Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease

Abstract

Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD. Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD. Anemia is a common complication of chronic kidney disease (CKD), driven predominantly by a relative deficiency in renal erythropoietin (EPO) production, concomitant functional and/or absolute iron deficiency, and resistance to EPO signaling.1Fishbane S. Nissenson A.R. Anemia management in chronic kidney disease.Kidney Int Suppl. 2010; : S3-S9Abstract Full Text Full Text PDF Scopus (25) Google Scholar, 2Koury M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar As the severity of kidney disease progresses, anemia increases in prevalence and affects nearly all patients with advanced-stage CKD.3Stauffer M.E. Fan T. Prevalence of anemia in chronic kidney disease in the United States.PLoS One. 2014; 9: e84943Crossref PubMed Scopus (293) Google Scholar The presence of anemia in patients with CKD is associated with increased risk for hospitalization, cognitive impairment, reduced quality of life, and major cardiovascular (CV) events, such as myocardial infarction and stroke; furthermore, the severity of anemia is also an independent predictor of mortality.4Efstratiadis G. Konstantinou D. Chytas I. Vergoulas G. Cardio-renal anemia syndrome.Hippokratia. 2008; 12: 11-16PubMed Google Scholar, 5Finkelstein F.O. Story K. Firanek C. et al.Health-related quality of life and hemoglobin levels in chronic kidney disease patients.Clin J Am Soc Nephrol. 2009; 4: 33-38Crossref PubMed Scopus (108) Google Scholar, 6Portoles J. Gorriz J.L. Rubio E. et al.The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease.BMC Nephrol. 2013; 14: 2Crossref Scopus (54) Google Scholar, 7van Nooten F.E. Green J. Brown R. et al.Burden of illness for patients with non-dialysis chronic kidney disease and anemia in the United States: review of the literature.J Med Econ. 2010; 13: 241-256Crossref Scopus (33) Google Scholar The administration of injectable preparations of recombinant EPO coupled with oral or i.v. iron supplementation are the current mainstay of treatment for anemia in CKD.8Macdougall I.C. Bircher A.J. Eckardt K.U. et al.Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference.Kidney Int. 2016; 89: 28-39Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 9Padhi S. Glen J. Pordes B.A. et al.Management of anaemia in chronic kidney disease: summary of updated NICE guidance.BMJ. 2015; 350: h2258Crossref Scopus (30) Google Scholar Though generally very effective therapeutically, the use of erythropoiesis-stimulating agents (ESAs) has raised significant safety concerns. ESA administration often results in substantial hemoglobin (Hb) oscillations and excursions above target range, which are associated with increased CV risk.9Padhi S. Glen J. Pordes B.A. et al.Management of anaemia in chronic kidney disease: summary of updated NICE guidance.BMJ. 2015; 350: h2258Crossref Scopus (30) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2273) Google Scholar, 11Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.for the TREAT InvestigatorsA trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1642) Google Scholar, 12Palmer S.C. Saglimbene V. Mavridis D. et al.Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.Cochrane Database Syst Rev. 2014; 12: CD010590PubMed Google Scholar Furthermore, patients who require very high ESA doses to reach target Hb, or who fail to reach target Hb levels at ESA doses that are normally effective, have increased mortality and hospitalization rates.13Weinhandl E.D. Gilbertson D.T. Collins A.J. Association of mean weekly epoetin alfa dose with mortality risk in a retrospective cohort study of Medicare hemodialysis patients.Am J Nephrol. 2011; 34: 298-308Crossref PubMed Scopus (15) Google Scholar, 14Kalantar-Zadeh K. Lee G.H. Miller J.E. et al.Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients.Am J Kidney Dis. 2009; 53: 823-834Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 15McCullough P.A. Barnhart H.X. Inrig J.K. et al.Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.Am J Nephrol. 2013; 37: 549-558Crossref PubMed Scopus (91) Google Scholar, 16Inrig J.K. Sapp S. Barnhart H. et al.Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of CHOIR.Nephrol Dial Transplant. 2012; 27: 3606-3614Crossref PubMed Scopus (20) Google Scholar, 17Okazaki M. Komatsu M. Kawaguchi H. et al.Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients.Blood Purif. 2014; 37: 106-112Crossref PubMed Scopus (37) Google Scholar, 18Kilpatrick R.D. Critchlow C.W. Fishbane S. et al.Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients.Clin J Am Soc Nephrol. 2008; 3: 1077-1083Crossref PubMed Scopus (175) Google Scholar Meanwhile, i.v. iron supplementation may place patients at increased risk of allergic reactions, infections, and CV events.19Hung S.C. Tarng D.C. ESA and iron therapy in chronic kidney disease: a balance between patient safety and hemoglobin target.Kidney Int. 2014; 86: 676-678Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 20Liles A.M. Intravenous versus oral iron for treatment of iron deficiency in non-hemodialysis-dependent patients with chronic kidney disease.Am J Health Syst Pharm. 2012; 69: 1206-1211Crossref PubMed Scopus (11) Google Scholar Therefore, a novel approach to anemia therapy that is effective without generating supraphysiologic plasma EPO levels and that reduces the need for iron supplementation is highly desirable. The pharmacologic targeting of the molecular machinery that regulates the hypoxic induction of erythropoiesis has the potential to solve some of the clinical dilemmas associated with conventional ESA therapy. EPO synthesis in the kidney and liver is regulated by hypoxia-inducible factor (HIF)-2, an oxygen-sensitive factor with regulates a of that and to M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar is controlled by and and which as In the presence of by the oxygen-sensitive targeting for by the of the hydroxylase 2008; Full Text Full Text PDF PubMed Scopus Google Scholar hypoxic is reduced and is in results in the of target EPO and iron by the of the hydroxylase 2008; Full Text Full Text PDF PubMed Scopus Google Scholar that a of that and increase endogenous EPO production, while also iron M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar, factor a for while 2016; Scopus Google Scholar also as is a novel, titratable, oral inhibitor in development for the treatment of anemia in both nondialysis-dependent and CKD In clinical vadadustat was in and patients with increased plasma and Hb levels in a C. C. et a hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while ferritin in a phase dose study in stage 3 and chronic kidney disease patients with Am Soc Nephrol. 2011; Scholar, R. C. C. et a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while increases and total iron capacity in Am Soc Nephrol. 2011; Scholar The increase in plasma EPO levels with vadadustat was comparable in to that at and a with a to levels to the R. C. C. et a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while increases and total iron capacity in Am Soc Nephrol. 2011; Scholar results also that vadadustat improved iron by hepcidin and C. C. et a hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while ferritin in a phase dose study in stage 3 and chronic kidney disease patients with Am Soc Nephrol. 2011; Scholar once-daily oral administration of to increase and Hb in the target range, may over conventional we the results of a phase 2b study vadadustat in patients with stages 3a to 5 CKD. a 20-week, phase 2b randomized, double-blind, study to the of once-daily vadadustat to anemia in patients with with stages and 5 from were on ESA treatment and Hb level at were ESA treatment and Hb 2 were with ESA and Hb 3 were with ESA and Hb g/dl to patients were to vadadustat or and to CKD stage and the presence or of diabetes The patients who the study and were in the safety The for all efficacy patients who a and Hb and blood The as the primary to to the primary all patients in the who also the study, efficacy were with study and major were patients who for the the patients who the study in the vadadustat and in the treatment to of the were for and at as in and to to of a for of all were and blood pressure blood pressure chronic kidney Hb, all patients who dose of study are or mean to to a for of all were in a chronic kidney Hb, all patients who dose of study are or mean The primary endpoint of the study was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained a mean Hb level of g/dl or an increase in Hb of g/dl over the predose of the 2 Hb at and who ESA or as therapy were as treatment who for were from the primary with vadadustat raised and maintained Hb levels in patients with anemia secondary to CKD In the 54.9% of patients with vadadustat achieved the primary endpoint compared with 10.3% of placebo-treated patients on patients with vadadustat were more patients with to a Hb of patients the primary endpoint Hb Hb of weeks and g/dl or Hb of weeks and g/dl higher predose a was the was for Hb at versus for vadadustat versus is from a with treatment, erythropoiesis-stimulating study CKD and diabetes as chronic kidney of Hb, Hb of weeks and g/dl or Hb of weeks and g/dl higher predose a was the was Vadadustat versus for vadadustat versus is from a with treatment, erythropoiesis-stimulating study CKD and diabetes as in a chronic kidney of Hb, Vadadustat increased and maintained Hb levels in patients the study mean Hb levels in the vadadustat increased from Hb levels by weeks to and were the weeks of treatment Hb versus in of the 3 study on ESA treatment is in Hb excursions g/dl occurred in of of patients in the vadadustat analysis that from weeks to of all Hb in the vadadustat and in the were between and of Hb in the vadadustat were between and g/dl and was g/dl and in the were patients in the vadadustat in the ESA therapy during the the patients who ESA during the study, patients the for ESA of the was in the and in the the patients who ESA 2 patients the of the was in the treatment 3 were in the and were in the of the patients and placebo-treated patient during the increase from in mean absolute was observed in the vadadustat at 2 versus a in the The mean in the vadadustat and by weeks to at a level higher that of the the Hb Significant decreases in hepcidin and and a significant increase in total iron-binding capacity were observed in the vadadustat compared with the at 3a to iron and were in the 2 treatment the of patients in the vadadustat and in the were iron the of the of patients in the vadadustat and in the were iron the study, of patients of in the vadadustat and of the patients in the i.v. The dose of vadadustat at study was the mean dose of vadadustat at was The of patients of in the vadadustat achieved and maintained a Hb level with dose the treatment of patients of dose The of patients who were with treatment was of in the vadadustat and of in the The percentage of patients who adverse was comparable between the vadadustat and of was in of patients of and of placebo-treated patients of in both treatment were or in in the vadadustat and was the in the patients and 3 placebo-treated patients the study of and in the of patients, with are that were in of the with with with and/or with of the patients who was to have a is in this study was to the for dose of study events were with events that with to study adverse adverse are that were in of the of the patients who was to have a is in this study was to the for dose of study events were in a adverse adverse were observed increases or in blood pressure over and the of blood pressure in patients with vadadustat was to that of patients with placebo. was as an in of patients of and of with of all of the patients a of the patients on vadadustat who an of during the study, to the an or in the dose of agents to the of the of and vadadustat treatment of total of patients adverse as placebo-treated patients the higher incidence of was to a higher incidence of in the vadadustat compared with the The for of an of the severity of renal was between the vadadustat of and of groups. events were to the study on the significant between the vadadustat and in the mean from in factor levels at or of treatment decreases from in levels were observed in the vadadustat at and of treatment significant mean increases from in were observed in the between the 2 treatment that the mean from to of treatment in levels was in the vadadustat in the from were in or were of vadadustat on the of patient in the vadadustat who an increase in liver to study in liver total or total renal blood or serum serum total or serum or serum were in either treatment during the Three deaths were the who were with for an overall mortality of The of were and myocardial patient with type 2 chronic and of a 2 patient with and disease to the with a of and was to for and an to an the hospitalization, the renal and 2 was the The deaths in 2 were to to the study The was to myocardial in a patient with type 2 and was to have a to the study as the at and was the of deaths were the we the results from a phase 2b study in patients with with the oral once-daily inhibitor Vadadustat raised and maintained Hb levels in a predictable while Hb excursions g/dl and iron mobilization. the has the potential to a more approach to anemia conventional ESA M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar, factor a for while 2016; Scopus Google Scholar which on the administration of high doses of recombinant EPO agents and can in and increased CV E.D. Gilbertson D.T. Collins A.J. Association of mean weekly epoetin alfa dose with mortality risk in a retrospective cohort study of Medicare hemodialysis patients.Am J Nephrol. 2011; 34: 298-308Crossref PubMed Scopus (15) Google Scholar, 14Kalantar-Zadeh K. Lee G.H. Miller J.E. et al.Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients.Am J Kidney Dis. 2009; 53: 823-834Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 15McCullough P.A. Barnhart H.X. Inrig J.K. et al.Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.Am J Nephrol. 2013; 37: 549-558Crossref PubMed Scopus (91) Google Scholar, 16Inrig J.K. Sapp S. Barnhart H. et al.Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of CHOIR.Nephrol Dial Transplant. 2012; 27: 3606-3614Crossref PubMed Scopus (20) Google Scholar, 17Okazaki M. Komatsu M. Kawaguchi H. et al.Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients.Blood Purif. 2014; 37: 106-112Crossref PubMed Scopus (37) Google Scholar, 18Kilpatrick R.D. Critchlow C.W. Fishbane S. et al.Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients.Clin J Am Soc Nephrol. 2008; 3: 1077-1083Crossref PubMed Scopus (175) Google Scholar, A.M. M.J. R. for a Engl J Med. 2010; PubMed Scopus Google Scholar the are Hb oscillations and supraphysiologic plasma EPO levels are to a in the of adverse CV events associated with recombinant EPO P.A. Barnhart H.X. Inrig J.K. et al.Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.Am J Nephrol. 2013; 37: 549-558Crossref PubMed Scopus (91) Google Scholar, of adverse in of anemia with erythropoietin in chronic kidney Dial Transplant. 2009; PubMed Scopus Google Scholar, S. J. is a hemoglobin level of to for chronic kidney disease patients Kidney Dis. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar with vadadustat were more patients with to the primary The in a controlled in Hb and of Hb levels the range, while the the to Lee the 2014; PubMed Scopus Google Scholar patients on vadadustat Hb excursions which have associated with an increased risk of and adverse CV A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2273) Google Scholar, 11Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.for the TREAT InvestigatorsA trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1642) Google Scholar, J.K. et al.The of as compared with in patients with disease who are hemodialysis and Engl J Med. PubMed Scopus Google Scholar, I.C. et in chronic kidney disease: the with J Am Soc Nephrol. 2009; 4: PubMed Scopus Google Scholar, et of hemoglobin level in patients with chronic kidney disease and Engl J Med. 2006; 355: PubMed Scopus Google Scholar The of patients dose during the treatment in of iron was also observed with significant of hepcidin and ferritin and increase in total iron-binding capacity iron in patients with which may the need for iron supplementation compared with conventional ESA evaluated in the phase 3 in have that regulates erythropoiesis by the induction of EPO with the of in iron M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar In to a in iron hypoxic a potential by which vadadustat enhances iron M. et iron in 2009; PubMed Scopus Google Scholar, hypoxia-inducible is for 2011; PubMed Scopus Google Scholar, M. et in of iron with 2013; PubMed Scopus Google Scholar The of vadadustat on hepcidin levels are as have that increased is for hepcidin in the of K. Haase V.H. factor regulates hepcidin 2012; PubMed Scopus Google Scholar, M. et hypoxia-inducible hepcidin in an increase in 2012; PubMed Scopus Google Scholar, S. et of plasma hepcidin by during 2016; Scopus (12) Google Scholar is a very factor that regulates a of hypoxia have the potential to and in CKD In the of on the CV and and the of CKD are In phase 2b vadadustat was by patients and was generally to that of which is with and of the CKD C. C. et a hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while ferritin in a phase dose study in stage 3 and chronic kidney disease patients with Am Soc Nephrol. 2011; Scholar, R. C. C. et a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while increases and total iron capacity in Am Soc Nephrol. 2011; Scholar The observed of deaths in this study was with that on on on the severity of mortality and of R. et of Kidney in the United J Kidney Dis. 2016; Scholar was an in during the study to renal events and to in the of severity for to as as that to with a renal or The for of an of the severity of renal was between the vadadustat and groups. the of patients who from the study of CKD that was comparable between the vadadustat and groups. in have that has the potential to and and of by hypoxia-inducible factor 2011; PubMed Scopus Google Scholar, V.H. 2012; Scopus Google Scholar, K. J.E. between type 2 and 2012; Full Text Full Text PDF PubMed Scopus Google Scholar which are in clinical anemia have to serum R. S. et versus epoetin alfa for anemia in patients a phase randomized, to safety and efficacy J Kidney Dis. 2016; Full Text Full Text PDF PubMed Scopus (175) Google Scholar the molecular that are In on serum levels was associated with vadadustat major safety of targeting the is the potential for increased of is a factor and has to to and to and and 2011; PubMed Scopus Google Scholar, and in hypoxic and Rev 2012; 12: Scopus Google Scholar levels were increased with vadadustat treatment in this phase 2b which is with C. C. et a hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while ferritin in a phase dose study in stage 3 and chronic kidney disease patients with Am Soc Nephrol. 2011; Scholar, R. C. C. et a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while increases and total iron capacity in Am Soc Nephrol. 2011; Scholar phase 3 to plasma levels in is in the of and blood pressure and is also to to the development of factor a for while 2016; Scopus Google Scholar, hypoxia-inducible and disease Rev 2014; 9: PubMed Scopus Google Scholar, G. L. et al.The factor 2 regulates pressure in 2016; Scopus Google Scholar was more as an in the vadadustat all of the for was as an an of and of in blood pressure or was observed during the 3 vadadustat with ESA therapy between on blood In we the results of the phase 2b study of a novel inhibitor that an effective and titratable, once-daily oral therapy for anemia in patients with CKD. Vadadustat over ESA therapy as a more of plasma EPO that Hb levels with and iron and mobilization. study results for phase 3 clinical to the safety and efficacy of The study was in with the of and and the was by the of patients were and or with a of CKD stages 3a to 5 who were to during the of the anemia secondary to CKD with an ESA and Hb level that met of the 3 study a ferritin level with a or a ferritin level of of is in the vadadustat was at and by to Hb of and of was the and Hb iron supplementation was the study to ferritin levels between and i.v. iron was for patients who were of oral therapy with ESA was Hb was g/dl in and or Hb was g/dl in the higher for of for 3 was the to Hb levels to in a Hb and iron and safety were at during the treatment and at the or and at the that was weeks the last dose of study for of hepcidin and were at and the blood with serum and and were the a of for vadadustat to with a total of patients for the primary we to the in the between vadadustat and the 3 study at the of patients to the target of patients was in to patients for the primary for the primary and secondary to percentage of of vadadustat to placebo. and were for treatment by safety were for and and in a by treatment were to all by to study and that in of study study was by is by and from and is by and from and was by is by is by the in and on the of The K. of and for with hemoglobin level over by erythropoiesis-stimulating study and The is the the and the mean is the the of vadadustat with at was with a at of with of patients with or 5 in the erythropoiesis-stimulating Hb, who an who dose of an ESA ESA therapy for weeks at the of who with an ESA for to doses the last and last dose weeks