Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. FDA label
Also known as vadadustat reference tablets, vadadustat reference, Vafseo, AKB-6548
Vadadustat · 20 trials · 15 indications
The hierarchical endpoints of all-cause mortality and all cause hospitalization will be analyzed by the win odds method with ranking all cause mortality more important than all cause hospitalization.
The Baseline Hb was defined as the average of last 2 central laboratory Hb measurements of samples taken at or prior to the first dose. The average for the PEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 20 through 26. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as PEP value minus the Baseline value.
The Baseline Hb was defined as the average of the last 2 central laboratory Hb values taken on or prior to the first dose date. The average for the PEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 20 through 26, regardless of intercurrent events. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as PEP value minus the Baseline value.
The Baseline average was calculated as the average of the Hb values obtained at the screening visit closest to the date of randomization and the randomization visit. The average for the Primary Efficacy Period was calculated as the average Hb value over Weeks 24 to 36. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with Baseline hemoglobin concentration (\<10.0 versus ≥10.0 g/dL), geographic region (United States \[US\] versus European Union \[EU\] versus Rest of World \[ROW\]), and New York Heart Association congestive heart failure (NYHA CHF) class (Class 0 \[no CHF\] or I versus II or III) as covariates.
MACE was defined as all-cause mortality, non-fatal myocardial infarction (MI), or non-fatal stroke. The primary safety outcome was positively adjudicated first MACE, which was defined as any death, Endpoint Adjudication Committee (EAC)-confirmed non-fatal MI, or EAC-confirmed non-fatal stroke occurring between the first dose date and each participant's last participation date. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
The primary outcome is a hierarchical composite endpoint with 3 components: Death (yes or no); Duration of mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) in days; and Duration of high-flow nasal oxygenation (HFNO) or noninvasive ventilation (NIV) in days. Data will be reported as a Win Ratio, which quantifies the relative benefit of treatment compared to control. The Win Ratio is calculated from all pairwise comparisons of each patient in the treatment group compared with each patient in the control group, using the following formula: Win Ratio = Number of Wins/Number of Losses. Number of Wins is defined as: The count of pairs where the treatment group patient has a better outcome than the control group patient. Number of Losses is defined as: The count of pairs where the control group patient has a better outcome than the treatment group patient.
National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS): 8 - Death 7 - Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 6 - Hospitalized, on non-invasive ventilation or high flow oxygen devices 5 - Hospitalized, requiring supplemental oxygen 4 - Hospitalized, not requiring supplemental oxygen - requiring ongoing care (COVID-19 related or otherwise) 3 - Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 2 - Not hospitalized, limitation on activities and/or requiring home oxygen 1 - Not hospitalized, no limitations on activities
Change from Baseline in Hb value was calculated as the PEP Hb value minus the Baseline Hb value. The PEP value was the average Hb value from Week 10 to Week 12. The Baseline Hb value was defined as the average of the final two Hb values prior to start of dosing on Day 1.
An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. TEAEs, defined as AEs that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, are reported.
Parameters assessed for laboratory values included hematology (excluding the primary and secondary efficacy endpoint results related to Hb), clinical chemistry, lipid profiles, and glucose. The investigator was responsible for reviewing laboratory results for clinically significant changes.
Parameters assessed for vital signs included sitting (at rest for a minimum of 5 minutes) heart rate, respiratory rate, body temperature, and blood pressure. The investigator was responsible for reviewing vital sign values for clinically significant changes.
The target range for Hb was from 10.0 to 11.0 grams per deciliter (g/dL). Hb outliers included participants with a Hb increase of more than 12.0 g/dL or \<8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline, and a Hb increase to more than 1.0 g/dL within any 2-week interval during the Study Period.
The pre-treatment average value for Hb was defined as the average of 3 values obtained prior to treatment, i.e., the qualifying screening value and the Baseline value. Change from Pre-treatment was calculated as the Week 6 value minus the Pre-treatment value.
A standard 12-lead ECG was performed following dosing in a supine position for approximately 10 minutes. ECGs were taken prior to blood draws when possible. The investigator was responsible for reviewing laboratory results for clinical significance.
A standard 12-lead ECG was performed following dosing in a supine position for approximately 10 minutes. ECGs were taken prior to blood draws when possible. The parameters evaluated from the participant ECG trace included PR interval, QT interval, QRS interval, and QTc (corrected). The baseline was defined as Day 1 pre-dose measurement. If missing, the last measurement prior to dosing was used.
The heart rate evaluation was performed after the participant had been resting comfortably in a supine position for approximately 10 minutes.
A baseline physical examination was performed at screening. Otherwise, abbreviated physical examinations were conducted and were to include heart, lung, and abdomen. The investigator was responsible for reviewing laboratory results for clinically significant changes.
Plasma samples were collected from the participants at the defined time points. Cmax was defined as the maximum observed plasma concentration. Cmax was calculated using the standard non-compartmental method.
Plasma samples were collected from the participants at the defined time points. Tmax was defined as the time to reach maximum plasma concentration. Tmax was calculated using the standard non-compartmental method.
Plasma samples were collected from the participants at the defined time points. λz was calculated using linear regression of the terminal linear portion of the log concentration vs. time curve. The parameter was calculated by linear least-squares regression analysis using three or more concentrations, excluding Cmax.
Plasma samples were collected from the participants at the defined time points. T½ was defined as apparent terminal elimination half-life. T½ was calculated using the standard non-compartmental method.
Plasma samples were collected from the participants at the defined time points. AUC\[0-T) was defined as the area under the plasma concentration-time curve, from time=0 to the last measurable concentration (Ct) up to 24 hours, calculated by the linear trapezoidal method. AUC\[0-T) was calculated using the standard noncompartmental method.
Plasma samples were collected from the participants at the defined time points. AUC\[0-∞\] was defined as the area under the plasma concentration-time curve from time=0 and extrapolated to infinity. AUC\[0-∞\] was calculated using the standard non-compartmental method.
Plasma samples were collected from the participants at the defined time points. CL/F was defined as apparent oral clearance, calculated as Dose/AUC(0-inf). CL/F was calculated using the standard non-compartmental method.
Plasma samples were collected from the participants at the defined time points. Vd/F was defined as the apparent volume of distribution during the terminal phase, calculated as Dose/\[λz \* AUC(0-inf)\]. Vd/F was calculated using the standard non-compartmental method.
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
| Arm | Type | Description |
|---|---|---|
| Vadadustat | EXPERIMENTAL | Vadadustat, 300 mg tablets, administered orally three times per week |
| Erythropoiesis-stimulating agent (ESA) - Standard of Care (SOC) | ACTIVE_COMPARATOR | Epoetin alfa (EPOGEN), Methoxy polyethylene glycol-epoetin beta (Mircera), or Darbepoetin alfa (Aranesp) administered as per standard of care |
| Phased transition from Epogen to three times weekly (TIW) oral vadadustat | EXPERIMENTAL | - |
| Erythropoiesis-Stimulating Agent (ESA) | ACTIVE_COMPARATOR | Dose adjustments will be determined by hemoglobin (Hb) change and current dose of ESA, per ESA dosing protocol |
| Vadadustat low dose | EXPERIMENTAL | Participants previously receiving Mircera® received vadadustat for up to 52 weeks with an initial dose of 600 milligrams (mg). |
| Vadadustat high dose | EXPERIMENTAL | Participants previously receiving Mircera® received vadadustat for up to 52 weeks with an initial dose of 900 mg. |
| Mircera® | ACTIVE_COMPARATOR | Participants will continue to receive Mircera® for up to 52 weeks. |
| Vadadustat once daily (QD) | EXPERIMENTAL | - |
| Vadadustat three times weekly (TIW) | EXPERIMENTAL | - |
| Darbepoetin alfa | ACTIVE_COMPARATOR | - |
| Vadadustat 900mg | EXPERIMENTAL | - |
| Vadadustat 1200mg | EXPERIMENTAL | - |
| Placebo | PLACEBO_COMPARATOR | - |
| Vadadustat TIW | EXPERIMENTAL | Participants randomized to Vadadustat (Main and erythropoiesis-stimulating agent \[ESA\] hyporesponder parallel studies) who complete a once-daily dosing regimen treatment period and meet eligibility criteria for transition to three times weekly (TIW) dosing will switch to TIW dosing |
| Epoetin Alfa | ACTIVE_COMPARATOR | Epoetin Alfa |
| Vadadustat, Dose 1 | EXPERIMENTAL | Daily oral dose |
| Vadadustat, Dose 2 | EXPERIMENTAL | Daily oral dose |
| Vadadustat, Dose 3 | EXPERIMENTAL | Daily oral dose |
| CKD, Stage 3 | EXPERIMENTAL | Participants with Stage 3 Chronic Kidney Disease (CKD) (Estimated Glomerular Filtration Rate \[eGFR\] 30 - 59 milliliters \[mL\]/minute) received a single 500 milligram (mg) oral dose of Vadadustat after fasting for at least 4 hours. |
| CKD, Stage 4 | EXPERIMENTAL | Participants with Stage 4 CKD (eGFR \<30 mL/minute and not yet on dialysis) received a single 500 mg oral dose of Vadadustat after fasting for at least 4 hours. |
| Vadadustat 600 mg | EXPERIMENTAL | Dialysis-dependent chronic kidney disease (DD-CKD) participants converting from erythropoiesis-stimulating agent (ESA) treatment will be administered fixed-dose treatment for 10 days with vadadustat 600 milligrams (mg) daily. |
| Vadadustat 750 mg | EXPERIMENTAL | DD-CKD participants converting from ESA treatment will be administered fixed-dose treatment for 10 days with vadadustat 750 mg daily. |
| Vadadustat 900 mg | EXPERIMENTAL | DD-CKD participants converting from ESA treatment will be administered fixed-dose treatment for 10 days with vadadustat 900 mg daily. |
| Erythropoiesis-stimulating agent | OTHER | Participants will continue to receive their existing treatment with intravenous erythropoiesis-stimulating agent (ESA; darbepoetin alfa or epoetin alfa) for 10 days. |
| Vadadustat, digoxin | EXPERIMENTAL | Arm 1: Subjects will receive a single oral dose of digoxin 0.5 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone and in combination with a single dose of digoxin 0.5 mg. |
| Vadadustat, adefovir | EXPERIMENTAL | Arm 2: Subjects will receive a single dose of oral adefovir 10 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone and in combination with a single dose of adefovir. |
| Vadadustat, Furosemide | EXPERIMENTAL | Arm 3: Subjects will receive a single dose of oral furosemide 40 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone, and in combination with a single dose of furosemide 40 mg. |
| Vadadustat, Cyclosporine | EXPERIMENTAL | Part 1: Arm 1: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg in a crossover design |
| Vadadustat; Probenecid | EXPERIMENTAL | Part 1: Arm 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral Probenecid 500 mg Q12h in a fixed sequence design |
| Vadadustat and Rifampin | EXPERIMENTAL | Part 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with IV rifampin 600 mg in a cross-over design |
| Rosuvastatin, Vadadustat | EXPERIMENTAL | Part 1: Subjects will receive rosuvastatin 20 mg alone, vadadustat 600 mg alone, followed by rosuvastatin 20 mg in combination with vadadustat 600 mg in a fixed-sequence dosing design. |
| Sulfasalazine. Pravastatin, Vadadustat | EXPERIMENTAL | Part 2, Arm 1: Subjects will receive sulfasalazine 500 mg alone followed by sulfasalazine 500 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. Part 2, Arm 2: Subjects will receive pravastatin 40 mg alone followed by pravastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. |
| Atorvastatin, Simvastatin, Vadadustat | EXPERIMENTAL | Part 3, Arm 1: Subjects will receive atorvastatin 40 mg alone followed by atorvastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. Part 3, Arm 2: 24 subjects will receive simvastatin 40 mg alone followed by simvastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. |
| Name | Type | Description |
|---|---|---|
| Vadadustat | DRUG | A synthetic, orally bioavailable, small molecule being developed as an inhibitor of hypoxia-inducible factor prolyl-hydroxylases for the treatment of anemia associated with chronic kidney disease. Intervention to be administered to maintain hemoglobin within a target range of 10-11 g/dL. |
| Erythropoiesis Stimulating Agent | DRUG | Standard of care erythropoiesis stimulating agent will be administered to maintain hemoglobin within a target range of 10-11 g/dL. |
| Epoetin alga (Epogen)/vadadustat | DRUG | Phased transition from Epogen to three times weekly (TIW) oral vadadustat |
| Erythropoiesis-Stimulating Agent (ESA) | DRUG | Administered by intra-venous (IV) infusion. |
| Mircera® | DRUG | intravenous administration |
| Darbepoetin alfa | DRUG | intravenous or subcutaneous solution |
| Vadadustat 900mg | DRUG | Participants will receive 900mg vadadustat (as oral tablets) for 14 days or until the date of discharge, whichever comes first, at approximately the same time each day without regard for timing of meals. |
| Vadadustat 1200mg | DRUG | Participants will receive 1200mg vadadustat (as oral tablets) for 14 days or until the date of discharge, whichever comes first, at approximately the same time each day without regard for timing of meals. |
| Placebo | DRUG | Participants will matching placebo (as oral tablets) for 14 days or until the date of discharge, whichever comes first, at approximately the same time each day without regard for timing of meals. |
| Epoetin Alfa | DRUG | Epoetin Alfa |
| Vadadustat TIW | DRUG | Oral Vadadustat |
| Furosemide | DRUG | Oral Furosemide |
| Adefovir | DRUG | Oral Adefovir |
| Digoxin | DRUG | Oral Digoxin |
| Rifampin | DRUG | IV Rifampin |
| Probenecid | DRUG | Oral Probenecid |
| Cyclosporins | DRUG | Oral Cyclosporine |
| Simvastatin | DRUG | Oral Simvastatin |
| Rosuvastatin | DRUG | Oral Rosuvastatin |
| Atorvastatin | DRUG | Oral Atorvastatin |
| Pravastatin | DRUG | Oral Pravastatin |
| Sulfasalazine | DRUG | Oral Sulfasalazine |
Inclusion Criteria: * Adult patients greater than or equal to 18 years of age. * Receiving outpatient in-center hemodialysis at least three times per week for end-stage kidney disease. * Currently prescribed or eligible for erythropoiesis-stimulating agent based on approved facility policy * Unders...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Bristol-Myers Squibb Company | BMY | 2 | PHASE3 | Luspatercept |
| Takeda Pharmaceutical Co. Ltd. Sponsored ADR | TAK | 2 | PHASE3 | Elritercept |
| Disc Medicine, Inc. | IRON | 2 | PHASE2 | DISC-0974 |
| Akebia Therapeutics, Inc. | AKBA | 2 | PHASE3 | Vadadustat |
| Sunshine Biopharma Incorporated | SBFM | 1 | PHASE2 | HEC53856, rHuEPO |
| Ascentage Pharma Group International Unsponsored ADR | AAPG | 1 | PHASE1 | APG-5918 |
| Bayer | BAYRY | 1 | - | Molidustat |
Vadadustat is an investigational oral small molecule developed by Akebia Therapeutics, Inc. (ticker AKBA) for anemia and related conditions, including anemia associated with chronic kidney disease and acute respiratory distress syndrome. It is being studied in clinical trials and is not described here as an approved product.
Vadadustat is being studied for the treatment of anemia of chronic kidney disease, including in patients receiving in-center hemodialysis. Clinical trials have evaluated it both as a three times weekly oral therapy and in phased transition from Epogen, with the goal of supporting red blood cell production in these patients.
Vadadustat targets EGLN1, EGLN2, and EGLN3, enzymes in the prolyl hydroxylase family. It acts as an inhibitor of these targets. Inhibiting EGLN enzymes is intended to increase erythropoietin production and support red blood cell formation, which is the basis for its study in anemia.
Vadadustat is developed by Akebia Therapeutics, Inc., which trades under the ticker AKBA. Akebia is the sponsor of the clinical trial program evaluating vadadustat across anemia of chronic kidney disease and acute respiratory distress syndrome indications.
Vadadustat is in clinical development, with a Phase 2 program and multiple Phase 3 trials across its indications. It is investigational and is not described here as FDA approved. Trials have included randomized, double-blind, placebo-controlled designs, and the program spans eight studies with about 8,004 total enrolled participants.
Vadadustat trials include NCT07565701, a Phase 3 study of phased transition from Epogen to three times weekly oral vadadustat in hemodialysis patients, and NCT07086755, a recruiting Phase 2 trial in nonintubated acute respiratory distress syndrome. Other studies include NCT06901505 and NCT06520826 in anemia of chronic kidney disease.