progression of its development into phase 3. Research and Clin J Am Soc Nephrol 14: ccc–ccc, 2019. doi: https://doi.org/10.2215/CJN.02510218 Development, and Pharmaceuticals, Bayer AG, Wuppertal, Germany Introduction Alternative treatment strategies are therefore worth Anemia is a common and important complication of pursuing for patients with anemia of CKD. One such Correspondence: Prof. Iain C. Macdougall, CKD (1). As CKD worsens, the risk of anemia approach is inhibition of hypoxia-inducible factor – Department of Renal increases (2 4), owing to a combination of several (HIF) prolyl hydroxylases (PHs). HIFs regulate the Medicine, King’s conditions such as reduced erythrocyte lifespan and physiologic response to hypoxia by activating the College Hospital, the reduced synthesis of erythropoietin (5,6). Eryth- transcription of erythropoietin and (to a lesser extent) Denmark Hill, London ropoiesis-stimulating agents (ESAs) mimic the actions several other hypoxia-inducible genes (20), which SE5 9RS, UK. Email: iain.macdougall@nhs. of endogenous erythropoietin and are the standard control multiple processes, including erythropoiesis, net treatment for patients with anemia of CKD (7). angiogenesis, and mitochondrial metabolism (19). In Although ESAs are effective in elevating hemoglobin the presence of oxygen, HIF-PH tags HIF-a subunits levels, their use is associated with an increased risk of for proteasomal degradation, and the transcription of cardiovascular adverse events (AEs) (8–11). This target genes ceases (21,22). appears to be related to the use of high doses to Molidustat (BAY 85–3934) is a novel, orally bio- achieve specified hemoglobin targets (12,13), as well available HIF-PH inhibitor that mimics hypoxia by as excessive increases in hemoglobin levels (14). ESAs stabilizing HIF-a subunits (20). Here, we report data have also been shown to elevate BP in healthy from three phase 2b studies that are part of the volunteers and in patients with CKD (15). Further- DIALOGUE (DaIly orAL treatment increasing en- more, ESAs are ineffective at elevating hemoglobin dOGenoUs Erythropoietin) program, which has levels in 10%–20% of patients, whether they are on been designed to evaluate the efficacy, safety, and dialysis (16,17) or not (18), largely owing to systemic tolerability of molidustat compared with placebo or inflammation and iron deficiency that inhibit the alternative ESA therapy in patients with anemia of erythropoietic response (19). CKD. www.cjasn.org Vol 14 January, 2019 Copyright © 2019 by the American Society of Nephrology 1 lnclJunlo h mrcnSceyo Nephrology of Society American the of Journal Clinical 2

Table 1. Methodological overview of DIALOGUEs 1, 2, and 4

DIALOGUE 1 DIALOGUE 2 DIALOGUE 4 Study Characteristics Clinicaltrials.gov Clinicaltrials.gov Clinicaltrials.gov identifier: NCT02021370a identifier: NCT02021409a identifier: NCT01975818b

Region Europe and the Asia-Pacific Europe and the Asia-Pacific United States and Japan Design Randomized, double-blind, placebo-controlled, Open-label, active comparator-controlled, Open-label, active comparator-controlled, fixed-dose trial variable-dose trial; comparator: variable-dose trial; comparator: epoetin darbepoetin alfa alfa or beta Patient Men and women (aged $18 yr) with a diagnosis of anemia of CKD population Main inclusion ESA-naïve eGFRc ,60 ml/min per 1.73 m2 On stable dose of darbepoetin alfa On stable dose of epoetin alfa/beta; criteria but not on dialysis; mean Hb ,10.5 g/dld eGFRc ,60 ml/min per 1.73 m2 on dialysis; mean Hb 9.0–11.5 g/dlf but not on dialysis; mean Hb 9.0–12.0 g/dle Treatment Fixed doses of molidustat Molidustat (starting doses 25, 50, Molidustat (starting doses 25, 50, 75, (25, 50, or 75 mg once daily; or 75 mg once daily) and plus or 150 mgg and plus optional 15, 100, 25 or 50 mg twice daily) or optional 15, 100, and 150 mg or 200 mg once daily) or continued placebo (1:1:1:1:1:1 randomization) continued darbepoetin treatment epoetin treatment (final (1:1:1:1 randomization) allocation, 1:1:1:0.6:1) Primary end point Mean change in Hb level between baseline and the last 4 wk of treatment Key secondary Change in Hb during first 12 wk of Response to treatmenti; time in target rangei; proportion of patients with Hb levels end pointsh treatment; rate of change of Hb over time above and below target rangei

DIALOGUE, DaIly orAL treatment increasing endOGenoUs Erythropoietin; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin. aRegistered December 2013. bRegistered October 2013. cDefined according to the Modification of Diet in Renal Disease (31) or the formula devised by Matsuo et al. (32). dMean of all local laboratory Hb measurements (at least two measurements must be taken $2 days apart) during the 4-week screening period, with the last screening Hb measurement within 10 days before randomization, all measurements come from the same local laboratory for any given subject, and the difference between the lowest value and the highest value is #1.2 g/dl. eMean of all local laboratory Hb measurements (at least two measurements must be taken $2 days apart) during the 4-week screening period, none of the measurements can be ,9.0 or .12.0 g/dl, none of the measurements can be ,9.0 g/dl, all measurements must come from the same local laboratory for any given subject, and the difference between the lowest level and the highest level is #1.2 g/dl. fMean of all local laboratory Hb measurements (at least two measurements must be taken $2 days apart) during the 4-week screening period, none of the measurements can be ,9.0 or .12.0 g/dl, all measurements come from the same local laboratory for any given subject, and the difference between the lowest level and the highest level is #1.2 g/dl. gAdded after a protocol amendment. hFor a full list of secondary end points, see Supplemental Table 2. iDefinitions of response and target range vary between DIALOGUE 2 and DIALOGUE 4; see Supplemental Table 2 for further information. Clin J Am Soc Nephrol 14: ccc–ccc, January, 2019 Molidustat for Anemia of CKD, Macdougall et al. 3

Enrollment

Assessed for Excluded (n=89) eligibility (n=210) • Screen failure (n=82) • Withdrawal by subject (n=5) • Adverse event (n=1) • Other (n=1) Randomized (n=121)

Allocation

Molidustat Molidustat Molidustat Molidustat Molidustat Placebo 25 mg once daily 50 mg once daily 75 mg once daily 25 mg twice daily 50 mg twice daily • Received allocated • Received allocated • Received allocated • Received allocated • Received allocated • Received allocated intervention (n=19) intervention (n=21) intervention (n=22) intervention (n=19) intervention (n=20) intervention (n=20)

Follow-up

Discontinued from Discontinued from Discontinued from Discontinued from Discontinued from Discontinued from the treatment the treatment the treatment the treatment the treatment the treatment period (n=9) period (n=10) period (n=18) period (n=8) period (n=15) period (n=2) • Protocol driven • Protocol driven • Protocol driven • Protocol driven • Protocol driven • Protocol driven decision point (n=4) decision point (n=8) decision point (n=13) decision point (n=5) decision point (n=14) decision point (n=1) • Adverse event (n=3) • Withdrawal by subject • Adverse event (n=3) • Adverse event (n=2) • Adverse event (n=1) • Other (n=1) • Protocol violation (n=1) • Protocol violation • Lost to follow-up (n=1) • Protocol violation (n=1) (n=1) • Other (n=1) (n=1) • Other (n=1)

Analyses

SAF (n=19) SAF (n=21) SAF (n=22) SAF (n=19) SAF (n=20) SAF (n=20) mITT (n=19) mITT (n=21) mITT (n=22) mITT (n=19) mITT (n=20) mITT (n=20)

Figure 1. | Patient disposition. mITT, modiﬁed intention-to-treat set; SAF, safety analysis set.

Materials and Methods DIALOGUE 5 long-term extension studies. DIALOGUE 1 DIALOGUEs 1, 2, and 4 were 16-week, multicenter, and DIALOGUE 2 were executed in the European Union, parallel group, randomized, controlled phase 2b trials in Israel, South Korea, Australia, and Japan, and DIALOGUE patients with anemia of CKD (Clinicaltrial.gov identi- 4 enrolled patients in the United States and Japan. fiers: NCT02021370, NCT02021409, and NCT01975818, respectively). An overview of each trial is provided in Patient Populations Table 1, with further details below and in Supplemental Key inclusion and exclusion criteria are summarized in – Tables 1 11. Supplemental Table 1 and Table 1. All three trials enrolled adults with anemia of CKD. Patients in DIALOGUE 1 and Study Design DIALOGUE 2 were excluded if they were on dialysis, The design of each study is summarized in Table 1. In whereas DIALOGUE 4 only included patients undergoing DIALOGUE 1, which was placebo-controlled, the aim of long-term, regular hemodialysis. Participants in DIA- treatment was to correct anemia. Both, patients and LOGUE 1 were not permitted to use ESAs in the 8 weeks physicians were blinded to treatment allocation. DIA- before the start of the trial (considered sufficient time for LOGUE 2 and DIALOGUE 4 were open-label trials with pharmacological washout and loss of effects on erythro- the aim of maintaining hemoglobin levels within prede- poiesis). In DIALOGUE 2 and DIALOGUE 4, patients had fined ranges. The comparator was darbepoetin alfa (sub- to be receiving stable doses of darbepoetin or epoetin, sequently referred to as darbepoetin) in DIALOGUE 2 and respectively, in the 8 weeks before randomization. epoetin alfa or beta (subsequently referred to as epoetin) in DIALOGUE 4. Treatments All trials comprised a screening phase (#4weeks)anda In DIALOGUE 1, patients were treated with oral, fixed randomized treatment phase (16 weeks, with an evaluation doses of molidustat or placebo. In DIALOGUE 2, patients phase in the last 4 weeks) (Supplemental Figure 1). At the were randomized to receive one of three starting doses end of the treatment phase, patients were followed up for 8 once daily of oral molidustat (25, 50, or 75 mg) or to weeks or (if eligible) could enter the DIALOGUE 3 or continue darbepoetin treatment. In DIALOGUE 4, patients 4 Clinical Journal of the American Society of Nephrology

Enrollment

Assessed for Excluded (n=72) eligibility (n=196) • Screen failure (n=68) • Withdrawal by subject (n=3) • Other (n=1) Randomized (n=124)

Allocation

Molidustat Molidustat Molidustat Molidustat Darbepoetin 25 mg once daily 50 mg once daily 75 mg once daily Combined • Received allocated • Received allocated • Received allocated • Received allocated • Received allocated intervention (n=32) intervention (n=30) intervention (n=30) intervention (n=32) intervention (n=92) • Did not received • Did not received allocated intervention allocated intervention (n=0) (n=0)

Treatment

Discontinued from Discontinued from Discontinued from Discontinued from Discontinued from the treatment the treatment the treatment the treatment the treatment period (n=9) period (n=5) period (n=6) period (n=20) period (n=5) • Adverse event (n=3) • Sponsor decision (n=1) • Adverse event (n=2) • Sponsor decision (n=1) • Adverse event (n=1) • Death (n=1) • Adverse event (n=4) • Physician decision (n=1) • Adverse event (n=8) • Death (n=1) • Withdrawal by subject • Protocol driven decision • Death (n=1) • Physician decision (n=1) (n=1) point (n=3) • Withdrawal by subject • Protocol driven decision • Physician decision (n=1) (n=1) point (n=2) • Protocol violation (n=1) • Physician decision (n=2) • Protocol driven decision • Protocol violation (n=1) point (n=3) • Protocol driven decision point (n=6)

Analyses

SAF (n=30) SAF (n=30) SAF (n=32) SAF (n=92) SAF (n=32) mITT (n=30) mITT (n=30) mITT (n=32) mITT (n=92) mITT (n=32)

Figure 1. | Continued. were randomized to receive one of three starting doses of Table 2. In all studies, iron supplementation was per in- molidustat once daily (25, 50, or 75 mg) or to continue vestigator discretion. epoetin treatment. After initial efficacy results, a fourth arm was added (once daily 150 mg). Randomization was Efficacy End Points stratified according to previous thromboembolic events The primary efficacy end point in each study was the (all three studies) and hyporesponsiveness to darbepoetin change in hemoglobin level between baseline and the or epoetin (DIALOGUE 2 and DIALOGUE 4, respectively). evaluation phase (the average of all measurements taken Patients in DIALOGUE 1 discontinued the study if they during the last 4 weeks of the treatment phase). Secondary experienced one of the following “stopping events”:he- efficacy end points are summarized in Supplemental Table moglobin level ,8.0 g/dl, hemoglobin level at least 13.0 g/ 3andTable1. dl, or an increase in hemoglobin level of .1.0 g/dl in 2 weeks. In DIALOGUE 2 and DIALOGUE 4, the doses of all Tolerability and Safety End Points drugs could be titrated up or down in a stepwise manner, Safety and tolerability were assessed by evaluating to maintain hemoglobin levels within predefined target AEs, heart rate, BP, electrocardiogram results, and lab- ranges (Supplemental Figure 2). Darbepoetin and epoetin oratory parameters. The latter included measures of iron were titrated according to the local label. Except in metabolism (iron, ferritin, total iron binding capacity, emergencies, dose titration was only permitted on days unsaturated iron binding capacity, transferrin saturation, 29, 57, and 85, although the dose could be reduced on day and hepcidin) and plasma lipid levels. In addition, 24- 15 if hemoglobin levels rose excessively. If hemoglobin hour ambulatory BP monitoring (ABPM) was conducted became too high (.13.0 g/dl or a rise in hemoglobin of at baseline, at the end of week 8, and at the end of .1.0 g/dl in 2 weeks), molidustat could be titrated down treatmentinDIALOGUE1andinasubsetofpatientsin or suspended. The daily average doses of molidustat in DIALOGUE 4. An independent adjudication commit- DIALOGUE 2 and DIALOGUE 4 are reported in Supplemental tee assessed all deaths and any serious AEs of severe Clin J Am Soc Nephrol 14: ccc–ccc, January, 2019 Molidustat for Anemia of CKD, Macdougall et al. 5

Enrollment

Excluded (n=148) Assessed for • Screen failure (n=140) eligibility (n=347) • Withdrawal by subject (n=5) • New site (n=1) • Study terminated by sponsor (n=1) Randomized • Adverse event (n=1) (n=199)

Allocation

Molidustat Molidustat Molidustat Molidustat Molidustat Epoetin 25 mg once daily 50 mg once daily 75 mg once daily 150 mg once daily Combined alfa/beta • Received allocated • Received allocated • Received allocated • Received allocated • Received allocated • Received allocated intervention (n=44) intervention (n=40) intervention (n=44) intervention (n=29) intervention (n=157) intervention (n=42) • Did not received • Did not received allocated intervention allocated intervention (n=0) (n=0)

Treatment

Discontinued from Discontinued from Discontinued from Discontinued from Discontinued from Discontinued from the treatment the treatment the treatment the treatment the treatment the treatment period (n=14) period (n=16) period (n=14) period (n=9) period (n=53) period (n=3) • Adverse event (n=7) • Adverse event (n=10) • Adverse event (n=10) • Adverse event (n=3) • Adverse event (n=30) • Adverse event (n=2) • Withdrawal by subject • Death (n=1) • Withdrawal by subject • Withdrawal by subject • Death (n=1) • Other (n=1) (n=3) • Withdrawal by subject (n=2) (n=3) • Withdrawal by subject • Protocol driven (n=3) • Protocol violation • Protocol violation (n=11) decision point (n=3) • Protocol violation (n=1) (n=2) • Protocol violation • Other (n=1) (n=1) • Protocol driven • Other (n=1) (n=4) • Other (n=1) decision point (n=1) • Protocol driven decision point (n=4) • Other (n=3)

Analyses

SAF (n=44) SAF (n=40) SAF (n=44) SAF (n=29) SAF (n=157) SAF (n=42) mITT (n=44) mITT (n=40) mITT (n=44) mITT (n=29) mITT (n=157) mITT (n=42)

Figure 1. | Continued. arrhythmias, thromboembolic events, syncope or symp- Ethics tomatic hypotension, or heart failure. All studies were conducted in compliance with the principles of the Declaration of Helsinki and in accordance Statistical Analyses with Good Clinical Practice guidelines. The protocols were Efficacy was assessed using observed case data from reviewed and approved by the institutional review board or the modified intention-to-treat set (all patients who were ethics committee of each participating center. All patients randomized, received at least one dose of study agent, provided written informed consent before study entry. and had at least one postbaseline efficacy value recor- ded). The estimates and the confidence intervals of the Results changes in hemoglobin levels were calculated using an Patient Disposition and Baseline Characteristics analysis of covariance model. The safety analysis set (all The numbers of patients randomized were 121 (DI- patients who were randomized and received at least one ALOGUE 1), 124 (DIALOGUE 2), and 199 (DIALOGUE 4). dose of study agent) was used to analyze safety vari- Patient disposition, including the number and reasons for ables. Within each study, safety analyses were per- discontinuation, during each of the three studies is shown formed in individual and pooled molidustat dose in Figure 1. The numbers of patients in DIALOGUE 1 who groups. Sample sizes were on the basis of external discontinued because of stopping events (25 mg once daily, benchmarks (e.g., sample sizes used in previous phase n=10; 50 mg once daily, n=9; 75 mg once daily, n=17; 25 mg 2 studies of treatments for anemia of CKD) and feasi- twice daily, n=8; and 50 mg twice daily, n=17) were almost bility, rather than statistical considerations. Further exclusively because of high hemoglobin levels. details of the statistical analyses are provided in Sup- Baseline demographic and clinical characteristics are plemental Material. summarized in Supplemental Table 4 and Table 2. In all 6 Clinical Journal of the American Society of Nephrology

Table 2. Baseline demographics and clinical characteristics in DIALOGUEs 1, 2, and 4

DIALOGUE 1 DIALOGUE 2 DIALOGUE 4 Patient Characteristics Molidustata Placebo Molidustata Darbepoetin Molidustata Epoetin (n=101) (n=20) (n=92) (n=32) (n=157) (n=42)

Mean age, yr (SD) 69 (12) 67 (16) 68 (11) 69 (9) 59 (13) 59 (9) Women, n (%) 45 (45) 11 (55) 47 (51) 14 (44) 66 (42) 13 (31) Race, n (%) White 63 (62) 15 (75) 69 (75) 25 (78) 84 (54) 18 (43) Asian 38 (38) 5 (25) 22 (24) 6 (19) 29 (18) 7 (17) Black 0 0 1 (1) 1 (3) 40 (25) 17 (40) Other 0 0 0 0 4 (3) 0 Mean CKD duration, yr (SD) 4.5 (4.5) 3.5 (2.7) 6.7 (6) 5.8 (5) 6 (6.2) 6 (4.3) Mean dialysis therapy duration, yr (SD) ––– – 5 (5.2) 5 (4.0) CKD etiology, n (%)b Diabetes 45 (45) 9 (45) 31 (34) 10 (31) 86 (55) 24 (57) Hypertension 45 (45) 6 (30) 31 (34) 13 (41) 48 (31) 18 (43) Mean eGFR, ml/min per 1.73 m2 (SD)c 23 (12) 23 (12) 20 (11) 22 (12) Mean Hb level, g/dl (SD) 9.5 (0.7) 9.5 (0.6) 10.8 (0.7) 10.9 (0.7) 10.5 (0.6) 10.6 (0.5) Mean prior ESA dose (mg/kg per wk) before ––0.2 (0.2) 0.3 (0.2) 114 (98) 103 (89) randomization (SD) Mean C-reactive protein, mg/L (SD) 7.2 (16.4) 4.3 (5.1) 7.4 (14.9) 6.5 (11.2) 0.8 (1.4) 0.7 (1.1)

DIALOGUE, DaIly orAL treatment increasing endOGenoUs Erythropoietin; –, not applicable; Hb, hemoglobin; ESA, erythropoiesis- stimulating agents. aFor DIALOGUE 2 and DIALOGUE 4, doses represent starting doses only. bPatients could have more than one etiology of CKD and the two most common etiologies are shown here. Other etiologies included autoimmune disease, cardiac diseases, GN, infection, and polycystic kidney disease. ceGFR was calculated using the Modiﬁcation of Diet in Renal Disease formula.

three studies, treatment groups were well balanced with remained within the target range during the 16-week respect to key baseline characteristics such as age, eGFR, treatment period (Figure 2C). Mean hemoglobin levels and hemoglobin values. increased again toward the end of the treatment period in the 25 and 50 mg once daily groups, after dose titrations. Primary Efficacy End Point The estimated mean changes and corresponding confi- Secondary Efficacy End Points dence intervals in hemoglobin level from baseline to the In DIALOGUE 1, the increase in hemoglobin leveled off evaluation period for the three studies are summarized in over time (Figure 2A); however, this apparent plateau has Table 3. predominantly been influenced by high levels of protocol- In DIALOGUE 1, mean hemoglobin levels in the moli- defined patient discontinuations because of overshooting dustat groups increased from baseline during the first 12 hemoglobin levels and/or exaggerated hemoglobin in- weeks of treatment and began to separate from those of the crease. placebo group at week 5. There were increases in hemo- In DIALOGUE 2, the response rate (as defined in globin level in each molidustat group between baseline and Supplemental Table 3) was numerically higher in the the evaluation period compared with placebo (Figure 2A, darbepoetin group (89%) than in the molidustat starting Table 3). dose groups (71%, 81%, and 61% for the 25, 50, and 75 mg In DIALOGUE 2, mean hemoglobin levels were main- dose groups, respectively). The mean (SD) percentage of tained within the target range (10.0–12.0 g/dl) for each days within the hemoglobin target range (10–12 g/dl) were molidustat dose group (Figure 2B). The mean change in also numerically higher in the darbepoetin group (83%, SD hemoglobin level between baseline and the evaluation 25) than in the molidustat dose groups (66%, SD 34; 71%, period appeared to be numerically greater with the moli- SD 31; and 56%, SD 30 for the 25, 50, and 75 mg dose dustat 75 mg once daily starting dose than with darbe- groups, respectively), with no evidence of a dose-response poetin (Table 3). effect with molidustat (Supplemental Table 6A). The pro- In DIALOGUE 4, there was a numerically small mean portion of patients with hemoglobin levels .12.0 g/dl was increase in hemoglobin levels between baseline and the numerically higher with molidustat (15%, 12%, and 29% for evaluation period in the molidustat 150 mg once daily the 25, 50, and 75 mg dose groups, respectively) than with group; there were small mean decreases in the other darbepoetin (3.6%). treatment groups (Table 3). Mean hemoglobin levels in In DIALOGUE 4, the response rates (as defined in the two lowest molidustat starting dose groups (25 and 50 Supplemental Table 3) in the molidustat groups were vari- mg once daily) fell below the target range (10.0–11.0 g/dl) able and were numerically lower (43%, 22%, 19%, and 40.0% in the first weeks of treatment, whereas mean hemoglobin for the 25, 50, 75, and 150 mg dose groups, respectively) than levels for the 75 and 150 mg once daily starting doses that seen with epoetin (49%). The mean (SD) percentage of Clin J Am Soc Nephrol 14: ccc–ccc, January, 2019 Molidustat for Anemia of CKD, Macdougall et al. 7

Table 3. Changes from baseline in mean local hemoglobin at evaluation period by starting dose in DIALOGUE 1, DIALOGUE 2, and DIALOGUE 4

Within-Group Change from Baseline Between-Group Comparison

Baseline Evaluation LS Mean 95% CI for LS Difference in LS 95% CI Starting Dose Group n Mean Period Mean Change Mean Change Mean Change for Difference

DIALOGUE 1 Molidustat 25 mg 12 9.5 10.9 1.4 (0.7 to 2.1) 1.3 (0.5 to 2.0) once daily Molidustat 50 mg 11 9.7 11.1 1.5 (0.7 to 2.3) 1.3 (0.5 to 2.0) once daily Molidustat 75 mg 5 10.0 11.8 1.8 (0.9 to 2.7) 1.7 (0.7 to 2.7) once daily Molidustat 25 mg 13 9.4 11.1 1.5 (0.8 to 2.3) 1.5 (0.7 to 2.2) twice daily Molidustat 50 mg 9 9.4 11.2 2.0 (1.1 to 2.8) 1.7 (0.8 to 2.5) twice daily Molidustat 50 9.5 11.1 1.6 (1.2 to 2.0) 1.4 (0.9 to 2.0) combined Placebo 19 9.6 9.7 0.2 (20.4 to 0.7) DIALOGUE 2 Molidustat 25 mg 26 11.0 11.1 0.4 (20.1 to 1.0) 0.0 (20.4 to 0.5) once daily Molidustat 50 mg 26 10.8 11.2 0.5 (0.1 to 0.9) 0.2 (20.2 to 0.6) once daily Molidustat 75 mg 28 10.7 11.5 0.9 (0.5 to 1.3) 0.6 (0.2 to 0.9) once daily Molidustat 80 10.8 11.3 0.5 (0.2 to 0.9) 0.2 (20.1 to 0.6) combined Darbepoetin 28 10.9 11.1 0.3 (20.1 to 0.7) DIALOGUE 4 Molidustat 25 mg 32 10.4 9.6 22.4 (23.4 to 21.4) 20.8 (21.3 to 20.4) once daily Molidustat 50 mg 27 10.4 9.9 22.2 (23.2 to 21.2) 20.5 (21.0 to 20.0) once daily Molidustat 75 mg 32 10.5 10.4 20.1 (21.0 to 0.7) 20.1 (20.6 to 0.4) once daily Molidustat 150 20 10.7 10.7 20.8 (21.4 to 20.1) 0.4 (20.1 to 0.8) mg once daily Molidustat 111 10.5 10.1 20.7 (21.3 to 0.0) 20.3 (20.7 to 0.1) combined Epoetin 39 10.6 10.4 20.4 (21.1 to 0.4)

n is number of subjects at evaluation period. LS mean and difference in LS mean are on the basis of analysis of covariance model including treatment, randomization stratiﬁcation, factors, and baseline as a covariate. DIALOGUE, DaIly orAL treatment increasing endOGenoUs Erythropoietin; LS, least square; 95% CI, 95% conﬁdence interval.

days within the hemoglobin target range of 10.0–11.0 g/dl and95daysinthemolidustatgroupsand112daysinthe were also numerically lower in the molidustat groups epoetin group in DIALOGUE 4. (34%, SD 29; 27%, SD 25; 27%, SD 26; and 38%, SD 28 for In DIALOGUE 1, the incidences of treatment-emergent the 25, 50, 75, and 150 mg dose groups, respectively) than in adverse events (TEAEs) and serious TEAEs in the molidu- the epoetin group (47%, SD 26), with no evidence of a dose- stat combined-dose group were numerically lower than response effect with molidustat (Supplemental Table 6B). those seen in the placebo group. The incidence of TEAEs in Compared with the epoetin group (23.1%), a numerically DIALOGUE 2 was numerically higher in the molidustat higher proportion of patients treated with the molidustat combined-dose group than in the darbepoetin group, and the 150 mg once daily starting dose (40.0%) had hemoglobin incidence of study drug-related TEAEs in both DIALOGUE 2 levels .11.0 g/dl. Data on rescue treatment are given in and DIALOGUE 4 was numerically higher in the molidustat Supplemental Table 7. groups than in the darbepoetin/epoetin groups (Table 4). Most TEAEs in each of the three studies were mild or Tolerability and Safety moderate in intensity. The most common TEAEs in each The mean duration of exposure to study agent was 75 study are shown in Table 5 (common TEAEs by molidustat days in the molidustat groups and 109 days in the placebo dose group are given in Supplemental Table 8). group in DIALOGUE 1, 105 days in the molidustat groups Study drug-related serious TEAEs occurred in only one and and 103 days in the darbepoetin group in DIALOGUE 2, two patients in the molidustat groups of DIALOGUE 2 and 8 Clinical Journal of the American Society of Nephrology

Treatment Molidustat starting dose 25 mg daily Molidustat starting dose 25 mg twice daily Molidustat starting dose 50 mg daily Molidustat starting dose 50 mg twice daily 12.5 Molidustat starting dose 75 mg daily Placebo 12.0 11.5 11.0 10.5 10.0 9.5 9.0

Mean (SE) local Hb level (g/dL) 0.0 2Bsl 3 4 5 6 7 8 9 10 11 12 Eva Visit Number of patients 25 mg OD 19 19 19 19 16 16 15 13 12 10 10 10 12 50 mg OD 21 21 20 19 13 13 10 11 10 11 11 11 11 75 mg OD 22 22 22 20 16 13 10 9 5 4 4 4 5 25 mg BID 19 19 18 16 16 14 13 13 13 13 12 12 13 50 mg BID 20 20 20 19 15 12 10 9 9 8 8 6 9 Placebo 20 20 19 20 20 19 19 19 18 18 18 18 19

Treatment Molidustat starting dose 25 mg daily Molidustat starting dose 75 mg daily 12.5 Molidustat starting dose 50 mg daily Darbepoetin

12.0

11.5

11.0

10.5

10.0

Mean (SE) local Hb level (g/dL) 0.0 2Bsl 3 4 5 6 7 8 9 10 11 12 Eva Visit Number of patients 25 mg OD 30 30 30 29 28 28 27 26 26 24 23 22 26 50 mg OD 30 30 30 29 28 28 27 26 24 26 24 25 26 75 mg OD 32 32 30 31 31 31 30 29 27 27 28 28 28 Darbeotin 32 29 30 30 29 29 27 28 27 27 26 27 28

Treatment Molidustat starting dose 25 mg daily Molidustat starting dose 150 mg daily 12.0 Molidustat starting dose 50 mg daily Epoetin Molidustat starting dose 75 mg daily 11.5

11.0

10.5

10.0

9.5

9.0

Mean (SE) local Hb level (g/dL) 0.0 Bsl2 345678910111312 Eva Visit Number of patients 25 mg OD 44 41 40 40 41 41 35 32 31 32 29 29 29 32 50 mg OD 40 38 37 38 38 35 34 27 27 26 27 25 25 27 75 mg OD 44 44 40 40 41 41 35 35 31 32 31 31 31 32 150 mg OD 29 27 27 27 24 24 24 23 20 19 18 18 20 20 Epoetin 42 40 41 39 42 40 42 39 39 36 38 37 39 39

Figure 2. | Molidustat was able to correct (DIALOGUE 1) and maintain Hb levels within a pre-specified range (DIALOGUE 2 and 4 [75 and 150 mg starting dose groups only]). Observed case data from modified intention-to-treat populations. Baseline was defined as the average of Clin J Am Soc Nephrol 14: ccc–ccc, January, 2019 Molidustat for Anemia of CKD, Macdougall et al. 9

Table 4. Overall adverse event proﬁle during treatment with molidustat or placebo/active comparator during DIALOGUEs 1, 2, and 4

DIALOGUE 1 DIALOGUE 2 DIALOGUE 4 TEAEs Molidustata Placebo Molidustata Darbepoetin Molidustata Epoetin (n=101) (n=20) (n=92) (n=32) (n=157) (n=42)

Any TEAE 67 (66) 16 (80) 64 (70) 17 (53) 126 (80) 32 (76) Any study drug-related TEAE 12 (12) 2 (10) 8 (9) 0 41 (26) 4 (10) Maximum intensity for any TEAE Mild 44 (44) 7 (35) 30 (33) 7 (22) 50 (32) 12 (29) Moderate 18 (18) 8 (40) 29 (32) 6 (19) 43 (27) 13 (31) Severe 5 (5) 1 (5) 5 (5) 4 (13) 33 (21) 7 (17) Any serious TEAE 14 (14) 5 (25) 19 (21) 6 (19) 34 (22) 7 (17) Any study drug-related serious 001(1)02(1)0 TEAE Any TEAE resulting in death 0 0 1 (1) 1 (3) 1 (1) 0 Any study drug-related TEAE 000 0 00 resulting in death

All data are given as n (%). All TEAEs reported were determined by the investigator. DIALOGUE, DaIly orAL treatment increasing endOGenoUs Erythropoietin; TEAE, treatment-emergent adverse event. aCombined-dose groups.

DIALOGUE 4, respectively (hyponatremia, prolonged QT 24-hour ABPM indicated that molidustat does not increase interval, and hypotension). Five, four, and 11 serious AEs BP. In DIALOGUE 1, molidustat had neither a beneficial overall (three, two, and nine in the molidustat groups) were nor a detrimental effect on BP relative to placebo, although positivelyadjudicatedinDIALOGUEs1,2,and4,respectively. the incidence of hypertension-related AEs was lower for Except for one report of a significant increase in alanine molidustat (10%) than for placebo (25%). transaminase levels in the placebo group of DIALOGUE 1, no liver function-related AEs were reported during the studies. Discussion There were generally no notable changes in laboratory The global, phase 2 DIALOGUE program was designed parameters, with the exception of measures of iron metab- to evaluate comprehensively the safety, efficacy, tolerabil- olism. In DIALOGUE 1, mean ferritin and hepcidin values ity, pharmacokinetics, and pharmacodynamics of molidu- decreased over time in the molidustat groups, whereas stat in patients with anemia of CKD, in individuals not on mean total and unsaturated iron binding capacity increased dialysis (DIALOGUE 1 and DIALOGUE 2) and in those on (Supplemental Tables 9A and 10A). In the placebo group, dialysis (DIALOGUE 4). iron metabolism parameters remained near baseline val- The fixed-dose, placebo-controlled study (DIALOGUE 1) ues, except for ferritin, which showed a transient increase. demonstrated that molidustat provides increases in hemo- In DIALOGUE 2, there were mean reductions (between globin levels in patients not on dialysis. The observed baseline and the end of treatment) in hepcidin and iron plateau in hemoglobin levels at later time points is largely levels in the molidustat groups compared with an increase because of the discontinuation rate caused by high hemo- in the darbepoetin group (Supplemental Tables 9B and globin values. This should not be interpreted as a plateau of 10B). In DIALOGUE 4, mean changes in iron metabolism the mode of action, i.e., stimulation of erythropoiesis. No parameters were similar in the molidustat and epoetin such plateau has been observed in preclinical experiments groups (Supplemental Tables 9C and 10C). (20). Efficacy in patients not on dialysis was also demon- Changes in LDL cholesterol between baseline and the strated in DIALOGUE 2, in which treatment was switched end of treatment were small; in DIALOGUE 1: mean (SD) from darbepoetin to molidustat or continued with darbe- changes were 0.7 (28.9) mg/dl in the combined molidustat poetin. All molidustat dose arms were able to maintain the group and 3.3 (30.7) mg/dl in the placebo group. Mean hemoglobin within the prespecified target range of 10.0– (SD) changes in DIALOGUE 2 were 1.9 (24) mg/dl in the 12.0 g/dl. The results, however, suggest that a molidustat combined molidustat group and 21.3 (18.7) mg/dl in the starting dose of 25 or 50 mg once daily may be more darbepoetin group. In DIALOGUE 4, mean (SD) changes appropriate in this patient population than 75 mg once were 20.7 (22.3) mg/dl in the combined molidustat group daily, which appears to be associated with an increased and 0.2 (15.7) mg/dl in the epoetin group. likelihood of hemoglobin levels rising above prespecified There were generally no notable changes in vital signs limits compared with continued darbepoetin. This is or electrocardiogram results in the three studies. Results of consistent with the findings from DIALOGUE 1, in which

Figure 2. | Continued. all values before dosing with the ﬁrst study agent. Dashed lines indicate target ranges. In DIALOGUE 2 and DIALOGUE 4, the doses of all drugs could be titrated up or down in a stepwise manner to maintain hemoglobin levels within predeﬁned target ranges. Error bars indicate SEM. Bsl, baseline; Eva, evaluation period; Hb, hemoglobin. 10 Clinical Journal of the American Society of Nephrology

Table 5. Treatment-emergent adverse events reported in >10% of patients in any group in DIALOGUEs 1, 2, and 4

TEAEs Molidustat Combined-Dose Group Control Groupa

DIALOGUE 1 n=101 n=20 Hyperparathyroidism, secondary 1 (1) 3 (15) Constipation 5 (5) 1 (5) Diarrhea 4 (4) 1 (5) Vomiting 2 (2) 1 (5) Nasopharyngitis 7 (7) 2 (10) Urinary tract infection 4 (4) 3 (15) Hyperkalemia 4 (4) 3 (15) Dizziness 5 (5) 3 (15) Hypertension 10 (10) 5 (25) DIALOGUE 2 n=92 n=32 Diarrhea 5 (5) 1 (3) Edema, peripheral 8 (9) 2 (6) CKD 10 (11) 0 Hypertension 14 (15) 4 (13) DIALOGUE 4 n=157 n=42 Diarrhea 12 (8) 2 (5) Nausea 8 (5) 2 (5) Vomiting 6 (4) 0 Nasopharyngitis 9 (6) 1 (2) Hemoglobin, decreasedb 15 (10) 2 (5) Hemoglobin, increasedb 13 (8) 2 (5) Hypertension 17 (11) 8 (19)

All data are given as n (%). DIALOGUE, DaIly orAL treatment increasing endOGenoUs Erythropoietin; TEAE, treatment-emergent adverse event. aPatients in the control group received placebo in DIALOGUE 1, continued darbepoetin treatment in DIALOGUE 2, and continued epoetin treatment in DIALOGUE 4. bAs judged by the investigator.

more stopping events were caused by high hemoglobin study of vadadustat (23) and two studies of roxadustat levels in the molidustat 75 mg once daily group than in the (24,25), as well as a placebo-controlled study of daprodu- 25 and 50 mg once daily groups. stat (26) and a dose-ranging study of daprodustat in both In patients on dialysis (DIALOGUE 4), only molidustat patients not on dialysis and those on hemodialysis (27); the starting doses of 75 and 150 mg once daily maintained results show that all agents increase and maintain hemo- hemoglobin levels within the target range after switching globin levels in these patients. Two additional roxadustat from epoetin. This was not unexpected, given the level of studies (also phase 2) have been conducted in patients on kidney function impairment of patients in this study. dialysis (28,29). In one of these, patients taking epoetin had Indeed, although both kidney and hepatic erythropoietin their treatment switched to roxadustat or continued on production are affected, molidustat mainly addresses epoetin, and the results show that hemoglobin levels were kidney erythropoietin production (20). In patients receiv- maintained when patients were switched to the HIF-PH ing dialysis treatment, switching from injectable ESA to inhibitor (29). The above-mentioned phase 2 trials on molidustat 25 or 50 mg once daily resulted in an initial daprodustat also enrolled patients on hemodialysis; in temporary drop in hemoglobin; understanding the un- one trial, patients were on sufficient epoetin treatment derlying reasons for this would require further exploration before starting daprodustat, and the second trial enrolled in a future trial. Compared with the epoetin group, patients epoetin-naïve patients. Hemoglobin was maintained in the treated with molidustat starting doses of 75 or 150 mg once switching study and it was increased in patients naïve to daily had lower response rates, spent less time within the epoetin treatment. target hemoglobin range, and were more likely to have Molidustat was generally well tolerated during the hemoglobin levels above the prespecified limit. In both the DIALOGUE studies. In DIALOGUE 2 and DIALOGUE 4, DIALOGUE 2 and DIALOGUE 4 studies, the reduced time the increased incidence of TEAEs in the molidustat groups in the target hemoglobin range compared with darbepoe- compared with that observed in the darbepoetin/epoetin tin/epoetin may reflect the inclusion criterion that therapy groups was not unexpected, given that the studies were in the darbepoetin/epoetin groups was stable before the open label and that the darbepoetin/epoetin doses had start of the study treatment period. been stabilized before the studies started. Of note, in the Several other HIF-PH inhibitors are in clinical develop- blinded DIALOGUE 1 trial, such imbalances were not seen. ment for anemia of CKD. These include vadadustat (AKB- The DIALOGUE studies were not powered to evaluate the 6548), roxadustat (FG-4592), and daprodustat signal for thromboembolic events compared with comparator (GSK1278863). Published phase 2 studies in patients with ESAs; however, serious thromboembolic events were inde- CKD who are not on dialysis include a placebo-controlled pendently adjudicated. A few of these occurred in the Clin J Am Soc Nephrol 14: ccc–ccc, January, 2019 Molidustat for Anemia of CKD, Macdougall et al. 11

molidustat treatment groups, but none were judged to be relevant information is provided in thestudy sponsors section of the related to therapy by the investigator (Supplemental Table 11). portal. Data access will be granted to anonymized patient-level Another recognized side effect of ESA therapy is hypertension data, protocols, and clinical study reports after approval by an (30). Data from these studies indicate that BP, which was independent scientific review panel. Bayer is not involved in the measured using 24-hour ABPM, was not increased by moli- decisions made by the independent review panel. Bayer will take all dustat; in fact, there was some suggestion that molidustat necessary measures to ensure that patient privacy is safeguarded. treatment may slightly decrease BP, although the small patient These studies were funded by Bayer AG. numbers preclude firm conclusions. Study concept, protocol, and statistical analysis plan as well as The DIALOGUE studies have several limitations. These analyses were performed on the basis of recommendations by both include low patient numbers per treatment group and a the steering committee and the sponsor. Interpretations were made relatively short duration of treatment contributing to the by the independent steering committee (authors of the manuscript) changes in hemoglobin levels observed after treatment initi- only. ation; however, this is customary for phase 2 clinical studies, which serve to provide data from which to design larger, Disclosures longer phase 3 trials. Other design elements of the DIALOGUE I.C.M. received research funding for the DIALOGUE studies, 1 study were robustness, as it included a placebo arm and was honoraria for steering committee activities, and speaker fees from double-blinded, whereas DIALOGUE 2 and DIALOGUE 4 Bayer. He has also received research support and speaker’s hono- were open label, which may have introduced bias (e.g.,inAE raria from Akebia, Astellas, FibroGen, and GlaxoSmithKline. T.A. reporting). Discontinuation rates in all three studies were received consulting fees from Astellas, Bayer Health Care, relatively high. However, for DIALOGUE 1, this mainly GlaxoSmithKline, JT Pharmaceuticals, Kissei Pharmaceutical Co. fl re ects the inclusion of stopping rules in the event of low/ Ltd., Kyowa Hakko Kirin, Nipro Corporation, Fuso Pharmaceutical high hemoglobin levels as well as exaggerated hemoglobin Industries Ltd., and Ono Pharmaceutical Co. Ltd., and lecture fees increase, designed to safeguard patients in the study because from Bayer Health Care, Chugai Pharmaceutical Co. Ltd., Kyowa fi dose modi cations were not permitted. In DIALOGUE 2 and Hakko Kirin, and Torii Pharmaceutical Co. Ltd. J.S.B. served on the DIALOGUE 4, completion rates in patients treated with steering committees for the DIALOGUE studies and for an Amgen- molidustat were lower than patients treated with darbepoetin sponsored darbepoetin clinical trial. T.B. and T.K. are employees of fl or epoetin, but again, this likely re ectsthefactthatESAdoses Bayer Pharma AG. were stable before patients entered the study. In conclusion, results of these phase 2b studies indicate This article contains the following supplemental material online that the overall efficacy/safety profile of molidustat en- at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/ ables further development in both patients with CKD who CJN.02510218/-/DCSupplemental. are not on dialysis and those with CKD who are on dialysis. Hemoglobin levels can be maintained after switching from Supplemental Material ESAs to a flexible dose of molidustat, with manageable side Supplemental Table 1. Key inclusion and exclusion criteria for effects. No serious thromboembolic events were related to DIALOGUEs 1, 2, and 4. treatment. Continued evaluation of molidustat in larger Supplemental Table 2. Daily average dosages of molidustat in (A) phase 3 studies is warranted. DIALOGUE 2 and (B) DIALOGUE 4. Supplemental Table 3. Secondary efficacy variables in the Acknowledgments DIALOGUE program 10. Medical writing support was provided by Jesse Alderson of Supplemental Table 4. Baseline demographics and clinical char- Oxford PharmaGenesis, Oxford, UK, with funding from Bayer AG. acteristics in DIALOGUEs 1, 2, and 4. Statistical analysis and interpretation of results was supported by Supplemental Table 5. Changes from baseline in mean local Gerald Staedtler, Bayer AG. hemoglobin at evaluation period by starting dose in DIALOGUE 1, Availability of the data underlying this publication will be de- DIALOGUE 2, and DIALOGUE 4 (last observation carry forward). termined according to Bayer’s commitment to the European Supplemental Table 6. Time within the hemoglobin range during Federation of Pharmaceutical Industries and Associations/Phar- treatment with molidustat andactive treatment in DIALOGUE 2and maceutical Research and Manufacturers of America “Principles for DIALOGUE 4. responsible clinical trial data sharing.” This pertains to scope, time Supplemental Table 7. Patients receiving red blood cell trans- point, and process of data access. As such, Bayer commits to sharing fusion and ESA treatment for low hemoglobin as rescue treatment upon request from qualified scientific and medical researchers pa- during the study by study and starting dose. tient-level clinical trial data, study-level clinical trial data, and pro- Supplemental Table 8. TEAEs reported in .10% of patients in any tocols from clinical trials in patients for medicines and indications group in DIALOGUEs 1, 2, and 4 by molidustat dose group. approved in the United States and European Union as necessary for Supplemental Table 9. Baseline values of measures of iron conducting legitimate research. This applies to data on new medi- metabolism in DIALOGUE 1, DIALOGUE 2, and DIALOGUE 4. cines and indications that have been approved by the European Supplemental Table 10. Changes in measures of iron metabolism Union and United States regulatory agencies on or after January 1, between baseline and end of treatment in DIALOGUE 1, DIA- 2014. LOGUE 2, and DIALOGUE 4. Interested researchers can use www.clinicalstudydatarequest. Supplemental Table 11. Patients with thromboembolic events in com to request access to anonymized patient-level data and sup- any group in DIALOGUEs 1, 2, and 4 by molidustat dose group. porting documents from clinical studies to conduct further research Supplemental Figure 1. Study design of (A) DIALOGUE 1, (B) that can help advance medical science or improve patient care. DIALOGUE 2, and (C) DIALOGUE 4. Molidustat doses were Information on the Bayer criteria for listing studies and other suspended if Hb was .13.0 g/dl or if the rise in Hb was .1.0 g/dl 12 Clinical Journal of the American Society of Nephrology

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Correction In Supplemental Table 4, the mean CRP (SD) Macdougall IC, Akizawa T, Berns JS, Bernhardt T, values for DIALOGUE 4 currently read 0.9 (1.7), 0.6 Krueger T: Effects of Molidustat in the Treatment of (0.8), 0.8 (1.2), 0.8 (1.7), 0.8 (1.4), 0.7 (1.1), and 0.8 Anemia in CKD. Clin J Am Soc Nephrol 14: 28–39, 2019, (1.3) for molidustat 25 mg, 50 mg, 75 mg, 150 mg, https://doi.org/10.2215/CJN.02510218. combined,controlgroup,andtotal,respectively. Because of author error, a correction has been issued These values should be 9.4 (16.6), 6.1 (8.4), 8.2 for the above referenced article. (11.8), 7.5 (16.7), 7.9 (13.5), 7.1 (11.1), and 7.7 (13.0), In Table 2, the mean CRP (SD) values for DIALOGUE respectively. 4 currently read 0.8 (1.4) and 0.7 (1.1) for molidustat and epoetin, respectively. These values should be 7.9 Published online ahead of print. Publication date available at (13.5) and 7.1 (11.1), respectively. www.cjasn.org.