Drug Trials Snapshots: VAFSEO
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the VAFSEO Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
VAFSEO (vadadustat)
(VAFF-see-oh)
Akebia Therapeutics, Inc.
Approval date: Akebia Therapeutics, Inc.
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
VAFSEO is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor that treats anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months.
How is this drug used?
VAFSEO is oral medication that is taken once daily, with or without food.
Who participated in the clinical trials?
The FDA approved VAFSEO based on evidence from two clinical trials, INNO2VATE-1 (NCT02865850) and INNO2VATE-2 (NCT02892149), in which 3,923 adult patients with anemia due to CKD who have been receiving dialysis for at least three months were equally randomized to receive either VAFSEO or darbepoetin alfa. The trials were conducted at 83 sites in one study and 275 sites in another study in a total of 18 countries in North America, South America, Europe, Africa, and Asia, of which 2,361 (60%) patients were from the United States. The same trials were used to evaluate the safety and efficacy of VAFSEO.
How were the trials designed?
VAFSEO was evaluated in two clinical trials in 3,923 adult patients with anemia due to CKD who have been receiving dialysis for at least three months.
INNO2VATE-1 and INNO2VATE-2 were both global, multi-center, randomized, active-controlled, non-inferiority, open-label trials. Patients in each trial were randomized equally to receive either VAFSEO with a starting dose of 300 mg once daily or darbepoetin alfa administered subcutaneously or intravenously as per the prescribing information for 52 weeks to assess the efficacy endpoints. VAFSEO was administered in increments of 150 mg up to 600 mg to achieve the hemoglobin (Hb) target. After 52 weeks, patients continued study medication to assess long-term safety until a major adverse cardiovascular event (MACE) occurred. Efficacy in each study was based on the difference in mean change of Hb from baseline to Weeks 24 to 36 of the trial. An additional efficacy endpoint was the difference in the average change of Hb from baseline to Weeks 40 to 52.
How were the trials designed?
The baseline Hb values were between 8 to 11 g/dL in the United States and 9 to 12 g/dL outside the United States. INNO2VATE-1 included patients with dialysis-dependent chronic kidney disease (DD CKD) who initiated dialysis within 16 weeks prior to the beginning their trial participation and who hand been treated with erythropoietin stimulating agents (ESA), had limited prior ESA use, or were maintained on ESAs. INNO2VATE-2 included patients on chronic maintenance dialysis for more than 12 weeks who had converted from prior ESA therapy. In INNO2VATE-1, INNO2VATE-2, and the pooled INNO2VATE program the median and range of time from initiating dialysis to starting VAFSEO was 0.1 (0.01 to 0.4), 2.7 (0.2 to 31.3), and 2.3 (0.01 to 31.3) years, respectively.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the combined clinical trials used to evaluate the efficacy of VAFSEO.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the combined clinical trials used to evaluate the efficacy of VAFSEO.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were enrolled in the combined clinical trials used to evaluate the efficacy of VAFSEO.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the combined clinical trials used to evaluate the efficacy of VAFSEO.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics
Characteristic |
VAFSEO N=1958 |
Darbepoetin Alfa N=1965 |
Total N=3923 |
|---|---|---|---|
| Sex, n (%) | |||
| Female | 861 (44.0) | 848 (43.2) | 1709 (43.6) |
| Male | 1097 (56.0) | 1117 (56.8) | 2214 (56.4) |
| Age, years | |||
| Mean, (SD) | 57.8 (14.0) | 58.1 (13.9) | 57.9 (14.0) |
| Median (min, max) | 59 (19, 93) | 59 (18, 96) | 59 (18, 96) |
| Age group, years, n (%) | |||
| 18 to <65 | 1289 (65.8) | 1298 (66.1) | 2587 (65.9) |
| ≥65 | 669 (34.2) | 667 (33.9) | 1336 (34.1) |
| Race | |||
| American Indian or Alaska Native | 20 (1.0) | 30 (1.5) | 50 (1.3) |
| Asian | 88 (4.5) | 107 (5.4) | 195 (5.0) |
| Black or African American | 470 (24.0) | 479 (24.4) | 949 (24.2) |
| Native Hawaiian or Pacific Islander | 13 (0.7) | 6 (0.3) | 19 (0.5) |
| White | 1264 (64.6) | 1239 (63.1) | 2503 (63.8) |
| Not reported | 52 (2.7) | 53 (2.7) | 105 (2.7) |
| Other | 42 (2.1) | 46 (2.3) | 88 (2.2) |
| Multiple | 9 (0.5) | 5 (0.3) | 14 (0.4) |
| Ethnicity | |||
| Hispanic or Latino | 753 (38.5) | 740 (37.7) | 1493 (38.1) |
| Not Hispanic or Latino | 1147 (58.6) | 1158 (58.9) | 2305 (58.8) |
| Not reported or unknown | 58 (3.0) | 67(3.4) | 125 (3.2) |
| Country of participation, n (%) | |||
| United States | 1187 (60.6) | 1188 (60.5) | 2375 (60.5) |
| Rest of the world | 771 (39.4) | 777 (39.5) | 1548 (39.5) |
Source: Adapted from FDA Review
Abbreviations: SD, standard deviation
What are the benefits of this drug?
The effectiveness of VAFSEO was established in two randomized, open-label, active-controlled, non-inferiority studies (INNO2VATE-1 and INNO2VATE-2) in a total of 3,923 randomized patients with DD-CKD. INNO2VATE-1 included patients with incident DD-CKD who initiated dialysis within 16 weeks prior to the beginning their trial participation and who were ESA-naive, had limited prior ESA use, or were maintained on ESAs. INNO2VATE-2 included patients on chronic maintenance dialysis for more than 12 weeks who had converted from prior ESA therapy.
The efficacy in each study was based on the difference in mean change of Hb from baseline to the primary evaluation period (Weeks 24 to 36). An additional efficacy endpoint was the difference in mean change of Hb from baseline to the secondary evaluation period (Weeks 40 to 52).In both trials, VAFSEO was non-inferior to darbepoetin alfa in correcting and maintaining Hb levels across geographic-specific target Hb ranges 10 to 11 g/dL in the United States and 10 to 12 g/dL outside the United States in adults with DD-CKD at Weeks 24 to 36 and Weeks 40 to 52.
What are the benefits of this drug (results of trials used to assess efficacy)?
Table 2 describes the results from the non-inferiority comparison of change from baseline in Hb for the primary and secondary evaluation periods. The lower bound of the 95% CI of the treatment difference was within the pre-specified non-inferiority margin of -0.75 g/dL, therefore, the non-inferiority of VAFSEO to darbepoetin alfa was demonstrated.
Table 2. Efficacy Results, Randomized Population
Hemoglobin (g/dL) |
INNO2VATE-1 | INNO2VATE-2 | ||
|---|---|---|---|---|
| VAFSEO N=181 |
Darbepoetin Alfa N=188 |
VAFSEO N=1777 |
Darbepoetin Alfa N=1777 |
|
| Baseline mean (SD) | 9.4 (1.1) | 9.2 (1.1) | 10.3 (0.9) | 10.2 (0.8) |
| Primary evaluation period: Week 24 to 36 | ||||
| Mean (SD) | 10.4 (1.1) | 10.6 (0.9) | 10.4 (1.0) | 10.5 (1.0) |
| Adjusted LSM change from Baseline (95% CI) | 1.3 (1.1, 1.5) | 1.6 (1.4, 1.8) | 0.2 (0.1, 0.3) | 0.4 (0.3, 0.4) |
| Treatment difference (95% CI) | -0.3 (-0.5, -0.1) | -0.2 (-0.2, -0.1) | ||
| Secondary evaluation period: Week 40 to 52 | ||||
| Mean (SD) | 10.5 (1.2) | 10.6 (1.1) | 10.4 (1.0) | 10.6 (1.0) |
| Adjusted LSM change from Baseline (95% CI) | 1.4 (1.2, 1.7) | 1.5 (1.2, 1.8) | 0.2 (0.2, 0.3) | 0.4 (0.3, 0.5) |
| Treatment difference (95% CI) | -0.1 (-0.3, 0.2) | -0.2 (-0.3, -0.1) | ||
Source: Adapted from VAFSEO Prescribing Information
A pre-specified non-inferiority margin of -0.75 g/dL was used to determine efficacy of VAFSEO.
The estimated treatment difference (VAFSEO – darbepoetin alfa) is obtained from an analysis of covariance (ANCOVA) model (treatment group, baseline hemoglobin level, stratification factors [region and New York Heart Association – Congestive Heart Failure] as predictor variables) with multiple imputation.
Abbreviations: CI, confidence interval; LSM, least squares mean; SD, standard deviation
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: VAFSEO worked similarly in males and females.
- Race: The majority of patients were White. VAFSEO appeared to work similarly in White and Black or African American patients.
- Age: VAFSEO was similarly effective in patients younger and older than 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3 describes the results for the subgroup analysis for the primary evaluation period. Due to small number of patients in some of the groups, a large confident interval may be observed. However, there were no apparent differences in response to VAFSEO across these subgroups.
Table 3. Change in Hemoglobin (g/dL) From Baseline to Average Values Over Weeks 24 to 36 by Subgroup, Randomized Population
Subgroup |
INNO2VATE-1, N=369 | INNO2VATE-2, N=3554 | ||
|---|---|---|---|---|
| n | Treatment Difference (95% CI) |
n | Treatment Difference (95% CI) |
|
| Sex | ||||
| Male | 220 | -0.31 (-0.60, -0.03) | 1994 | -0.17 (-0.25, -0.08) |
| Female | 149 | -0.27 (-0.58, 0.03) | 1560 | -0.17 (-0.27, -0.08) |
| Race | ||||
| White | 272 | -0.44 (-0.68, -0.20) | 2231 | -0.14 (-0.22, -0.06) |
| Black or African American | 73 | 0.11 (-0.38, 0.59) | 876 | -0.23 (-0.36, -0.11) |
| All others1 | 24 | 0.51 (-0.20, 1.22) | 447 | -0.22 (-0.40, -0.03) |
| Age group, years | ||||
| <65 | 259 | -0.21 ( -0.47, 0.04) | 2328 | -0.17 (-0.25, -0.09) |
| ≥65 | 110 | -0.57 ( -0.94, -0.19) | 1226 | -0.18 (-0.29, -0.07) |
Source: Adapted from FDA Review
1Includes Asian, American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple, not reported, and other Abbreviations: CI, confidence interval
What are the possible side effects?
VAFSEO has a boxed warning for an increased risk of thrombotic vascular (blood clotting) events including death, heart attack, stroke, and blood clots in the lungs, legs, or dialysis access site. VAFSEO’s warnings and precautions include a risk of liver toxicity, high blood pressure, seizures, stomach erosions and gastrointestinal bleeding, and may have unfavorable effects on cancer growth. VAFSEO is not approved for patients with anemia due to CKD who are not on dialysis because its safety has not been established in that population.
The most common side effects of VAFSEO include high blood pressure and diarrhea. Patients should not use VAFSEO if they have a history of hypersensitivity to VAFSEO or any of its components or if they have uncontrolled high blood pressure.
What are the possible side effects (results of trials used to assess safety)?
The most common adverse reactions (>10% of VAFSEO-treated patients) were hypertension and diarrhea.
Table 4. Adverse Reactions (≥5%) in Patients With DD-CKD During INNO2VATE-1 and INNO2VATE-2, Safety Population
Adverse Reactions |
VAFSEO N=1947 % |
Darbepoetin Alfa N=1955 % |
|---|---|---|
| Hypertension* | 14 | 17 |
| Diarrhea* | 13 | 10 |
| Headache* | 9 | 8 |
| Nausea* | 8 | 8 |
| Fatigue* | 8 | 5 |
| Abdominal pain* | 7 | 7 |
| Vomiting* | 7 | 7 |
| Gastrointestinal erosion* | 6 | 5 |
| Dizziness* | 6 | 5 |
| Dyspnea* | 6 | 7 |
| Arteriovenous fistula thrombosis | 6 | 5 |
| Dialysis related complication | 5 | 7 |
Source: VAFSEO Prescribing Information
* Grouped terms
Hypertension includes hypertensive crisis, pre-eclampsia, and hypertensive encephalopathy.
Headache includes occipital neuralgia.
Fatigue includes asthenia, lethargy, and malaise.
Vomiting includes hematemesis.
Gastrointestinal erosion includes duodenal ulcers and perforation, gastrointestinal ulcers and perforation, esophageal ulcers and perforation, and unspecified site or hematemesis, gastrointestinal hemorrhage, helicobacter duodenitis and gastritis, melaena, and gastric hemorrhage.
Dizziness includes labyrinthitis, vertigo, vestibular neuronitis, and presyncope.
Dyspnea includes orthopnea and respiratory distress.
Abbreviations: DD-CKD, dialysis-dependent chronic kidney disease
Adjudicated fatal and non-fatal thrombotic vascular events were observed in 9.0 per 100 person years of patients in the pooled VAFSEO arm and in 8.7 per 100 person years of patients in the pooled darbepoetin alfa.
Table 5. Adjudicated Thrombotic Vascular Events in Patients With DD-CKD (Fatal and Non-Fatal Events)a
Event |
VAFSEO N=1947 Rate per 100 PYb |
Darbepoetin Alfa N=1955 Rate per 100 PYb |
|---|---|---|
| Vascular access thrombosis | 4.8 | 3.9 |
| Myocardial infarction | 2.9 | 2.8 |
| Stroke | 1.1 | 1.4 |
| Deep vein thrombosis | 0.5 | 0.6 |
| Pulmonary embolism | 0.2 | 0.3 |
| Arterial thrombosis | 0.2 | 0.1 |
Source: VAFSEO Prescribing Information
a These data are not an adequate basis for comparison of rates between the study drug and active control.
b Based on time to first event analysis.
Abbreviations: DD-CKD, dialysis-dependent chronic kidney disease; PY, person years
Major adverse cardiovascular events (MACE; defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke) was assessed in a combined analysis of INNO2VATE-1 and INNO2VATE-2. VAFSEO was non-inferior to darbepoetin alfa in time to first occurrence of MACE (hazard ratio 0.96; 95% CI 0.83, 1.11). Non-inferiority of VAFSEO was established because the upper bound of the 95% CI for the MACE hazard ratio was less than the pre-specified non-inferiority margin of 1.25. The results were consistent for the individual components of the MACE endpoint.
Table 6. MACE in the INNO2VATE Trials (ITT Analysesa)
Parameter |
VAFSEO N=1947 PY=3134.4 |
Darbepoetin Alfa N=1955 PY=3164.0 |
|
|---|---|---|---|
| First occurrence of MACE | 355 | 377 | |
| All-cause mortality, n | 253 | 253 | |
| Non-fatal myocardial infarction, n | 76 | 87 | |
| Non-fatal stroke, n | 26 | 37 | |
| MACE hazard ratiob (95% CI) | 0.96 (0.83, 1.11) | ||
| MACE incidence rate per 100 PY | 11.3 | 11.9 | |
Source: VAFSEO Prescribing Information
a ITT analyses included events on and off treatment after randomization in patients who received at least one dose of study medication.
b Adjusted for baseline covariates
Abbreviations: CI, confidence interval; ITT, Intent-to-treat; MACE, major adverse cardiovascular events; PY, person years
Were there any differences in side effects among sex, race and age?
- Sex: The observed relative risk of MACE in VAESO patients compared to darbepoetin alfa patients was smaller in females than males.
- Race: The observed relative risk of MACE in VAESO patients compared to darbepoetin alfa patients was smaller in White patients than Black or African American or other race patients.
- Age: The observed relative risk of MACE in VAESO patients compared to darbepoetin alfa patients was similar in patients younger and older than 65 years of age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 7. MACE by Subgroup, Safety Population
Subgroup |
VAFSEO N=1947 n/Ns (%) |
Darbepoetin Alfa N=1955 n/Ns (%) |
Hazard Ratio (95% CI) |
|---|---|---|---|
| Sex | |||
| Female | 139/858 (16) | 159/845 (19) | 0.87 (0.69, 1.09) |
| Male | 216/1089 (20) | 218/1110 (20) | 1.03 (0.85, 1.24) |
| Age, years | |||
| <65 | 178/1280 (14) | 187/1292 (14) | 1.00 (0.81, 1.23) |
| ≥65 | 177/667 (26) | 190/663 (29) | 0.92 (0.75, 1.13) |
| Race | |||
| White | 219/1255 (17) | 248/1231 (20) | 0.84 (0.70, 1.01) |
| Black | 99/470 (21) | 89/478 (19) | 1.17 (0.88, 1.56) |
| All others1 | 37/222 (17) | 40/246 (16) | 1.21 (0.76, 1.91) |
| Region | |||
| United States | 265/1180 (22) | 269/1181 (23) | 1.00 (0.84, 1.18) |
| Europe | 36/277 (13) | 45/295 (15) | 0.89 (0.57, 1.39) |
| Others | 54/490 (11) | 63/479 (13) | 0.87 (0.61, 1.26) |
Source: Adapted from FDA Review
1Includes Asian, American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple, not reported, and other
Abbreviations: CI, confidence interval; MACE, major adverse cardiovascular event; N, number of patients in treatment arm; n, number of patients with adverse event; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.