Abstract
Introduction
Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production.
Methods
To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.
Results
In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.
Discussion/Conclusion
Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Keywords: Vadadustat, Adverse events, Anemia, Chronic kidney disease, Hypoxia-inducible factor pathway
Introduction
Anemia is a common complication of chronic kidney disease (CKD), which largely results from inappropriately low erythropoietin (EPO) production by the failing kidneys [1]. The prevalence of anemia is higher with more advanced CKD, ranging from approximately 20% at stage 3–50% at stage 5 [2]. CKD-related anemia [2] is associated with diminished health-related quality of life, excess healthcare costs, cardiovascular events, and mortality [3, 4, 5, 6]. Current treatment options for anemia include iron supplementation, erythropoiesis-stimulating agents (ESAs), and red blood cell transfusions [7, 8, 9]. Although ESAs are successful in raising hemoglobin concentrations, they may increase the risks of stroke and other thromboembolic events when used to achieve hemoglobin concentrations in the near-normal or normal range. Moreover, ESAs require parenteral administration and include a boxed warning noting that ESAs have been associated with hypertension and, in rare cases, seizures, as well as the progression of selected malignancies [10, 11, 12, 13, 14, 15, 16].
Hypoxia-inducible factor (HIF) is a transcription factor that regulates the expression of various hypoxia-sensitive genes, including EPO, which serves as a key stimulus of erythropoiesis [17, 18]. HIF is regulated by oxygen-dependent proteasomal degradation, with a family of prolyl hydroxylases serving as oxygen sensors [17, 18, 19, 20]. HIF-prolyl hydroxylase inhibitors (HIF-PHIs) constitute a recently identified class of compounds that stabilize HIF, promote EPO expression, and, as a result, have the potential to correct CKD-related anemia [21]. However, since activation of HIF and its downstream genes mediates a widespread response to hypoxia, there is a theoretical risk of adverse events (AEs), including neoplasia, due to promotion of the HIF pathway [22].
Vadadustat is an oral HIF-PHI being developed for the treatment of CKD-related anemia [19, 20]. Vadadustat increased and maintained hemoglobin concentrations in patients with CKD-related anemia in phase 2 studies, irrespective of whether or not patients were receiving dialysis [23, 24, 25]. In phase 3 studies, vadadustat was found to be noninferior to the ESA darbepoetin alfa, with respect to hematologic efficacy [19, 20].
The cardiovascular safety profile of vadadustat was shown to be noninferior to darbepoetin alfa in the INNO2VATE trials in patients with dialysis-dependent CKD (DD-CKD) [20]. The INNO2VATE trials randomized 3,923 patients to vadadustat (1947) or darbepoetin alfa (1955), and the hazard ratio for time to the first major adverse cardiovascular event (MACE; i.e., a composite end point of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke) was 0.96 (95% confidence interval [CI], 0.83–1.11), which met the prespecified noninferiority margin of 1.25 [20].
However, in the PRO2TECT trials in patients with non-dialysis-dependent CKD (NDD-CKD), vadadustat did not meet its prespecified noninferiority margin for cardiovascular safety [19]. Specifically, in the pooled analysis of the PRO2TECT trials in patients with NDD-CKD, in which 1,739 patients received vadadustat and 1,732 received darbepoetin alfa, the hazard ratio for time to first MACE was 1.17 (95% CI, 1.01–1.36), which did not meet the prespecified noninferiority margin of 1.25 [19]. Although differences in safety outcomes among patients with DD- and NDD-CKD have been reported previously for drugs used to treat anemia [26, 27], the reasons for this difference remain unclear.
Safety has previously been reported within the DD-CKD and NDD-CKD trial populations [19, 20]. Therefore, we strive to provide a comprehensive adverse event profile of vadadustat across a continuum of CKD disease severity, and to that end, we have pooled data from the four global phase 3 clinical trials (i.e., the two INNO2VATE and two PRO2TECT phase 3 trials) that included patients with DD- and NDD-CKD.
Materials and Methods
Trial Design
Details regarding the rationale, trial design, methods, statistics, efficacy, and major cardiovascular safety results of the two INNO2VATE and two PRO2TECT phase 3 trials have been published previously [19, 20, 28, 29]. 7,373 adult patients with anemia and DD-CKD (i.e., the INNO2VATE clinical program, comprised of the incident DD-CKD trial [ClinicalTrials.gov identifier NCT02865850] and the prevalent DD-CKD trial [ClinicalTrials.gov identifier NCT02892149]) or NDD-CKD (i.e., the PRO2TECT clinical program, comprised of the ESA-untreated trial [ClinicalTrials.gov identifier NCT02648347] and the ESA-treated trial [ClinicalTrials.gov identifier NCT02680574]) were included. Patients from both the INNO2VATE and PRO2TECT clinical trials were randomized 1:1 to receive either vadadustat or darbepoetin alfa. The starting dose of vadadustat was 300 mg orally once daily, with doses of 150, 450, and 600 mg available for adjustment of the dose to a maximum of 600 mg daily. Darbepoetin alfa was administered subcutaneously or intravenously; the initial dose was based on the prior dose for patients already on darbepoetin alfa and based on product label for those not on darbepoetin alfa prior to randomization. Target hemoglobin concentrations were 10–11 g/dL in the USA and 10–12 g/dL in all other regions. The trials had four defined phases: a correction or conversion period (weeks 0–23), a maintenance period (weeks 24–52) that comprised both the prespecified primary (weeks 24–36) and secondary (weeks 40–52) efficacy evaluation periods, a long-term treatment period (week 53–end of treatment), and a 4-week safety follow-up period.
Study investigators solicited and tabulated potential adverse events at each study visit over the course of each trial. Data were pooled from weeks 0–52 from all 4 trials for a total population analysis. We performed all analyses using the safety population, which included all enrolled patients who received ≥1 dose of study drug.
Analysis of Treatment-Emergent Adverse Events
A treatment-emergent adverse event (TEAE; see online suppl. Table 1 for a list of all safety-related terms, abbreviations, and definitions; see www.karger.com/doi/10.1159/000528443 for all online suppl. material) was defined as an adverse event that started (or a preexisting adverse event that worsened) on or after the first dose of the study drug. TEAEs were summarized by Medical Dictionary for Regulatory Activities (MedDRA; version 23.0) System Organ Class and preferred term overall, seriousness, relationship to study drug (related or not related as assessed by the investigator), and whether the TEAE led to death.
Adverse events of special interest (AESIs) were identified over the course of the clinical development program from nonclinical findings, potential class effects of HIF stabilizers, and ongoing safety surveillance. AESI medical topics included hypertension, congestive heart failure, hyperkalemia, hypersensitivity, hepatotoxicity, malignant or unspecified tumors, pulmonary hypertension, cardiac valve disorders, and retinal effects due to vascular endothelial growth factor expression. We defined the duration of exposure as the number of days between the dates that the first and last doses of the study drug were administered.
To further assess AESIs pertaining to hepatotoxicity, blood samples to assess liver function were collected at screening visit 1, baseline, weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52. Liver function tests include the following: total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase.
Statistical Analysis
Continuous variables are summarized by descriptive statistics. Categorical variables are tabulated by frequency count and percentage. Counts, proportions, events, and event rates per 100 patient-years were calculated for patients who experienced a TEAE, AESI, and/or treatment-emergent serious adverse event (TE-SAE). Rate ratios and 95% CIs were calculated for each AESI to evaluate potential differences between treatment arms.
Results
Baseline Characteristics and Treatment Exposure
Overall, demographics and other baseline characteristics in the pooled DD-CKD, NDD-CKD, and total safety populations for the four global phase 3 trials were well balanced across the vadadustat and darbepoetin alfa treatment groups (Table 1). Patients in the NDD-CKD population were older and more likely to be women, have diabetes mellitus, and use statins compared with the DD-CKD population (Table 1).
Table 1.
Demographics and baseline characteristics - DD-CKD and NDD-CKD safety populations for global phase 3 studies
| Characteristic | DD-CKD population |
NDD-CKD population |
Total safety population |
|||
|---|---|---|---|---|---|---|
| VADA (N = 1,947) | DA (N = 1,955) | VADA (N = 1,739) | DA (N = 1,732) | VADA (N = 3,686) | DA (N = 3,687) | |
| Age, years, mean (SD) | 57.8 (14.0) | 58.1 (13.9) | 66.2 (13.8) | 65.7 (13.6) | 61.8 (14.5) | 61.7 (14.3) |
| >65 years, n (%) | 667 (34.3) | 663 (33.9) | 1,030 (59.2) | 1,022 (59.0) | 1,697 (46.0) | 1,685 (45.7) |
| Sex, male, n (%) | 1,089 (55.9) | 1,110 (56.8) | 797 (45.8) | 738 (42.6) | 1,886 (51.2) | 1,848 (50.1) |
| Race, n (%) | ||||||
| White | 1,255 (64.5) | 1,231 (63.0) | 1,177 (67.7) | 1,172 (67.7) | 2,432 (66.0) | 2,403 (65.2) |
| Black | 470 (24.1) | 478 (24.5) | 280 (16.1) | 302 (17.4) | 750 (20.3) | 780 (21.2) |
| Asian | 88 (4.5) | 106 (5.4) | 110 (6.3) | 92 (5.3) | 198 (5.4) | 198 (5.4) |
| American Indian or Alaskan Native | 20 (1.0) | 30 (1.5) | 54 (3.1) | 49 (2.8) | 74 (2.0) | 79 (2.1) |
| Othera | 73 (3.7) | 64 (3.3) | 99 (5.7) | 98 (5.7) | 162 (4.4) | 155 (4.2) |
| Region, n (%)b | ||||||
| US | 1,180 (60.6) | 1,181 (60.4) | 861 (49.5) | 862 (49.8) | 2,041 (55.4) | 2,043 (55.4) |
| Europe | 277 (14.2) | 295 (15.1) | 295 (17.0) | 288 (16.6) | 572 (15.5) | 583 (15.8) |
| Non-US/Europe | 490 (25.2) | 479 (24.5) | 583 (33.5) | 582 (33.6) | 1,073 (29.1) | 1,061 (28.8) |
| BMI, kg/m2, mean (SD) | 28.5 (7.14) | 28.4 (7.07) | 29.4 (7.13) | 29.7 (7.25) | 28.9 (7.15) | 29.1 (7.18) |
| Diabetes mellitus, n (%) | 1,070 (55.0) | 1,088 (55.7) | 1,098 (63.1) | 1,115 (64.4) | 2,168 (58.8) | 2,203 (59.8) |
| Statin use, n (%) | 943 (48.4) | 969 (49.6) | 1,055 (60.7) | 1,042 (60.2) | 1,998 (54.2) | 2,011 (54.5) |
BMI, body mass index; CKD, chronic kidney disease; DA, darbepoetin alfa; DD, dialysis-dependent; NDD, non-dialysis-dependent; US, United States; VADA, vadadustat.
Native Hawaiian or other Pacific Islander, multiple or not reported.
Europe (DD-CKD population) included Bulgaria, France, Germany, Italy, Poland, Portugal, Serbia, Ukraine, the UK; Europe (NDD-CKD population) included Austria, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Poland, Romania, Serbia, Slovakia, Spain, Turkey, the UK; Non-US/Europe (DD-CKD population) included Argentina, Australia, Brazil, Canada, Israel, Mexico, Russia, South Korea; Non-US/Europe (NDD-CKD population) included Argentina, Australia, Brazil, Canada, Chile, Colombia, Israel, Malaysia, Mexico, New Zealand, Russia, South Africa, South Korea, and Ukraine.
In the NDD-CKD population, the mean (SD) estimated glomerular filtration rate was 21.9 (11.8) mL/min/1.73 m2 in the vadadustat treatment group and 22.3 (12.3) mL/min/1.73 m2 in the darbepoetin alfa treatment group.
Across the four pooled studies, 3,686 patients were exposed to vadadustat and 3,687 to darbepoetin alfa for a median (25%, 75% range) duration of 56.7 (31.9–91.7) weeks and 70.0 (39.9–102.1) weeks, respectively. Treatment exposure in the NDD-CKD, DD-CKD, and total safety populations is reported in online supplementary Table 2, and total treatment exposure by time period is reported in online supplementary Table 3. Overall, a total of 2,011 (54.6%) patients were exposed to vadadustat, and 2,368 (64.2%) patients were exposed to darbepoetin alfa for ≥52 weeks. A total of 695 (18.9%) patients were exposed to vadadustat, and 887 (24.1%) patients were exposed to darbepoetin alfa for ≥104 weeks. Discontinuations from study drug treatment were more frequent during the first 26 weeks of the study in the vadadustat group than in the darbepoetin alfa group.
Treatment-Emergent Adverse Events
Rates of TEAEs in the vadadustat and darbepoetin alfa groups across the pooled studies were similar, with 88.9% of patients treated with vadadustat and 89.3% of patients treated with darbepoetin alfa experiencing ≥1 TEAE (Table 2). Expressed in patient-years of exposure, rates of any TEAE in the vadadustat and darbepoetin alfa groups were 432.8 events/100 patient-years and 441.4 events/100 patient-years, respectively. A summary of TEAEs reported for subjects in the pooled CKD population for global Phase 3 studies is presented over time and by treatment group in online supplementary Table 4. Overall, total TEAEs were reported more frequently from day 1 to week 13 period, with slightly higher reporting in the vadadustat treatment group than the darbepoetin alfa treatment group. Drug-related TEAEs, drug-related treatment-emergent SAEs, TEAEs that led to discontinuation from study drug, and drug-related TEAEs that led to discontinuation were reported more frequently from day 1 to week 13 and were more frequently reported in the vadadustat treatment group than the darbepoetin alfa treatment group. After 13 weeks, the frequency of occurrence of all the abovementioned TEAEs tended to decrease slightly over time, with no clear difference between the treatment groups.
Table 2.
Summary of treatment-emergent adverse events and treatment-emergent adverse events by system organ class reported in <5% of patients in any treatment group - pooled total population
| Treatment-emergent adverse events | Vadadustat (W = 3,686) Exposure = 6,335.3 PY |
Darbepoetin alfa (W = 3,687) Exposure = 6,420.1 PY |
||
|---|---|---|---|---|
| n (%) | Events (events per 100 PY) | n (%) | Events (events per 100 PY) | |
| Summary | ||||
| Any TEAE | 3,277 (88.9) | 27,417 (432.8) | 3,292 (89.3) | 28,340 (441.4) |
| Severity | ||||
| Mild | 589 (16.0) | 12,477 (196.9) | 601 (16.3) | 12,781 (199.1) |
| Moderate | 1,106 (30.0) | 10,361 (163.5) | 1,095 (29.7) | 10,926 (170.2) |
| Severe | 1,582 (42.9) | 4,579 (72.3) | 1,596 (43.3) | 4,633 (72.2) |
| Any drug-related TEAE | 371 (10.1) | 576 (9.1) | 174 (4.7) | 218 (3.4) |
| Any severe TEAE | 1,582 (42.9) | 4,579 (72.3) | 1,596 (43.3) | 4,633 (72.2) |
| Any TE-SAE | 2,139 (58.0) | 6,981 (110.2) | 2,186 (59.3) | 7,159 (111.5) |
| Any drug-related TE-SAE | 66 (1.8) | 75 (1.2) | 55 (1.5) | 64 (1.0) |
| Any TEAE leading to discontinuation | 259 (7.0) | 321 (5.1) | 126 (3.4) | 159 (2.5) |
| Any drug-related TEAE leading to discontinuation | 73 (2.0) | 85 (1.3) | 11 (0.3) | 12 (0.2) |
| Any TEAE leading to death | 593 (16.1) | 593 (9.4) | 596 (16.2) | 597 (9.3) |
| By MedDRA System Organ Class, reported in >5% of patients | ||||
| Any TEAE | 3,277 (88.9) | 432.8 | 3,292 (89.3) | 441.4 |
| Infections and infestations | 1,873 (50.8) | 68.6 | 1,942 (52.7) | 71.6 |
| Gastrointestinal disorders | 1,483 (40.2) | 52.4 | 1,297 (35.2) | 46.7 |
| Metabolism and nutrition disorders | 1,274 (34.6) | 42.3 | 1,336 (36.2) | 42.1 |
| Vascular disorders | 1,140 (30.9) | 30.6 | 1,213 (32.9) | 32.8 |
| Injury, poisoning, and procedural complications | 1,088 (29.5) | 36.8 | 1,132 (30.7) | 39.7 |
| Respiratory, thoracic, and mediastinal disorders | 902 (24.5) | 26.9 | 966 (26.2) | 28.9 |
| General disorders and administration site conditions | 984 (26.7) | 24.1 | 883 (23.9) | 21.9 |
| Nervous system disorders | 880 (23.9) | 23.7 | 892 (24.2) | 22.4 |
| Musculoskeletal and connective tissue disorders | 843 (22.9) | 22.7 | 895 (24.3) | 24.3 |
| Renal and urinary disorders | 872 (23.7) | 19.1 | 860 (23.3) | 18.8 |
MedDRA, Medical Dictionary for Regulatory Activities; PY, patient-years; TEAE, treatment-emergent adverse event; TE-SAE, treatment-emergent serious adverse event.
A total of 10.1% of the patients in the vadadustat group and 4.7% of the patients in the darbepoetin alfa group had ≥1 drug-related TEAE (Table 2). 1.8% of the patients in the vadadustat group and 1.5% of the patients in the darbepoetin alfa group had ≥1 drug-related TE-SAE (Table 2). Discontinuation of the study drug due to drug-related TEAEs occurred in 2.0% of the patients in the vadadustat group and 0.3% of the patients in the darbepoetin alfa group (Table 2). In the vadadustat treatment group, a drug-related TEAE was considered to have led to the death of 1 patient (cardiac arrest), while drug-related TEAEs were considered to have led to the death of 4 patients in the darbepoetin alfa treatment group (investigator-reported causes of death: aspiration pneumonia, cardiac arrest, myocardial infarction (MI), and acute MI).
The most common TEAEs by MedDRA System Organ Class in either treatment group were infections and infestations, gastrointestinal disorders, and metabolism and nutrition disorders (online suppl. Table 5). The most common TEAEs by MedDRA preferred term reported in >10% of patients in either treatment group were end-stage renal disease, hypertension, diarrhea, and hyperkalemia (online suppl. Table 5). The occurrence of seizures was 0.8% across the four pooled studies in both the vadadustat and darbepoetin alfa groups and similar between the treatment groups.
Treatment-Emergent Serious Adverse Events
Rates of TE-SAEs in the vadadustat and darbepoetin alfa groups across the pooled studies were similar, as 58.0% of patients treated with vadadustat and 59.3% of patients treated with darbepoetin alfa experienced ≥1 TE-SAE (Table 3). Rates of any TE-SAEs in the vadadustat and darbepoetin alfa groups were 110.2 events/100 patient-years and 111.5 events/100 patient-years, respectively.
Table 3.
Treatment-emergent serious adverse events by system organ class reported in >2% of patients in any treatment group − pooled total population
| MedDRA system organ class | Vadadustat (N = 3,686) Exposure = 6,335.3 PY |
Darbepoetin alfa (N = 3,687) Exposure = 6,420.1 PY |
||
|---|---|---|---|---|
| n (%) | Events (events per 100 PY) | n (%) | Events (events per 100 PY) | |
| Any TE-SAE | 2,139 (58.0) | 6,981 (110.2) | 2,186 (59.3) | 7,159 (111.5) |
| Infections and infestations | 858 (23.3) | 1,494 (23.6) | 884 (24.0) | 1,504 (23.4) |
| Renal and urinary disorders | 684 (18.6) | 790 (12.5) | 667 (18.1) | 763 (11.9) |
| Cardiac disorders | 600 (16.3) | 1,017 (16.1) | 670 (18.2) | 1,106 (17.2) |
| Metabolism and nutrition disorders | 394 (10.7) | 569 (9.0) | 387 (10.5) | 537 (8.4) |
| Respiratory, thoracic, and mediastinal disorders | 307 (8.3) | 449 (7.1) | 336 (9.1) | 480 (7.5) |
| Blood and lymphatic system disorders | 131 (3.6) | 159 (2.5) | 142 (3.9) | 172 (2.7) |
MedDRA, Medical Dictionary for Regulatory Activities; PY, patient-years; TE-SAE, treatment-emergent serious adverse event.
The most common TE-SAEs by MedDRA System Organ Class in either treatment group were infections and infestations, renal and urinary disorders, and cardiac disorders (online suppl. Table 6). The most frequently experienced TE-SAEs by MedDRA preferred term reported in >5% of patients in either treatment group were end-stage renal disease (most of which were documented in the NDD-CKD population) and pneumonia (online suppl. Table 6).
TEAEs Leading to Death
Rates of TEAEs leading to death were similar in the vadadustat (16.1%) and darbepoetin alfa (16.2%) groups (Table 2). The most common TEAEs leading to death by MedDRA System Organ Class in either treatment group were cardiac disorders, infections, and infestations (online suppl. Table 7). TEAEs leading to death for >1% of patients by MedDRA preferred term in either treatment group were cardiac arrest and end-stage renal disease (online suppl. Table 7).
Adverse Events of Special Interest
Overall, AESIs were reported for 41.1% and 45.2% of patients in the vadadustat and darbepoetin alfa treatment groups, respectively, corresponding to a relative risk (95% CI) of 0.91 (0.86, 0.96) (Fig. 1). The rate of events per 100 patient-years was also numerically lower in the vadadustat treatment group compared to the darbepoetin alfa treatment group (49.5 and 54.9 TEAEs per 100 patient-years, respectively). AESI per medical topics (grouping of preferred terms) that occurred in >3% of patients in the vadadustat and darbepoetin alfa groups were hypertension (18.0% and 21.0%), congestive heart failure (10.3% and 11.5%), hyperkalemia (9.9% and 11.9%), hypersensitivity (7.7% and 7.9%), hepatotoxicity (6.8% and 6.5%), and malignancy (3.3% and 4.0%) (Fig. 1).
Fig. 1.
Treatment-emergent adverse events of special interest in any treatment group − pooled total population. Medical topics include events identified as a result of the broad search of Standardized MedDRA Queries and/or group of preferred terms. AESI, adverse event of special interest; DA, darbepoetin alfa; MedDRA, Medical Dictionary for Regulatory Activities; PY, patient-years; VADA, vadadustat; VEGF, vascular endothelial growth factor.
Hypertension as a medical topic was reported for 18.0% of patients in the vadadustat group and 21.0% of patients in the darbepoetin alfa group. The most frequent AESI preferred term for hypertension among patients in the vadadustat and darbepoetin alfa treatment groups, respectively, was hypertension (13.4% vs. 15.9%).
Pulmonary hypertension was reported for 2.4% of patients in the vadadustat group and 2.6% of patients in the darbepoetin alfa group. The most frequent AESI preferred term for pulmonary hypertension among patients in the vadadustat and darbepoetin alfa treatment groups, respectively, was pulmonary hypertension (1.6% vs. 1.9%).
Congestive heart failure was reported for 10.3% of patients in the vadadustat group and 11.5% of patients in the darbepoetin alfa group. The most frequent AESI preferred terms for congestive heart failure among patients in the vadadustat and darbepoetin alfa treatment groups, respectively, were congestive cardiac failure (3.9% vs. 4.3%), pulmonary edema (2.4% vs. 2.8%), acute cardiac failure (1.6% in each treatment group), cardiac failure (1.4% vs. 1.7%), and acute pulmonary edema (1.0% vs. 0.8%).
Hyperkalemia was reported for 9.9% of patients in the vadadustat group and 11.9% of patients in the darbepoetin alfa group. Among patients in the vadadustat and darbepoetin alfa treatment groups, respectively, a blood potassium increase was reported for 0.2% and 0.6% of patients.
Hypersensitivity was reported for 7.7% of patients in the vadadustat group and 7.9% of patients in the darbepoetin alfa group. The most frequent AESI preferred terms were facial edema (1.4% vs. 1.2%) and rash (1.4% vs. 1.1%).
Hepatotoxicity was reported for 6.8% of patients in the vadadustat group and 6.5% of patients in the darbepoetin alfa group. The most frequent AESI preferred terms for hepatotoxicity were transaminases increased (1.3% vs. 1.2%); ALT increased (1.0% vs. 1.1%); and AST increased (0.7% vs. 1.2%) (online suppl. Table 8). The number of patients with abnormal hepatic lab parameters across all study periods (between weeks 2–52) was generally similar across the vadadustat and darbepoetin alfa treatment groups (online suppl. Table 9). Most liver function test changes were due to increased transaminases without any change in bilirubin.
Malignancies were reported in 3.3% of patients in the vadadustat group and 4.0% of patients in the darbepoetin alfa group. The most frequent malignancies by preferred term in the vadadustat and darbepoetin alfa groups, respectively, were basal cell carcinoma (0.4% vs. 0.5%), squamous cell carcinoma of the skin (0.4% vs. 0.3%), and prostate cancer (0.1% vs. 0.3%). TE-SAEs of neoplasm (which include benign, malignant, and unspecified growths) were reported in 2.7% in the vadadustat group and 3.6% in the darbepoetin alfa group. TEAEs of neoplasm resulting in death were reported in 0.4% of the vadadustat group and 0.8% of the darbepoetin alfa group (online suppl. Table 10).
Discussion
In a pooled analysis of the safety populations from four phase 3 clinical trials evaluating the treatment of anemia in patients with DD- and NDD-CKD, the safety profile of vadadustat was generally similar to that of darbepoetin alfa, with similar incidence of TEAEs, TE-SAEs, and deaths observed. Although a difference was observed in the rate of drug-related TEAEs between the vadadustat (10.1%) and darbepoetin alfa (4.7%) groups, the difference can be attributed to the open-label nature of the studies and the fact that the majority of participants were previously treated with an ESA [19, 20]. Despite the high-risk patient population with advanced CKD or kidney failure included in this analysis, the overall adverse event profile of vadadustat was comparable to that of darbepoetin alfa in the treatment of CKD-related anemia across a large global clinical development program. These present data, in combination with the previously reported MACE and expanded MACE data in discrete NDD- and DD-CKD patient populations, can better inform the full safety profile of vadadustat as a treatment for anemia due to CKD [19, 20].
The occurrence of AESIs such as hypertension, congestive heart failure, and hyperkalemia were numerically less frequent in patients randomized to vadadustat relative to darbepoetin. In addition, the proportion of patients with abnormal liver enzymes (i.e., ALT, AST, and total bilirubin) was similar across the vadadustat and darbepoetin alfa treatment groups. Although HIF activation raises theoretical concerns of malignancy [21, 30], no such signals were observed in the INNO2VATE and PRO2TECT phase 3 trials. While the follow-up duration may have been too short for meaningful evaluation of cancer incidence, malignancies and death due to malignancies were numerically less frequent in vadadustat-treated patients compared with darbepoetin alfa-treated patients (TEAEs of neoplasm: vadadustat group, 174 [4.7%]; darbepoetin alfa group, 223 [6.0]; TEAEs of neoplasm resulting in death: vadadustat group, 16 [0.4%]; and darbepoetin alfa group, 31 [0.8%]).
Other HIF-PHIs being developed for CKD-related anemia have demonstrated variability in the risk of these adverse events in phase 3 studies. For roxadustat, investigators reported no clinically meaningful differences in neoplasm-related adverse event rates compared with epoetin alfa [31]. Roxadustat resulted in numerically higher rates of treatment-emergent seizures compared with placebo in patients with NDD-CKD [32]. For daprodustat, in contrast, the frequency of cancer-related death, tumor progression, and cancer recurrence were higher in patients with NDD-CKD treated with daprodustat compared to those treated with darbepoetin alfa [33].
It is important to note the limitations of the INNO2VATE and PRO2TECT trials. For both trials, investigators were aware of the treatment assignments. The lack of a double-blind study design to mask the treatment assignments may have led to a proclivity to consider an adverse event as being more frequently associated with the new interventional drug as compared to darbepoetin alfa. However, although differences in drug-related TEAEs may be attributable to the open-label design of each study, one cannot exclude the possibility that they are due to differences between the treatments. Second, we used darbepoetin alfa as the control in these trials and cannot assess noninferiority to other ESAs. Finally, although the sample size was relatively large and the median follow-up was >1.5 years, the analysis has limited power to detect differences in adverse events that require longer drug exposure to become apparent.
In conclusion, the safety profile of vadadustat was found to be similar to that of darbepoetin alfa in an analysis of the pooled safety population from four phase 3 clinical trials of patients with CKD-related anemia.
Statement of Ethics
Before initiating a study, each investigator received approval from their respective Institutional Review Board (IRB) and/or Independent Ethics Committee (IEC). Study investigators obtained additional study approvals and written informed patient consents as required by national and local ethics regulations. The present manuscript is a secondary analysis of original research previously published in the New England Journal of Medicine [15, 16]. For a list of the study investigators who participated in the original phase 3 trials and therefore received IRB/IEC approval and written patient consent forms, please see these original manuscripts.
An independent Ethics Committee approved the informed consent forms. We conducted all trials in accordance with the International Conference on Harmonization with Good Clinical Practice guidelines, US Food and Drug Administration regulations, and the principles of the Declaration of Helsinki.
Conflict of Interest Statement
Rajiv Agarwal reports personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals Inc., Akebia Therapeutics, Inc., Boehringer Ingelheim, Eli Lilly, and Vifor Pharma; he has received personal fees from Lexicon and Reata; he is a member of data safety monitoring committees for Vertex and Chinook; he is a member of steering committees of randomized trials for Akebia Therapeutics Inc., Bayer, and Relypsa, and a member of adjudication committees for Bayer; he has served as associate editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation, has been an author for UpToDate, and has received research grants from the NIH and the U.S. Veterans Administration. Sanjeev Anand, Christine Solinsky, Dennis Vargo, and Wenli Luo are employees of Akebia Therapeutics, Inc. Kai-Uwe Eckardt has received 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. Patrick S. Parfrey has received personal fees from Akebia Therapeutics Inc. During the conduct of the study, and advisory board fees from Vifor Pharma. Mark J. Sarnak has received steering committee fees from Akebia Therapeutics Inc., which was paid to Tufts Medical Center. Wolfang C. Winkelmayer has received steering committee fees from Akebia Therapeutics Inc., advisory fees from AstraZeneca, Bayer, Janssen, Merck, Otsuka, Reata, and Zydus, steering committee and data safety monitoring fees from Bayer and Merck, and an honorarium for an invited lecture by Pharmacosmos. He receives stipends for being an associate editor for JAMA. He has received research grants from several institutes within the NIH. Glenn M. Chertow serves on the board of directors for Satellite Healthcare. He has served as a steering committee cochair, member, or advisor with Akebia Therapeutics Inc., Ardelyx, AstraZeneca, CloudCath, Cricket, DiaMedica, Durect, Gilead, Miromatrix, Outset, Reata, Sanifit, and Vertex. He has served as chair or member of DSMB/DMCs with Angion, Bayer, Mineralys, Palladio, and ReCor. He has received research grants from NIAID, NIDDK, and NHLBI.
Funding Sources
These studies were funded by Akebia Therapeutics, Inc., and Otsuka Pharmaceutical.
Author Contributions
Rajiv Agarwal, Kai-Uwe Eckardt, Patrick S. Parfrey, Mark J. Sarnak, Wolfgang C. Winkelmayer, and Glenn M. Chertow provided substantial contributions to the conception of the work. All authors substantially contributed to the acquisition, analysis, or interpretation of data for the manuscript. All authors participated in drafting, revising, and critically reviewing the manuscript for important intellectual content. All authors approved the final version of this manuscript to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Data Availability Statement
Proposals for access to original data should be sent to medicalinfo@akebia.com. De-identified patient-level data will be available 12 months after US and EU approval to qualified researchers with an appropriate research proposal. The research proposal is subject to review by an independent review board with final approval by Akebia Therapeutics, Inc.
Supplementary Material
Supplementary data
Acknowledgments
Medical writing assistance was provided by Cadent Medical Communications, LLC, a Syneos Health® group company, and was supported by Akebia Therapeutics, Inc.
Funding Statement
These studies were funded by Akebia Therapeutics, Inc., and Otsuka Pharmaceutical.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data
Data Availability Statement
Proposals for access to original data should be sent to medicalinfo@akebia.com. De-identified patient-level data will be available 12 months after US and EU approval to qualified researchers with an appropriate research proposal. The research proposal is subject to review by an independent review board with final approval by Akebia Therapeutics, Inc.