In a post-hoc win-odds analysis of the Phase 3 INNO2VATE program, vadadustat (Vafseo) outperformed darbepoetin alfa on a hierarchical composite of all-cause mortality and hospitalization in adults on maintenance dialysis for CKD-related anemia. The on-study inverted win-odds were 0.93 (95% CI, 0.87–0.99; p=0.03) and 0.86 (95% CI, 0.81–0.95; p<0.0001) on-treatment plus 28 days, where values below one favor vadadustat, given the analytic orientation reported. The signal was presented at ASN Kidney Week 2025 and is based on two global, open-label, randomized noninferiority trials that originally used MACE as the primary safety endpoint. The core development is not new efficacy data but a reframing of INNO2VATE outcomes using a prioritized composite that places mortality above hospitalization and counts all events. That framing matters. Vafseo, an oral HIF-PHI approved in the U.S. since January 2025 for dialysis-dependent CKD anemia, is competing directly with injectable ESAs inside highly protocolized dialysis organizations. Showing an advantage on death and hospital utilization—even in a post-hoc construct—gives Akebia a clinically intuitive narrative to take to medical directors, quality committees, and payers who manage total cost of care as much as hemoglobin targets. Strategically, this is an adoption play. Akebia is leaning into outcomes that resonate with dialysis providers’ financial and operational levers while advancing real-world evidence, including the VOICE pragmatic program, designed around mortality and hospitalization. The company is effectively shifting the conversation from hematologic noninferiority to prioritized clinical outcomes that drive network benchmarks and contracting. The choice of win-odds underscores a broader trial design trend: sponsors are turning to hierarchical composites and win-based methods to capture clinically meaningful differences without inflating sample size or endpoint multiplicity, particularly in settings where event profiles are multifactorial and labeling pathways are mature. For stakeholders, the implications vary. Dialysis organizations weighing conversion economics now have an analysis showing fewer deaths and admissions with vadadustat relative to darbepoetin, potentially aligning with quality metrics and readmission penalties. Operationally, an oral, once-daily option could reduce injection workflows but shift the emphasis to blood pressure control, hepatic labs, and drug–drug interactions noted in the label—variables that will factor into protocol updates, nurse training, and pharmacy coordination. For CROs and sites, the methodology signals more demand for event adjudication frameworks, rigorous hospitalization coding, and statistical plans that pre-specify hierarchy to withstand regulatory and payer scrutiny. For payers and PBMs serving ESRD plans, prioritized composites provide a bridge between clinical effects and budget impact models. Still, the open-label and post-hoc nature will temper conclusions until prospective data arrive. The following checkpoints are executional. VOICE and other pragmatic efforts will need to replicate the mortality/hospitalization signal prospectively, with clear event definitions and minimal ascertainment bias. Any move to translate these findings into labeling or guideline influence will hinge on prespecified analyses and durability across subgroups commonly seen in dialysis units, including those with high cardiovascular burden. Watch for how large dialysis organizations incorporate the signal into formulary decisions and whether competing HIF-PHIs pursue similar win-based analyses to shape negotiations. The unresolved questions are whether the advantage persists under real-world prescribing pressure, how heterogeneity in hospitalization coding will be managed, and whether the safety monitoring obligations of HIF stabilization offset the operational simplicity of oral dosing.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
