Vadadustat 300mg tablets

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) is a new therapy option for anemia in chronic kidney disease (CKD) patients. We aimed to evaluate evidence from randomized controlled trials (RCTs) on HIF-PHIs for anemia in non-dialysis dependent (NDD)-CKD patients. Materials and Methods: We searched three electronic databases (PubMed, CINAHL, Cochrane Central Register of Controlled Trials databases), trial registries, and manually screened reference list. Two authors independently conducted screening, data extraction, and assessed risk of bias. We used RevMan 5.3 for meta-analysis using standard methods. Certainty of evidence was assessed by Grading of Recommendations, Assessment, Development, and Evaluations. Results: We included 12 RCTs involving 8611 patients with anemia of kidney disease. The studies included roxadustat (n = 2), daprodustat (n = 3), molidustat (n = 3), vadadustat (n = 2), enarodustat (n = 1), and desidustat (n = 1). Desidustat and daprodustat reported no difference in the hemoglobin levels from baseline up to 24-52 weeks as compared to darbepoetin alpha [Mean Difference (MD): 0.09 g/dL (CI 95% 0.15-0.33); p = 0.46; 529 participants; low certainty evidence; and MD: 0.08 g/dL (CI 95% 0.08-0.08); p < 0.00001; two studies; 4089 participants; low certainty evidence, respectively]. Broadly, HIF-PHI molecules exhibited little difference when compared to other alternatives like erythropoietin stimulating agents (ESAs), but the evidence is not of high certainty. Conclusion: Our meta-analysis provides evidence on the use of HIF-PHIs as an alternative to ESAs for anemia in NDD-CKDs.

Abstract licence: CC BY-NC-SA

HIF–prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to erythropoiesis-stimulating agents (ESAs) for anemia in chronic kidney disease (CKD). We performed a network meta-analysis comparing six HIF-PHIs (roxadustat, daprodustat, vadadustat, molidustat, enarodustat, desidustat) versus ESAs or placebo across hemoglobin efficacy, iron indices, and adverse events, with prespecified subgroup analyses by dialysis status. Forty-five randomized trials enrolling over 32,000 participants were analyzed using both frequentist and Bayesian frameworks with inconsistency checks. Outcomes included hemoglobin, ferritin, hepcidin, serum iron, total iron-binding capacity, and transferrin saturation; VEGF and lipid endpoints were not synthesized due to sparse, heterogeneous reporting. Across analyses, roxadustat and daprodustat increased hemoglobin more than ESA or placebo overall. Roxadustat tended to rank highest for hemoglobin, particularly in non-dialysis populations, whereas daprodustat showed advantages among dialysis-dependent patients and was associated with greater improvements in iron mobilization (lower hepcidin and ferritin, higher transferrin saturation). Estimates for desidustat and vadadustat were favorable but less precise, while evidence for enarodustat and molidustat was limited. Safety appeared class-neutral in aggregate; however, agent-specific patterns emerged—roxadustat showed higher rates of vascular occlusive events in some trials, daprodustat more gastrointestinal events, and molidustat a lower risk of hyperkalemia. Because SUCRA ranks reflect probability rather than effect magnitude, rankings were interpreted alongside absolute effects and study design. In sum, HIF-PHIs are not interchangeable; efficacy and safety vary by agent and dialysis status. Choice of therapy should consider inflammatory burden, iron handling, and adherence context. Head-to-head trials and real-world studies are needed to validate comparative findings and guide personalized use.

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BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Abstract licence: CC BY-NC

RATIONALE & OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative to erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in the setting of chronic kidney disease (CKD). The objective of this study was to investigate the efficacy and safety of conversion from the long-acting ESA methoxy polyethylene glycol-epoetin-ß (MPG-EPO) to the oral HIF-PHI vadadustat 3 times weekly versus maintenance therapy with MPG-EPO. STUDY DESIGN: Phase 3b, open-label, noninferiority trial. SETTING & PARTICIPANTS: Multicenter study in the United States in 456 adult participants with anemia and dialysis-dependent CKD. INTERVENTION: Participants were randomized 1:1:1 to vadadustat at a starting dose of 600mg thrice weekly, vadadustat at a starting dose of 900mg thrice weekly, or MPG-EPO for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination. OUTCOMES: Primary and secondary efficacy end points were the mean change in hemoglobin concentration from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75g/dL for the difference in mean change in hemoglobin concentration from baseline. Other efficacy end points were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Primary safety end points were any treatment-emergent and serious adverse events (AEs). RESULTS: After combining the vadadustat groups (600mg and 900mg thrice weekly; n=304), vadadustat was noninferior to MPG-EPO (n=152) for primary (least-squares mean treatment difference, -0.33; 95% CI, -0.53 to-0.13) and secondary (-0.33; -0.56 to-0.09) efficacy end points. Mean hemoglobin concentrations were stable for all groups except for an initial slight decrease in the vadadustat 600mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups. LIMITATIONS: Potential errors in attribution of AEs as drug-related. CONCLUSIONS: Three-times-weekly vadadustat was noninferior to MPG-EPO in its effect on hemoglobin levels without detectable differences in AEs. FUNDING: Funding from a private entity (Akebia Therapeutics, Inc). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study identifier NCT04707768. PLAIN-LANGUAGE SUMMARY: Vadadustat, taken 3 times a week, was noninferior to methoxy polyethylene glycol-epoetin-ß (MPG-EPO) in treating anemia. Vadadustat is an oral drug used to treat anemia in people with chronic kidney disease. This study enrolled participants undergoing dialysis for kidney failure and compared the efficacy and safety of continuing to receive MPG-EPO, a long-acting injectable anemia treatment, or switching to vadadustat, taken by mouth 3 times per week for 1 year. Vadadustat was noninferior to MPG-EPO in maintaining hemoglobin levels. Hemoglobin levels remained stable across all groups, except for a slight decrease in the lower-dose vadadustat group, which stabilized with dose titration by week 12. The occurrence of new or serious side effects was similar across treatment groups.

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