Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD

Abstract

Background

Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.

Methods

In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non–dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.

Results

A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, −0.04 to 0.15) in the trial involving ESA-untreated patients and −0.01 g per deciliter (95% CI, −0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of −0.75 g per deciliter.

Conclusions

Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO₂TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.)

Anemia is a common complication of chronic kidney disease (CKD). Among patients with moderate-to-advanced non–dialysis-dependent CKD (NDD-CKD), the prevalence of anemia, defined as a hemoglobin concentration below 13 g per deciliter in men and below 12 g per deciliter in women, is approximately 30 to 40%.¹,² Conventional treatment of anemia in patients with NDD-CKD includes correction of iron deficiency and the provision of recombinant erythropoietin and its analogues, referred to as erythropoiesis-stimulating agents (ESAs), to maintain the hemoglobin concentration within the range of 9 to 12 g per deciliter. Treatment with ESAs reduces the need for red-cell transfusion, but an increased risk of certain cardiovascular events has been identified when hemoglobin concentrations in the near-normal range are targeted.³–⁵

Hypoxia-inducible factor (HIF) is a transcription factor that regulates many physiological responses to hypoxia, including erythropoietin production by the liver and kidneys. HIF is regulated by oxygen-dependent proteasomal degradation, with a family of prolyl hydroxylases serving as oxygen sensors.⁶,⁷ HIF prolyl hydroxylase inhibitors comprise a new class of compounds that stabilize HIF, which in turn stimulates endogenous erythropoietin production.⁸,⁹

Vadadustat is an oral HIF prolyl hydroxylase inhibitor that is under investigation for the treatment of anemia associated with CKD. We conducted four phase 3, international, randomized, controlled trials: two trials involved patients with dialysis-dependent (DD)–CKD (the INNO₂VATE trials), and two involved patients with NDD-CKD (the PRO₂TECT trials). The INNO₂VATE trials, which are also reported in this issue of the Journal, showed that vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety (major adverse cardiovascular events [MACE]) and hematologic efficacy.¹⁰ Here, we report the results of the two trials that examined the cardiovascular safety and hematologic efficacy of vadadustat in patients with NDD-CKD; one trial involved patients with anemia who had not received previous treatment with ESAs (ESA-untreated), and the other involved patients with anemia actively treated with ESAs (ESA-treated).

Methods

Trial Design and Oversight

The design and methods of these two trials have been described previously,¹¹ and the protocols are available with the full text of this article at NEJM.org. Both trials were randomized, open-label, active-controlled, event-driven trials that were designed to evaluate the cardiovascular safety and hematologic efficacy of vadadustat, as compared with darbepoetin alfa, for the treatment of anemia in patients with NDD-CKD: one trial (previously called “Correction”) involved ESA-untreated patients, and the other (previously called “Conversion”) involved ESA-treated patients. In both trials, personnel at Akebia Therapeutics and Otsuka Pharmaceutical (the funders) were unaware of the treatment assignments.

The target enrollment in each trial was approximately 1850 patients, randomly assigned in a 1:1 ratio across the two treatments.¹¹ The two trials were designed similarly. The protocols prespecified that the cardiovascular safety end points would be pooled across the two trials to achieve sufficient power. Hematologic efficacy was prespecified to be assessed separately in each trial (see the Supplemental Methods section in the Supplementary Appendix, available at NEJM.org).

Akebia Therapeutics designed the trials and protocols with input from an executive steering committee, and Otsuka Pharmaceutical participated in the executive steering committee meetings and provided input on trial protocol amendments. An independent ethics committee approved the informed consent forms. Trial investigators conducted the trials in collaboration with Akebia Therapeutics. The executive steering committee supervised the trial conduct and progress. The trials were monitored by an independent data and safety monitoring committee. The first and last authors wrote the first draft of the manuscript and made final decisions regarding the content of the submitted manuscript. All the authors had access to the trial data, critically reviewed the manuscript, and approved it for submission. The investigators vouch for the accuracy and completeness of the data; the authors and Akebia Therapeutics vouch for the fidelity of the trials to the protocols and for the analysis of the data.

Participants

In both trials, eligible patients were at least 18 years of age and had NDD-CKD (defined as an estimated glomerular filtration rate [GFR] of ≤60 ml per minute per 1.73 m² of body-surface area, as calculated with the use of the Chronic Kidney Disease Epidemiology Collaboration equation, incorporating a term for patient-reported race [Black or non-Black], as originally defined¹²). In the trial involving ESA-untreated patients, patients were required to have a hemoglobin concentration of less than 10 g per deciliter and were excluded if they had received any ESA within 8 weeks before randomization. In the trial involving ESA-treated patients, patients had to be actively receiving maintenance ESA therapy, with at least one dose received within 6 weeks before screening or during screening, and were also required to have a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries).

In both trials, patients were required to have a serum ferritin concentration of at least 100 ng per milliliter and a transferrin saturation of at least 20%. Patients were excluded if the investigator judged that the anemia was due to causes other than CKD or if a potential participant had uncontrolled hypertension or had had a recent cardiovascular event. Table S1 in the Supplementary Appendix lists all the inclusion and exclusion criteria. All the patients provided written informed consent.

Randomization and Trial Periods

Eligible patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa, with stratification according to geographic region (United States vs. Europe vs. other), New York Heart Association (NYHA) congestive heart failure class (0 or I vs. II or III), and hemoglobin concentration at entry (in ESA-untreated patients: <9.5 vs. ≥9.5 g per deciliter; in ESA-treated patients: <10 vs. ≥10 g per deciliter). The trials had four defined trial periods: a correction or conversion period (weeks 0 through 23), a maintenance period (weeks 24 through 52) that comprised both primary (weeks 24 through 36) and secondary (weeks 40 through 52) efficacy evaluation periods, a long-term treatment period (weeks 53 to end of treatment), and a 4-week safety follow-up period. Figure S1 shows the schema for both trials.

End Points

The primary safety end point, assessed in a time-to-event analysis, was the first adjudicated MACE, which was a composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Key secondary safety end points, assessed in time-to-event analyses, were the first occurrence of expanded MACE (defined as a MACE plus hospitalization for either heart failure or a thromboembolic event, excluding vascular access failure); a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (so-called classic MACE); death from cardiovascular causes; and death from any cause. An independent clinical end-points committee, whose members were unaware of the treatment assignments, adjudicated MACE.

The primary efficacy end point was the mean change in the hemoglobin concentration from the baseline value to the mean concentration during the primary evaluation period. The key secondary efficacy end point was the mean change in the hemoglobin concentration from the baseline value to the mean concentration during the secondary evaluation period.

Intervention

The starting dose of vadadustat was 300 mg orally once daily, with doses of 150 mg, 450 mg, and 600 mg available for adjustment to a maximum dose of 600 mg daily. Drug doses were adjusted according to protocol-specified dose-adjustment algorithms to achieve target hemoglobin concentrations (in the United States: 10 to 11 g per deciliter; in other countries: 10 to 12 g per deciliter). Darbepoetin alfa was administered subcutaneously or intravenously. In contrast to the initial uniform dosing in the vadadustat group, the initial dose of darbepoetin alfa was based on the patient’s previous dose of darbepoetin alfa or on the local product label for patients who had not been receiving darbepoetin alfa before randomization. Investigators were encouraged to prescribe iron supplementation such that a ferritin concentration of at least 100 ng per milliliter or a transferrin saturation of at least 20% would be maintained.

Starting at week 6, patients in the two treatment groups could receive ESAs as rescue therapy if they had worsening symptoms of anemia with a hemoglobin concentration of less than 9.0 g per deciliter. In a post hoc analysis, patients who had been randomly assigned to receive darbepoetin alfa were also considered to have received rescue therapy with ESAs if the darbepoetin alfa dose was increased to at least double the previous dose. While receiving ESAs as rescue therapy, patients temporarily discontinued vadadustat or darbepoetin alfa, the latter only if the rescue therapy was an ESA other than darbepoetin alfa. Receipt of red-cell transfusions did not require discontinuation of the trial drug.

Statistical Analysis

All the safety and efficacy analyses were prespecified except where noted. Noninferiority margins were an upper boundary of the 95% confidence interval not exceeding 1.25 or 1.3 (both margins were prespecified in consultation with U.S. and European Union regulators, respectively) for the hazard ratio of the primary safety end point and a lower boundary of the 95% confidence interval for the hemoglobin concentration that was not below −0.75 g per deciliter for the primary efficacy end point.

To evaluate the primary and key secondary efficacy end points, we used analysis of covariance with multiple imputation for missing data, with baseline hemoglobin concentration (in ESA-untreated patients: <9.5 vs. ≥9.5 g per deciliter; in ESA-treated patients: <10 vs. ≥10 g per deciliter), geographic region (United States vs. Europe vs. other), and NYHA class (0 or I vs. II or III) as covariates. We used a Cox proportional-hazards model stratified according to trial to analyze the first MACE in a time-to-event analysis. The Cox model included the following covariates: baseline hemoglobin concentration, geographic region, NYHA class, sex, age (>65 vs. ≤65 years), race (White vs. non-White), cardiovascular disease (yes vs. no), and diabetes mellitus (yes vs. no). We conducted a series of subgroup analyses, which included subgroups defined according to the stratification factors (see the Supplemental Methods section).

Results

Patients

Across the two trials, 3476 patients underwent randomization, with 1751 patients in the trial involving ESA-untreated patients and 1725 in the trial involving ESA-treated patients (Fig. S2). The median duration of follow-up was 1.63 years (interquartile range, 0.94 to 2.49) and 1.80 years (interquartile range, 0.97 to 2.67), respectively. The randomized groups in both trials were generally well balanced (Table 1; Table S2 provides a more comprehensive comparison).

Primary and Key Secondary Safety End Points

We conducted all the analyses related to MACE safety end points using the safety population (all patients who received at least one dose of the trial drug), pooled across the two trials; therefore, 1739 patients were included in the vadadustat group and 1732 in the darbepoetin alfa group. Figure 1A shows the time to the first MACE. A first MACE occurred in 382 of 1739 patients (22.0%) in the vadadustat group and in 344 of 1732 patients (19.9%) in the darbepoetin alfa group (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.36). The results of the prespecified subgroup analyses of MACE are shown in Figure S3. With regard to the components of MACE, death from any cause occurred in 319 patients (18.3%) in the vadadustat group and in 307 (17.7%) in the darbepoetin alfa group; nonfatal myocardial infarction in 67 (3.9%) and 48 (2.8%), respectively; and nonfatal stroke in 34 (2.0%) and 28 (1.6%), respectively.

Figure 1B shows the time to the first expanded MACE, which occurred in 451 patients (25.9%) in the vadadustat group and in 424 (24.5%) in the darbepoetin alfa group (hazard ratio, 1.11; 95% CI, 0.97 to 1.27). Figures 1C and 1D show the time to death from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.79 to 1.29) and the time to death from any cause (hazard ratio, 1.09; 95% CI, 0.93 to 1.27), respectively. Figure S4 shows the time to the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio, 1.16; 95% CI, 0.95 to 1.42).

The time to CKD progression, which was defined as the provision of maintenance dialysis, receipt of kidney transplant, or a decrease in the estimated GFR to below 15 ml per minute per 1.73 m² or a decrease of 40% or more in the estimated GFR (with the two estimated GFR criteria confirmed after ≥4 weeks), was similar in the two treatment groups in the two trials (Fig. S5). The mean systolic and diastolic blood pressures in the two treatment groups were similar over the course of both trials (Fig. S6). Figure S7 shows the median doses of the trial drugs in both trials.

Prespecified Subgroup Analyses of Safety End Points According to Region

Figure 2 shows the time to the first MACE and the time to the first expanded MACE in the U.S. and non-U.S. populations. Figure S8 shows the time to death from any cause in the U.S. and non-U.S. populations. Table S3 shows a breakdown of first MACE events in these two populations, and Table S4 shows the components of first MACE as well as death from any cause in these populations.

Efficacy End Points

Trial Involving ESA-Untreated Patients

Figure 3A shows the mean hemoglobin concentrations over time in the two treatment groups. The least-squares mean (±SE) changes in the hemoglobin concentration from the baseline value to the mean of the values in weeks 24 through 36 were 1.43±0.05 g per deciliter in the vadadustat group and 1.38±0.05 g per deciliter in the darbepoetin alfa group; the corresponding least-squares mean difference between the groups was 0.05±0.05 g per deciliter (95% CI, −0.04 to 0.15). The least-squares mean (±SD) change in the hemoglobin concentration from the baseline value to the mean of the values in weeks 40 though 52 was 1.52±0.05 g per deciliter in the vadadustat group and 1.48±0.05 g per deciliter in the darbepoetin alfa group; the corresponding least-squares mean between-group difference was 0.04±0.05 g per deciliter (95% CI, −0.06 to 0.14). Thus, for both the primary and secondary efficacy end points, the lower boundaries of the 95% confidence intervals (−0.04 and −0.06, respectively) were above −0.75 g per deciliter, which showed the noninferiority of vadadustat to darbepoetin alfa.

The percentage of patients who received red-cell transfusions was 2.7% in the vadadustat group and 2.2% in the darbepoetin alfa group during weeks 24 through 36. The corresponding percentages were 2.4% and 2.2% during weeks 40 through 52. Table S5 shows the percentages of patients with a mean hemoglobin concentration within the region-specific target range during weeks 24 through 36 and weeks 40 through 52.

Trial Involving ESA-Treated Patients

Figure 3B shows the mean hemoglobin concentrations in the two treatment groups. The least-squares mean (±SE) changes in the hemoglobin concentration from the baseline value to the mean of the values in weeks 24 through 36 were 0.41±0.04 g per deciliter in the vadadustat group and 0.42±0.04 g per deciliter in the darbepoetin alfa group; the corresponding least-squares mean difference between the groups was −0.01±0.04 g per deciliter (95% CI, −0.09 to 0.07). The least-squares mean (±SD) change in the hemoglobin concentration from the baseline value to the mean of the values in weeks 40 through 52 was 0.43±0.04 g per deciliter in the vadadustat group and 0.44±0.04 g per deciliter in the darbepoetin alfa group; the corresponding least-squares mean between-group difference was 0.00±0.05 g per deciliter (95% CI, −0.10 to 0.09). Thus, for both the primary and secondary efficacy end points, the lower boundaries of the 95% confidence intervals (−0.09 and −0.10, respectively) were above −0.75 g per deciliter, which showed the noninferiority of vadadustat to darbepoetin alfa.

The percentage of patients who received red-cell transfusions was 1.6% in the vadadustat group and 1.2% in the darbepoetin alfa group during weeks 24 through 36 and 2.4% and 1.9%, respectively, during weeks 40 through 52. Table S5 shows the percentages of patients with a mean hemoglobin concentration within the region-specific target range during weeks 24 through 36 and weeks 40 through 52.

Rescue Therapy with an ESA

Table S6 shows the percentages of patients randomly assigned to receive vadadustat or darbepoetin alfa who received ESA rescue therapy for symptomatic anemia with a hemoglobin concentration below the target range. The use of ESA rescue therapy was less common among patients who had been randomly assigned to the vadadustat group than among those who had been randomly assigned to the darbepoetin alfa group.

Adverse Events

Table 2 shows a summary of the adverse events that occurred after the start of trial treatment, including the adverse events that were reported in at least 10% of the patients in either treatment group in both trials. A full list of all the adverse events in the trials is provided in Table S7.

Discussion

The pooled results from these two randomized trials involving patients with NDD-CKD in which we compared vadadustat, a HIF prolyl hydroxylase inhibitor, with darbepoetin alfa, a commonly prescribed ESA — with one trial involving patients who had not previously received treatment with ESAs and the other involving patients who were receiving active ESA therapy — showed that vadadustat did not meet its prespecified noninferiority margin with respect to MACE, defined as death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Vadadustat met its noninferiority margin with respect to hematologic efficacy in each trial.

The safety and efficacy of vadadustat in patients with NDD-CKD have previously been examined in several smaller studies, none of which suggested a cardiovascular safety signal.¹³–¹⁵ The pooled results of our trials contrast with those reported in patients with DD-CKD (the INNO₂VATE trials),¹⁰ which compared vadadustat and darbepoetin alfa for the treatment of anemia in 3923 patients with DD-CKD, including 3554 patients who had been undergoing maintenance dialysis and had been receiving treatment with ESAs and 369 patients who were new to dialysis and had had limited previous exposure to ESAs. Pooled across those two trials, the hazard ratios for MACE and expanded MACE were 0.96 (95% CI, 0.83 to 1.11) and 0.96 (95% CI, 0.84 to 1.10), respectively. Point estimates for all components of MACE, as well as cardiovascular death, were below 1.0.

The difference in outcomes between the current pooled trials involving patients with NDD-CKD and the pooled trials involving patients with DD-CKD¹⁰ is not the first example in which the relative safety of drugs used to treat anemia differed between DD-CKD and NDD-CKD populations. In the EMERALD (Efficacy and Safety of Peginesatide for the Maintenance Treatment of Anemia in Patients with Chronic Renal Failure Who Were Receiving Hemodialysis and Were Previously Treated with Epoetin) trials, peginesatide, a synthetic peptide-based erythropoietin receptor agonist, was shown to be noninferior to epoetin alfa in patients with DD-CKD with respect to safety, on the basis of a composite end point that was not unlike our expanded MACE (death from any cause, nonfatal myocardial infarction or stroke, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia) (hazard ratio, 0.95; 95% CI, 0.77 to 1.17).¹⁶ In contrast, in the PEARL (Peginesatide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents) trials, which involved patients with NDD-CKD, peginesatide did not meet its noninferiority margin for safety as compared with darbepoetin alfa (hazard ratio, 1.32; 95% CI, 0.97 to 1.81).¹⁷ The reasons for these discrepant results among patients with DD-CKD and those with NDD-CKD remain unclear.

Other studies of ESAs in patients with NDD-CKD have shown higher risks with hemoglobin targets in the normal or near-normal range than with lower targets³,⁴ or placebo.⁵ In the PRO₂TECT trials, we chose to use region-specific hemoglobin target ranges to account for differences in regional guidelines and usual clinical practice. In the United States, the results of these trials were in line with what was observed in the INNO₂VATE trials (hazard ratio for MACE, 1.00 [95% CI, 0.84 to 1.18]; hazard ratio for expanded MACE, 0.99 [95% CI, 0.85 to 1.15]). In contrast, in the non-U.S. regions, the risks of MACE and expanded MACE in the PRO₂TECT trials were considerably higher among patients who had been randomly assigned to the vadadustat group than among those assigned to the darbepoetin alfa group. Whether this difference between regions is causally related to the difference in hemoglobin targets or other factors is unclear.

Analysis of events in the current trials revealed that the higher risk that was observed among patients who had been randomly assigned to the vadadustat group than among those in the darbepoetin alfa group was due largely to an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes. We could not identify a reason for the excess in noncardiovascular deaths. Adverse events were evenly distributed between the vadadustat group and the darbepoetin alfa group. The cumulative incidences of pulmonary hypertension and cancer, which are theoretical consequences of HIF pathway activation, were similar in the two treatment groups.

The current trials have many strengths, including — in combination — the relatively large sample size, the diverse population of patients (according to age, sex, race or ethnic group, and primary cause of kidney disease), and the inclusion of a sizable fraction of patients with stage G4 or G5 CKD.¹⁸ The use of region-specific inclusion criteria and target hemoglobin concentrations was a strength with respect to generalizability to different regions but hampered the trial in that treatment was not uniform. Limitations included the fact that, on the basis of guidance from regulatory agencies, these two trials were not placebo-controlled.

In these two trials, we found that, among patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa with regard to hematologic efficacy but did not meet the prespecified noninferiority criterion for cardiovascular safety, which was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Akebia Therapeutics and Otsuka Pharmaceutical.

Dr. Chertow reports receiving advisory board fees and owning stock options in Ardelyx, Miromatrix Medical, and Unicycive Therapeutics, receiving steering committee fees from AstraZeneca, Gilead Sciences, Sanifit, and Vertex Pharmaceuticals, receiving advisory board fees from Baxter, Cricket Health, DiaMedica Therapeutics, and Reata Pharmaceuticals, serving on an advisory board and owning stock options in CloudCath, Durect, and Outset Medical, receiving fees for serving on a data and safety monitoring board from Angion, Bayer, and ReCor Medical, and receiving grant support, paid to his institution, from Amgen; Dr. Pergola, receiving consulting fees and fees for serving on a speaker’s bureau from AstraZeneca, consulting fees and advisory board fees from Bayer, Gilead Sciences, Corvidia Therapeutics, FibroGen, Tricida, Ardelyx, and Unicycive Therapeutics, and consulting fees and honoraria from Reata Pharmaceuticals and being employed by Renal Associates; Dr. Farag, being employed by Akebia Therapeutics; Dr. Agarwal, receiving steering committee fees, adjudication committee fees, consulting fees, and travel support from Bayer HealthCare Pharmaceuticals and Janssen Research and Development, steering committee fees, consulting fees, and travel support from Vifor Fresenius Medical Care Renal Pharma, Sanofi US Services, Sanofi Aventis US, and Reata Pharmaceuticals, adjudication committee fees, consulting fees, and travel support from Boehringer Ingelheim International, consulting fees and travel support from Eli Lilly, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Boehringer Ingelheim Pharma, and Merck, fees for serving on a data and safety monitoring board from AstraZeneca, Ironwood Pharmaceuticals, and Chinook Therapeutics, lecture fees and travel support from Fresenius USA Marketing, meal reimbursement from Otsuka America Pharmaceutical, OPKO Pharmaceuticals, and E.R. Squibb and Sons, and consulting fees from Lexicon Pharmaceuticals and DiaMedica Therapeutics; Dr. Block, receiving grant support, steering committee fees, and travel support from Akebia Therapeutics and being employed by U.S. Renal Care; Dr. Burke, being employed by and owning stock in Akebia Therapeutics; Dr. Khawaja, being employed by Akebia Therapeutics; Dr. Koury, receiving consulting fees from FibroGen, fees for serving on a data safety and management committee from TG Therapeutics, and consulting fees and fees for serving on a data and safety management committee from Micelle BioPharma; Dr. Lewis, receiving grant support from Akebia Therapeutics; Dr. Luo, being employed by Akebia Therapeutics; Dr. Maroni, being employed by and receiving consulting fees from Akebia Therapeutics and holding a pending patent (number, PCT/US16/25235) on compositions and methods for treating anemia, licensed to Akebia Therapeutics; Dr. Matsushita, receiving grant support and consulting fees from Kyowa Kirin and grant support and honoraria from Fukuda Denshi; Dr. Parfrey, receiving advisory board fees from Vifor Pharma; Dr. Roy-Chaudhury, receiving consulting fees from W.L. Gore, BD, Medtronic, Akebia Therapeutics, Bayer, CorMedix, Reata Pharmaceuticals, Humacyte, and Eko and being employed by Inovasc; Dr. Sarnak, receiving advisory board fees from Bayer and consulting fees from Cardurion Pharmaceuticals; Dr. Sharma, being employed by Bayer U.S. Pharma; Dr. Spinowitz, receiving advisory board fees from Akebia Therapeutics and Otsuka Pharmaceutical; Dr. Vargo, being employed by Akebia Therapeutics; Dr. Walters, being employed by Statistics Collaborative; Dr. Winkelmayer, receiving steering committee fees from Akebia, advisory fees from AstraZeneca, Janssen, Merck, Otsuka Pharmaceutical, and Reata Pharmaceuticals, steering committee fees and advisory fees from Bayer, and advisory fees and consulting fees from Vifor Fresenius Medical Care Renal Pharma (including Relypsa); Dr. Wittes, being employed by Statistics Collaborative; and Dr. Eckardt, receiving grant support from Amgen and Fresenius, lecture fees from Astellas Pharma, grant support and lecture fees from AstraZeneca, Bayer, and Genzyme, consulting fees from Boehringer Ingelheim, advisory board fees from Retrophin, and grant support, advisory board fees, and lecture fees from Vifor Pharma. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.