Kidney Week

Abstract: TH-PO901

On-Treatment Analyses of Cardiovascular Safety in the Vadadustat Phase 3 Program

Session Information

• Anemia and Iron Metabolism
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

• 200 Anemia and Iron Metabolism

Authors

• Winkelmayer, Wolfgang C., Baylor College of Medicine Margaret M and Albert B Alkek Department of Medicine, Houston, Texas, United States

Wolfgang C. Winkelmayer, MD, ScD, MPH, FASN

• Burke, Steven K., Akebia Therapeutics Inc, Cambridge, Massachusetts, United States

Steven K. Burke, MD

• Chertow, Glenn M., Stanford University School of Medicine, Stanford, California, United States

Glenn M. Chertow, MD, MPH, FASN

• Dykstra, Kevin, Akebia Therapeutics Inc, Cambridge, Massachusetts, United States

Kevin Dykstra, PhD

• Eckardt, Kai-Uwe, Charité–Universitätsmedizin Berlin, Berlin, Germany

Kai-Uwe Eckardt, MD

• Koury, Mark, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Mark Koury, MD

• Luo, Wenli, Akebia Therapeutics Inc, Cambridge, Massachusetts, United States

Wenli Luo, MD, PhD

• Minga, Todd Eric, Akebia Therapeutics Inc, Cambridge, Massachusetts, United States

Todd Eric Minga, MD

• Lewis, Eldrin F., Stanford University School of Medicine, Stanford, California, United States

Eldrin F. Lewis, MD

Background

Vadadustat (VADA) is an oral HIF-PHI for treating anemia in CKD. In the Phase 3 clinical program (INNO₂VATE: incident dialysis-dependent [DD]-CKD or prevalent DD-CKD; PRO₂TECT: ESA-untreated and ESA-treated non-DD [NDD]-CKD), VADA demonstrated noninferiority (HR=1.25 threshold) to darbepoetin alfa (DA) for MACE risk in DD-CKD (HR: 0.96, 95% CI, 0.83 to 1.11) but not NDD-CKD (HR: 1.17, 95% CI, 1.01 to 1.36) in primary ITT analyses. We conducted on-treatment analyses taking PK/PD profiles into account to better understand MACE risk.

Methods

The primary safety endpoint was time to first MACE (all-cause mortality, nonfatal MI, nonfatal stroke). Secondary safety endpoints were time to expanded MACE (MACE plus hospitalization for either heart failure or major thromboembolic event), CV MACE, CV mortality, and all-cause mortality. We adjusted on-treatment time at risk to include time to last treatment drug administration plus 28 days plus dosing frequency to account for PK/PD differences (VADA vs DA). For considering dosing frequency, we added 1 day for VADA and variable days (7-28 days) for DA.

Results

INNO₂VATE trials randomized 3902 patients (VADA=1947, DA=1955); PRO₂TECT trials randomized 3476 patients (VADA=1739, DA=1732). In the on-treatment analysis of DD-CKD, the risk of MACE was similar between treatment groups, consistent with results from ITT analyses (Figure). In the on-treatment analysis of NDD-CKD, the risk of MACE was similar between groups, and similar to results derived from the ITT analyses, inclusive of crossing the non-inferiority threshold. On-treatment analyses of secondary safety endpoints for DD-CKD and NDD-CKD populations were similar to their respective ITT analyses.

Conclusion

On-treatment dose-frequency-adjusted analyses address imbalances in PK/PD profiles and effective treatment duration between comparators and can complement results derived from ITT analyses.

Figure. On-treatment Safety Endpoints

Funding

• Commercial Support – Akebia Therapeutics, Inc.