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Abstract: TH-OR01

Global Phase 3 Clinical Trials of Vadadustat vs. Darbepoetin Alfa for Treatment of Anemia in Patients with Dialysis-Dependent CKD

Session Information

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Author

  • Eckardt, Kai-Uwe, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Group or Team Name

  • INNO2VATE Author Group
Background

Vadadustat (VADA) is an investigational, oral, hypoxia-inducible factor prolyl hydroxylase inhibitor that has advanced to phase 3 development for treatment of anemia of CKD. In phase 2 trials, VADA raised and maintained Hb concentrations.

Methods

Two randomized, phase 3, global, open-label, sponsor-blind, parallel-group active-controlled noninferiority (NI) trials comparing VADA vs darbepoetin alfa (DA) were conducted in patients with anemia of DD-CKD (INNO2VATE trials). The trials included 1) Correction/Conversion trial of patients new to dialysis (incident trial, NCT02865850) and 2) Conversion trial of patients on maintenance dialysis (prevalent trial, NCT02892149). The primary safety endpoint was time to first major adverse cardiovascular event (MACE: all-cause mortality, nonfatal MI, nonfatal stroke) prespecified as a pooled analysis of both trials. Primary and key secondary efficacy endpoints, prespecified as separate analyses for each trial, were mean difference in change in Hb from baseline between VADA vs DA to wks 24-36 and wks 40-52, respectively.

Results

3923 patients were randomized 1:1 to VADA or DA (incident, N=369; prevalent, N=3554). Median (Q1, Q3) duration of follow-up was 1.2 (0.8, 1.7) and 1.7 (1.2, 2.2) years in the incident and prevalent trials, respectively. VADA was noninferior to DA for time to first MACE (HR 0.96; 95% CI: 0.83, 1.11) and met a prespecified NI margin of 1.25. Among incident dialysis patients, the least squares (LS) mean difference in change in Hb between VADA vs DA from baseline to wks 24-36 was -0.31 g/dL (95% CI: -0.53, -0.10) and from wks 40-52 was -0.07 g/dL (95% CI: -0.34, 0.19). In the prevalent trial, the LS mean difference in change in Hb from baseline to wks 24-36 was -0.17 g/dL (95% CI: -0.23, -0.10), and wks 40-52 was -0.18 g/dL (95% CI: -0.25, -0.12). Primary and key secondary efficacy endpoints met the prespecified NI margin of -0.75 g/dL in both trials. Incidence of treatment-emergent adverse events (TEAEs) in VADA vs DA was 83.8% vs 85.5% in the incident trial and 88.3% vs. 89.3% in the prevalent trial, respectively.

Conclusion

VADA was noninferior to DA in time to first MACE and correction/maintenance of Hb in DD-CKD patients with anemia. The incidence of TEAEs was comparable between VADA and DA.

Funding

  • Commercial Support