Vadadustat for Anemia in Patients with Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD) and is associated with a reduced health-related quality of life, an increase in the need for red blood cell transfusions, and an increased risk for cardiovascular events. Standard care for the management of anemia in patients with CKD is the use of erythropoiesis-stimulating agents (ESAs) (recombinant human erythropoietin and its derivatives). Previous studies have demonstrated an increase in the risk of stroke, vascular access thrombosis, and death associated with the use of ESAs to target hemoglobin concentrations in the normal or near-normal range in patients with CKD, resulting in recommendations for caution in the use of ESAs and for only partial correction of anemia in that patient population.

Hypoxia-inducing factor (HIF) stimulates erythropoietin production by the liver and kidneys. HIF is regulated by oxygen-dependent proteasomal degradation through a family of prolyl hydroxylases that serve as oxygen sensors. HIF prolyl hydroxylase inhibitors represent a recently developed  class of compounds that stabilize HIF, thereby stimulating endogenous erythropoietin production and ultimately erythropoiesis.

Vadadustat is an investigational oral HIF prolyl hydroxylase inhibitor in development for the treatment of CKD-related anemia. The phase 3 development process included four phase 3 trials: two that included patients with non-dialysis-dependent CKD (PRO₂TECT) and two that included patients with dialysis-dependent CKD (DD-CKD) (INNO₂VATE). All four trials evaluated the cardiovascular safety and efficacy of vadadustat compared with darbepoetin alfa.

INNO₂VATE Trials

Kai-Uwe Eckardt, MD, and colleagues reported results of the INNO₂VATE trials evaluating the cardiovascular safety and hematologic efficacy of vadadustat compared with darbepoetin alfa [New England Journal of Medicine; 2021;384(17):1601-1612].

The primary safety end point of interest (assessed in a time-to-event analysis) was the first occurrence of a major cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction [MI], or a non-fatal stroke), pooled across the trials (noninferiority margin, 1.25). A secondary safety point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary efficacy end point was the mean change in hemoglobin from baseline to weeks 24 and 36; the key secondary efficacy end point was the change in hemoglobin from baseline to weeks 40 to 52, in each trial (noninferiority margin, –0.75 g per deciliter).

The starting dose of vadadustat was 300 mg orally once daily, with doses of 150, 450, and 600 mg available for dose adjustment to a maximum of 600 mg per day. Darbepoetin alfa was administered subcutaneously or intravenously; the initial dose was based on the previous dose, or, in the case of patients who had not received darbepoetin alfa prior to randomization, on information on the product label.

A total of 3923 patients underwent randomization across the two trials: 369 in the incident DD-CKD trial and 3354 in the prevalent DD-CKD trial. Median duration of follow-up was 1.2 years in the incident DD-CKD trial and 1.7 years in the prevalent DD-CKD trial.

In both trials, baseline characteristics of the two treatment groups were generally well balanced with the exception that in the incident DD-CKD trial the percentage of patients with diabetes mellitus was higher among patients randomized to the vadadustat group than among those randomized to the darbepoetin alfa group (58.0% vs 51.1%).

The safety end points analyses were based on the pooled safety population: 1947 in the vadadustat group and 1955 in the darbepoetin alfa group. A first MACE occurred in 18.2% of patients in the vadadustat group (355/1947) and in 19.3% of patients in the darbepoetin alfa group (377/1955) (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.83-1.11). In the vadadustat group, the percentages and numbers of patients in whom the first MACE was death from any cause, a nonfatal MI, or a nonfatal stroke were 13.0% (253), 3.9% (76), and 1.3% (26), respectively. The corresponding percentages and numbers in the darbepoetin alfa group were 12.9% (253), 4.5% (87), and 1.9% (37), respectively.

Within each trial, the results were qualitatively consistent; however, the CI in the incident DD-CKD trial was wide (incident DD-CKD trial: HR of a first MACE, 0.97; 95% CI, 0.54-1.76; prevalent DD-CKD trial: HR, 0.96; 95% CI, 0.83-1.12).

In the incident DD-CKD trial, the mean differences between the groups in the change in hemoglobin concentration were –0.31 g per deciliter (95% CI, –0.53 to –0.10) at weeks 24 to 36, and –0.07 g per deciliter (95% CI, –0.34 to 0.19) at weeks 40 to 52. In the prevalent DD-CKD trial, the mean differences were ­–0.17 g per deciliter (95% CI, –0.23 to –0.10) at weeks 24 to 36, and –0.18 g per deciliter (95% CI, –0.25 to –0.12) at weeks 40 to 52.

In the incident DD-CKD trial, the incidence of at least one adverse event was 83.8% of patients in the vadadustat group and 85.5% of patients in the darbepoetin alfa group. The incidence of any serious adverse event was 49.7% in the vadadustat group and 56.5% in the darbepoetin alfa group.

In the prevalent DD-CKD trial, the incidence of at least one adverse event was 88.3% in the vadadustat group and 89.3% in the darbepoetin alfa group. The incidence of any serious event was 55.0% in the vadadustat group and 58.3% in the darbepoetin alfa group.

In the prevalent DD-CKD trial, 88.3% of patients in the vadadustat group had at least one adverse event; 89.3% of patients in the darbepoetin alfa group had at least one adverse event. Serious adverse events occurred in 55.0% of the vadadustat group and 58.3% of the darbepoetin alfa group.

Common adverse events across all four trials included hypertension, diarrhea, pneumonia, hyperkalemia, fluid overload, fall, headache, hypotension, nausea, urinary tract infection, and cough.

The authors cited some limitations to the two trials: the investigators were aware of the treatment assignments, precluding a meaningful evaluation of patient-reported physical function and fatigue; lack of measurement of  residual kidney function; the use of darbepoetin alfa as control in both trials; and lack of real-world data from longer-term clinical practice.

In summary, the researchers said, “In these two trials, we found that vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations in patients with CKD who were undergoing dialysis.”

The trials were supported by Akebia Therapeutics and Otsuka Pharmaceutical.

Takeaway Points

1. Results of the INNO₂VATE trials examining the safety and efficacy of vadadustat as compared with darbepoetin alfa for anemia in patients undergoing dialysis were reported.
2. The primary safety end point was the first occurrence of a major adverse cardiovascular event in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease; the primary efficacy end point was change in hemoglobin from baseline to weeks 24 to 36.
3. Compared with darbepoetin alfa, vadadustat was noninferior in cardiovascular safety and correction and maintenance of hemoglobin concentrations among patients with anemia and CKD undergoing dialysis.

PRO₂TECT Trials

Glenn M. Chertow, MD, MPH, and colleagues reported the results of the PRO₂TECT trials among patients with anemia and non-dialysis-dependent chronic kidney disease (NDD-CKD) [New England Journal of Medicine; 384(17):1589-1600]. The study population included patients with NDD-CKD not previously treated with an erythropoiesis-stimulating agent (ESA) and a hemoglobin concentration of <10 g per deciliter and 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 of interest (assessed in a time-to-event analysis) was the first occurrence of a major cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction [MI], or a non-fatal stroke), pooled across the trials (noninferiority margin, 1.25). A secondary safety point was the first occurrence of expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary efficacy end point was the mean change in hemoglobin from baseline to weeks 24 and 36; the key secondary efficacy end point was the change in hemoglobin from baseline to weeks 40 to 52, in each trial.

The starting dose of vadadustat was 300 mg orally once daily, with doses of 150, 450, and 600 mg available for dose adjustment to a maximum of 600 mg per day. Darbepoetin alfa was administered subcutaneously or intravenously; the initial dose was based on the previous dose, or, in the case of patients who had not received darbepoetin alfa prior to randomization, on information on the product label.

A total of 3476 patients underwent randomization; 1751 patients were randomized to the trial among ESA-untreated patients (879 in the vadadustat group and 872 in the darbepoetin alfa group) and 1725 (862 in the vadadustat group and 863 in the darbepoetin alfa group) were randomized to the trial involving patients previously treated with an ESA. Median duration of follow-up was 1.63 years in the ESA-untreated trial and 1.80 years in the previously ESA-treated trial. The randomized groups were generally well balanced in both trials.

The safety analyses were conducted using all patients who received at least one dose of the trial drug (safety population) pooled across the two trials: 1739 in the vadadustat group and 1732 in the darbepoetin alfa group. A first MACE occurred in 22.0% of patients (382/1739) in the vadadustat group and 19.9% of patients (344/1732) in the darbepoetin alfa group (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.01-1.36). The HR did not meet the prespecified noninferiority margin of 1.25.

In subgroup analyses of MACE, death from any cause occurred in 18.3% of patients (n=319) in the vadadustat group and 17.7% of patients (n=307) in the darbepoetin alfa group; nonfatal MI in 3.9% (n=67) and 2.8% (n=48), respectively; and nonfatal stroke in 2.0% (n=34) and 1.6% (n=28), respectively. The first expanded MACE occurred in 25.9% of patients (n=451) in the vadadustat group and 24.5% of patients (n=424) in the darbepoetin alfa group (HR, 1.11; 95% CI, 0.97-1.27).

The time to CKD progression was similar between the two treatment groups in the two trials. Mean systolic and diastolic blood pressures in the two treatment groups were similar over the course of both trials.

The mean differences between groups in the change in hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, –0.04 to 0.15) in the trial with ESA-untreated patients and –­0.01 g per deciliter (95% CI, –0.09 to 0.07) in the trial among ESA-treated patients, meeting the prespecified noninferiority margin of –0.75 g per deciliter.

In the ESA-untreated NDD-CKD trials, the incidence of at least one adverse event was 90.9% in the vadadustat group and 91.6% in the darbepoetin alfa group. The incidence of any serious adverse event was 65.3% in the vadadustat group and 64.5% in the darbepoetin alfa group.

In the ESA-treated NDD-CKD trials, the incidence of at least one adverse event was 89.1% in the vadadustat group and 87.7% in the darbepoetin alfa group. The incidence of any serious adverse event was 58.5% in the vadadustat group and 56.6% in the darbepoetin group.

Common adverse events across all trials were diarrhea, end-stage renal disease hyperkalemia, hypertension, peripheral edema, fall, pneumonia, urinary tract infection, and nausea.

The primary study limitation cited by the authors was, based on guidance from regulatory agencies, the trials were not placebo-controlled.

In summary, the researchers said, “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.”

The trials were supported by Akebia Therapeutics and Otsuka Pharmaceutical.

Takeaway Points

1. Results of the PRO₂TECT trials examining the safety and efficacy of vadadustat as compared with darbepoetin alfa for anemia in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) were reported.
2. The primary safety end point was the first occurrence of a major adverse cardiovascular event in patients with CKD-related anemia who had not received previous treatment with an erythropoiesis-stimulating agent (ESA) and in patients with anemia actively treated with ESAs; the primary efficacy end point was change in hemoglobin from baseline to weeks 24 to 36.
3. Vadadustat met the prespecified noninferiority criterion for hematologic efficacy but did not meet the prespecified noninferiority criterion for cardiovascular safety.