Vafseo (vadadustat) / Akebia Therap, Mitsubishi Tanabe, CSL Behring, Medice - LARVOL DELTA

Safety and Efficacy of Vadadustat Versus Darbepoetin Alfa for Chronic Kidney Disease-Related Anemia in Patients Receiving Dialysis by Baseline Erythropoiesis-Stimulating Agent Dose. (PubMed, Hemodial Int) - "Comparing safety and efficacy by baseline ESA dose among patients with CKD on maintenance dialysis, vadadustat was noninferior to darbepoetin alfa for all ESA dose subgroups, including patients with high baseline ESA requirements."

Journal • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Discovery of 3-(Arylamido)pyrazolopyridine HIF-2α Agonists and a Codrug Strategy with Prolyl Hydroxylase Inhibition for Synergistic Treatment of Renal Anemia. (PubMed, J Med Chem) - "In cellular assays, 48 synergistically enhanced HIF-2α-dependent EPO gene expression when combined with the clinically approved prolyl hydroxylase domain (PHD) inhibitor Vadadustat...Notably, codrug 50 induced superior upregulation of EPO levels in vivo compared to coadministration of the two individual agents. Together, these findings demonstrate the first rationally designed codrug integrating an HIF-2α agonist and a PHD inhibitor, highlighting a new direction for the development of renal anemia therapies."

Journal • Anemia • Hematological Disorders • EPAS1 • EPO

Treatment of an Anemic Patient with CKD with Oral Vadadustat (KIDNEY WEEK 2025) - "Patient's extra-renal systemic lupus has stablized with use of hydroxychloroquine and low dose mycophenolate...In January of 2025 she was swithced from epogen to vadadustat 300 mg oral daily...This case demonstrates that some patients may respond quicker, reducing requirement of frequent high dose of synthetic erythropoietin. Anemia Management Report"

Clinical • Anemia • Chronic Kidney Disease • Glomerulonephritis • Hematological Disorders • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • STAT3

Model-Based Vadadustat Starting Dose Recommendations in Patients with Dialysis-Dependent CKD (KIDNEY WEEK 2025) - "Simulations were performed in virtual dialysis-dependent patients with bl characteristics of interest (ESA experienced/naïve, bl Hb ≥ or <10 g/dL, and bl standardized ESA dose ≥ or < 90 IU/kg/wk Epogen equivalents). Patients with higher bl Hb or lower prior ESA dose were more likely to achieve satisfactory Hb response at a lower VADA starting dose. Conclusion A VADA starting dose of 450 mg QD or 900 mg TIW should ameliorate the transitory decline in Hb following a switch from ESA in most patients."

Clinical • Late-breaking abstract • Anemia • Chronic Kidney Disease • Hematological Disorders

Three Times Weekly In-Center Vadadustat vs. Standard of Care Erythropoiesis-Stimulating Agent (ESA) for Treatment of CKD-Related Anemia in Patients Undergoing Dialysis (VOCAL) (KIDNEY WEEK 2025) - P3 | "This study will provide additional data on the efficacy of TIW vadadustat compared to SOC ESA for the treatment of anemia in patients receiving TIW ICHD."

Clinical • Anemia • Chronic Kidney Disease • Hematological Disorders

Vadadustat Outcomes In-Center Experience (VOICE) Study: Pragmatic Randomized Controlled Trial to Test the Safety of Three Times Weekly Vadadustat (KIDNEY WEEK 2025) - P3 | "Methods This randomized controlled trial is testing whether TIW vadadustat is non-inferior to epoetin alfa on the primary hierarchical outcome of all-cause mortality and all-cause hospitalization analyzed using the win ratio ( NCT06520826) . Conclusion The VOICE trial design showcases a pragmatic approach to embed individual-level randomized clinical trials in routine dialysis care. The trial will generate critical data on the safety of a new anemia management strategy while leveraging a composite hierarchical outcome to optimize statistical efficiency and clinical relevance."

Clinical • Anemia • Hematological Disorders

Consistency of the Estimate of Responsiveness of Vadadustat vs. Darbepoetin (KIDNEY WEEK 2025) - "Conclusion Lower responsiveness variability in NDD and DD Vadadustat-treated patients suggests more precise Hb control, supporting the potential of a personalized dosing algorithm to improve anemia management. Normalized responsiveness histograms: Darbepoetin vs. Vadadustat in NDD and DD trials Table 1: Adjusted standard deviations of responsiveness"

Anemia • Hematological Disorders • Inflammation

Win-Odds Analysis of Deaths and Hospitalization in Patients Taking Vadadustat or Darbepoetin Alfa for CKD-Related Anemia Undergoing Dialysis (KIDNEY WEEK 2025) - "The win odds (95% CI) for VADA compared to DA was 0.93 (0.87–0.99; p=0.03). Conclusion In a post-hoc analysis, the composite of all-cause mortality and hospitalizations was statistically significantly lower for VADA compared to DA in a win-odds analysis among patients with DD- CKD."

Clinical • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Myocardial Infarction

Pharmacological Evaluation of a First-in-Class Hemoglobin Elevating Agent (HbEA) AND017 in a Rat 5/6 Nephrectomy Model (ASH 2024) - "BackgroundTwo hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI), daprodustat and vadadustat, have been approved by FDA to treat dialysis dependent (DD) chronic kidney disease (CKD) anemia patients in US while all HIF-PHIs failed in getting approval by FDA in treating non-dialysis dependent (NDD) CKD anemia in US due to safety concerns. The hematocrits (%) for 5 groups were between 38.2±1.5 and 39.4±2.0 on day 1, were 41.6±1.6**, 36.3±1.9, 36.3±1.4, 37.2±1.2, and 36.3±1.7 respectively on day 35, were 41.8±1.3**, 36.8±2.4, 39.4±1.9*, 43.9±1.4**, and 51.4±2.8** respectively on day 49, and were 41.0±1.2**, 35.2±2.3, 39.0±3.6*, 45.7±3.1**, and 59.1±3.7** respectively on day 63. (Significance analysis was compared to group 2,* p<0.05,** p < 0.01)ConclusionThe rat 5/6 nephrectomy CKD anemia model was successfully established; on day 63, RBC, HGB, and HCT for rats in three..."

Preclinical • Anemia • Beta-Thalassemia • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Nephrology • Renal Disease • Sickle Cell Disease • MYC

Pharmacological Evaluation of a First-in-Class Hemoglobin Elevating Agent (HbEA) AND017 in Sprague Dawley Rats (ASH 2024) - "BackgroundInhibiting hypoxia-inducible factor prolyl hydroxylase (HIF-PH) by oral small molecules has been intensively pursued in treating chronic kidney disease (CKD) anemia during the past 20 years, leading to approval of daprodustat and vadadustat by FDA in treating dialysis-dependent (DD) CKD anemia in US while both plus roxadustat failed in getting approval by FDA in treating non-dialysis dependent (NDD) CKD anemia in US due to safety concerns. The hematocrits (%) for group 1 to 4 were between 38.7 and 39.1 on day 1, were 41.7±1.5, 44.0±2.0, 48.6±2.5**, and 57.9±2.7** respectively on day 28, and were 42.5±1.4, 41.7±1.5, 43.6±1.5, and 41.9±0.9 respectively on day 56. (Significance analysis was compared to group 1,* p<0.05,** p<0.01)ConclusionRBC, HGB, and HCT in normal SD male rats were significantly increased after dosing AND017 at 2.5 and 5 mg/kg PO QD for 4 weeks and gradually recovered to background levels after..."

Preclinical • Anemia • Beta-Thalassemia • Cardiovascular • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Nephrology • Renal Disease • Sickle Cell Disease • MYC

The cocrystal advantage: overcoming polymorph patent barriers in generic drug development. (PubMed, Mol Divers) - "Through case studies of recently developed cocrystals for APIs like Daprodustat, Roxadustat, and Vadadustat, we illustrate the practical application and commercial potential of this strategy. Ultimately, pharmaceutical cocrystals represent a critical convergence of materials science, regulatory law, and drug delivery, offering an innovative and effective route for accelerating patient access to affordable and improved medicines."

Journal • Review

Vadadustat for the Treatment of Nonintubated Acute Respiratory Distress Syndrome Due to Pathogen-Associated Lung Injury (clinicaltrials.gov) - P2/3 | N=1100 | Recruiting | Sponsor: Bentley J. Bobrow | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases

Erythropoiesis-Stimulating Agents (ESAs) in Chronic Kidney Disease and Cancer-Related Anemia: A Narrative Review of Literature. (PubMed, Cureus) - "Anemia associated with chronic kidney disease (CKD) and cancer is conventionally managed with packed red blood cell (PRBC) transfusions or erythropoietin-stimulating agents (ESAs) like epoetin alfa; however, transfusions are limited by complications such as alloimmunization and infection risk, which has led to ESAs becoming the preferred standard of care...The emerging alternative of HIF-PHIs shows promise in mitigating these adverse risks with a similar treatment efficacy to ESAs. However, there is still a lack of long-term safety data on these treatment options, and future research should focus on determining this risk profile as well as potential dosing strategies to potentially guide the use of HIF-PHIs in future clinical practice as a novel therapeutic alternative for anemia of CKD and cancer-related anemia."

Journal • Review • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Infectious Disease • Nephrology • Oncology • Renal Disease

Hypoxia-inducible Factor-2a Stabilization in Regulatory T Cells Promotes Cardioprotection after Myocardial Ischemia and Reperfusion Injury (ASA 2025) - "Therapeutic stabilization of HIFs with the clinically approved drug vadadustat enhances injury-associated Treg accumulation and stabilizes HIFs in cardiac Tregs, thereby mitigating adverse ventricular remodeling and preventing the progression to heart failure. These data identify a novel role for HIF-2α in Tregs in promoting cardioprotection after myocardial I/R injury and provide critical scientific insights into the potential use of HIF stabilizers for cardioprotection in anesthesiology and perioperative medicine."

Anesthesia • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Heart Failure • Myocardial Ischemia • Reperfusion Injury • AREG • EPAS1 • HIF1A

Orthogonal chemical-biological profiling of bioactive components from Olea europaea L. fruits for mitigating hypoxia-induced cellular injury. (PubMed, J Pharm Biomed Anal) - "Unlike vadadustat's Fe²⁺-chelating mechanism, these constituents act as potential competitive PHD2 inhibitors via non-chelating interactions at the catalytic site. Molecular docking suggests that OEL-F polyphenols may stabilize HIF-1α through PHD2 inhibition, proposing a novel natural product-driven strategy for safer hypoxia intervention."

Journal • Cardiovascular • CNS Disorders • HIF1A

CORRECTION: Study to Evaluate the Safety and Efficacy of Oral Vadadustat in Pediatric Participants With Anemia of Chronic Kidney Disease Naive to Erythropoiesis-Stimulating Agents (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Akebia Therapeutics | N=71 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Pediatrics • Renal Disease

CONVERSION: Study to Evaluate the Safety and Efficacy of Oral Vadadustat in Pediatric Participants With Anemia of Chronic Kidney Disease (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Akebia Therapeutics | N=71 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Pediatrics • Renal Disease

Light-driven biosensor for the rapid and selective detection of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors in aqueous media and saliva. (PubMed, Mikrochim Acta) - "HIF inhibitors such as Molidustat and Vadadustat are used as doping agents in racing sports. The new materials were also utilised for the rapid screening of HIF-PHI in spiked saliva samples. The new materials and light-driven surface functionalisation process can be easily adopted to develop new screening methods for multiple biomolecules (e.g. drugs, proteins, disease biomarkers, environmental toxins) for many applications (e.g. therapeutic drug monitoring, doping control, clinical diagnostics environmental monitoring)."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

Therapeutic hypoxia-inducible factor 1α stabilization activates antimicrobial peptide expression and prevents pneumonia (ERS 2025) - "We found that treating lung epithelia by inhalation with the prolyl-hydroxylase domain inhibitor vadadustat stabilized HIF-1α, resulting in activation of HIF-1α-dependent signaling that protected against Pseudomonas pneumonia in mice...These data indicate that HIF-1α signaling contributes to ODN-inducible resistance. This finding offers insights for rational design of alternate strategies to protect against fatal lung infection in patients with impaired immunity."

Infectious Disease • Pneumonia • HIF1A

To Evaluate the Efficacy of Three Times Weekly (TIW) Vadadustat Compared to Standard of Care ESA in Patients With Anemia of CKD Receiving In-Center Hemodialysis (clinicaltrials.gov) - P3 | N=350 | Recruiting | Sponsor: Akebia Therapeutics | Not yet recruiting ➔ Recruiting | N=500 ➔ 350 | Initiation date: Apr 2025 ➔ Jul 2025

Enrollment change • Enrollment open • Trial initiation date • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Vadadustat for the Treatment of Nonintubated Acute Respiratory Distress Syndrome Due to Pathogen-Associated Lung Injury (clinicaltrials.gov) - P2/3 | N=1100 | Not yet recruiting | Sponsor: Bentley J. Bobrow

New P2/3 trial • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases

A randomized trial to evaluate the pharmacokinetics, pharmacodynamics, and safety of vadadustat in patients with anemia associated with chronic kidney disease receiving hemodialysis. (PubMed, BMC Nephrol) - P1b | "The current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies."

Clinical • Journal • PK/PD data • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Unveiling Vadadustat: Comprehensive Review of its Chemistry, Pharmacology, Bioanalysis, and Patent Landscape as a Novel HIF-PH Inhibitor. (PubMed, Curr Top Med Chem) - "This review examines therapeutic, pharmacological, analytical, and regulatory aspects related to Vadadustat."

Journal • Cardiovascular • Hematological Disorders

Real-World Safety and Effectiveness of Vadadustat in Patients with Chronic Kidney Disease-Related Anemia: Interim Analysis of Postmarketing Surveillance in Japan. (PubMed, Adv Ther) - "In this interim analysis, we identified no new safety concerns beyond those outlined in the Japanese package insert for vadadustat, which is based on the results from pivotal clinical trials. The ongoing PMS will continue to offer valuable insights into the safety and effectiveness of vadadustat in real-world clinical practice."

Journal • P4 data • Real-world evidence • Anemia • Autosomal Dominant Polycystic Kidney Disease • Cardiovascular • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Hepatology • Hypertension • Nephrology • Oncology • Polycystic Kidney Disease • Renal Disease • Retinal Disorders • Solid Tumor

Identification of hypoxia-inducible factor HIF1A as a therapeutic target during SARS-CoV-2-associated lung injury. (PubMed, JCI Insight) - "Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF-stabilizer vadadustat...HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted."

Clinical • Journal • Acute Lung Injury • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • HIF1A