Breakthrough Clinical Results
Akebia Therapeutics announced the initiation of VOCAL, a post-marketing study evaluating the efficacy and safety of Vafseo® (vadadustat) administered three times weekly in patients with anemia due to chronic kidney disease (CKD) receiving hemodialysis. The open-label, active-controlled trial, conducted in DaVita dialysis clinics, will compare Vafseo to standard-of-care erythropoiesis-stimulating agents (ESAs). The primary endpoint is the change in hemoglobin levels. A sub-study will analyze the impact of Vafseo on red blood cell phenotypes. Vafseo, approved by the FDA in March 2024, is a once-daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates endogenous erythropoietin production.
Key Highlights
- Initiation of VOCAL post-marketing study for Vafseo (vadadustat)
- Evaluation of three-times-weekly dosing of Vafseo compared to ESAs
- Study conducted in DaVita dialysis clinics, enrolling approximately 350 patients
- Sub-study to analyze Vafseo's impact on red blood cell phenotypes
Drug used in other indications
Vafseo (Vadadustat) Clinical Trials Beyond CKD Anemia
Based on a comprehensive review of the available information, there is no evidence that Vafseo (vadadustat) is currently being trialed for any indications other than anemia due to chronic kidney disease.
The only clinical trial program identified in the data is the INNO2VATE program, which specifically evaluates vadadustat versus darbepoetin alfa for anemia in patients with dialysis-dependent chronic kidney disease.
Without additional clinical trials targeting other indications, there are no alternative intervention models to report beyond those used in the CKD anemia studies.
The current research focus appears to remain exclusively on vadadustat's application in treating renal anemia, with no expansion into other therapeutic areas at this time.
Should vadadustat's mechanism as a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prove beneficial for other conditions in the future, new clinical trials with specific intervention protocols would need to be established.
Incidence and Prevalence
Global Prevalence of Anemia in Chronic Kidney Disease
Regional Prevalence Variations
The prevalence of anemia among chronic kidney disease (CKD) patients shows significant variation across different regions globally. Recent studies provide insights into these regional differences:
- In Ethiopia, a 2021 study at St. Paulo's Hospital Millennium Medical College found an anemia prevalence of 65.91% among CKD patients
- A 2023 study from Johannesburg, South Africa reported anemia prevalence of 43.18% (95% CI: 38.1%-48.4%) among CKD participants
- In Saudi Arabia (2007), the estimated prevalence of anemia (Hb < 110 g/L) varied by CKD stage: 11%, 17%, 38%, 59%, and 78% in stages 1, 2, 3, 4, and 5, respectively
Demographic and Risk Factor Patterns
Several demographic factors and comorbidities influence anemia prevalence in CKD:
- Ethnic disparities were observed in South Africa, with Blacks having the highest prevalence (46.9%) and Indians/Asians the lowest (18.2%)
- In Ethiopia, anemic CKD patients were predominantly from rural areas (35.23%) and within the age group of 49-58 years (67.3%)
- Diabetes mellitus shows strong association with anemia in CKD patients (odds ratio =2.31, P-value =0.005 in the South African study)
- The Ethiopian study found diabetes and hypertension were high in anemic CKD patients at 33.81% and 36.36%, respectively
CKD Stage and Anemia Correlation
The relationship between CKD progression and anemia development is well-documented:
- A 2015 Singapore study demonstrated that the probability of developing anemia was significantly greater for patients with stage 5 CKD (OR 16.76, p<0.001)
- In diabetic patients, anemia prevalence increased progressively with worsening CKD
- People with CKD stage 3 accounted for the largest number of anemic individuals in the diabetic population, with 18% (95% CI 13-24%) having Hb < 110 g/l
Special Populations
Certain populations show unique patterns:
- A 2007 nursing home study found that 59.6% of residents were anemic, and 43.1% had CKD
- Residents with CKD were more likely to have anemia (64.9% with vs 55.7% without CKD; odds ratio=1.47)
- In the US, according to NHANES III data analysis, the overall burden of CRI associated anemia was estimated at 800,000 adults
Gender Differences
Gender disparities in anemia prevalence among CKD patients are notable:
- NHANES data showed that at any given level of CrCl, men had a larger decrease in hemoglobin than women
- Among those with CrCl 20 to 30 ml/min, 46% of women and 19% of men had transferrin saturation <20%
- 47% of women and 44% of men had serum ferritin <100 ng/ml, indicating insufficient iron stores
Pathophysiology and Treatment Considerations
Anemia in CKD is characterized by:
- Inappropriate increase in erythropoietin production and diminished iron availability
- HIF stabilizers are emerging as a new treatment option, with ongoing safety studies as of 2021
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Anemia due to Chronic Kidney Disease
Study Designs
Randomized trials have been the cornerstone for evaluating treatments for anemia in chronic kidney disease (CKD) patients. Notable studies include the NEPHRODIAB2 study which randomly assigned 89 type 2 diabetes patients with moderate anemia, the FIND-CKD 1-year multicenter trial evaluating iron therapy, and the SKIPPER trial, a Phase 2 open-label study of C.E.R.A. in pediatric patients. The TREAT trial compared darbepoetin versus placebo in patients with type 2 diabetes and CKD, while the POWER study evaluated once-weekly epoetin alfa in an open-label design.
Patient Populations
Trial populations included pediatric patients (3 months to 17 years), adult patients with CKD not yet on dialysis, patients with type 2 diabetes and CKD stages 3-4, and patients both receiving maintenance dialysis and those not treated with dialysis. Most studies excluded patients with active infection or elevated C-reactive protein.
Interventions
The primary interventions studied were erythropoiesis-stimulating agents (ESAs) including: - Epoetin alfa administered weekly - Darbepoetin alfa administered every 2 weeks - C.E.R.A. (continuous erythropoietin receptor activator) administered every 4 weeks
Additional interventions included oral iron supplementation (200 mg elemental iron/day) and newer agents like daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor.
Primary Endpoints
Key primary endpoints across trials included: - Change in hemoglobin concentration between baseline and evaluation period - Estimated glomerular filtration rate (eGFR) decline - Proportion of patients achieving target hemoglobin levels (typically ≥11.0 g/dl) - Left ventricular mass index (LVMI) and ejection fraction changes
In the TREAT trial, primary outcomes included all-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke.
Secondary Endpoints
Common secondary endpoints included: - Iron and erythropoietin dosage requirements - Quality of life measured by standardized surveys - Response rates (defined as ≥1 g/dL increase in hemoglobin) - Time to response - Maintenance of hemoglobin within target ranges (e.g., 10-12 g/dL)
Safety Assessments
Safety monitoring typically included: - Adverse events tracking - Blood pressure measurements - Renal function parameters - Proteinuria assessment - Antibody development against treatment agents
Recent Findings
The SKIPPER trial (2023) demonstrated that pediatric patients could safely switch to C.E.R.A. administered every 4 weeks. The FIND-CKD study (2019) showed limited efficacy of oral iron therapy. The TREAT trial found no significant differences in mortality between darbepoetin and placebo groups, but noted a higher stroke incidence in the darbepoetin group. A recent study on daprodustat showed effectiveness in patients who had responded inadequately to ESAs.
Clinical trials consistently demonstrated that darbepoetin alfa is equivalent to recombinant human erythropoietin in increasing hemoglobin concentration while requiring less frequent administration, and that ESA therapy is associated with significant quality of life improvements.