Vadadustat Noninferior to Long-Acting ESA for Anemia in Hemodialysis Patients

Vadadustat was found to be noninferior to a long-acting erythropoiesis-stimulating agent (ESA) for the maintenance treatment of anemia due to chronic kidney disease (CKD) in hemodialysis patients, according to findings from the phase 3 FO₂CUS study.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. This results in increased red blood cell production and improved oxygen delivery to tissues.

The open-label, active-controlled, sponsor-blinded FO₂CUS study (ClinicalTrials.gov Identifier: NCT04707768) included 456 hemodialysis patients who were randomly assigned 1:1:1 to receive vadadustat 600mg or 900mg orally three times weekly, or a long-acting ESA (Mircera). The primary endpoint was the mean change in hemoglobin (Hb) between baseline and the primary evaluation period (weeks 20-26). The secondary endpoint was the mean change in Hb between baseline and the secondary evaluation period (weeks 46-52).

Results showed that vadadustat met the primary endpoint demonstrating noninferiority to Mircera with a least square mean difference in Hb of -0.43 g/dL (-0.67, -0.20) for the 600mg-treated group, -0.23 g/dL (-0.46, 0.01) for the 900mg-treated group, and -0.33 g/dL (-0.53, -0.13) for the combined vadadustat-treated group. During the primary evaluation period, the mean Hb level for the combined vadadustat-treated group was 10.11 (0.061) g/dL vs 10.41 (0.068) g/dL for the Mircera group.

Vadadustat also met the secondary endpoint demonstrating noninferiority to Mircera with a least square mean difference in Hb of -0.27 g/dL (-0.54, -0.00) for the 600mg-treated group, -0.38 g/dL (-0.67, -0.10) for the 900mg-treated group, and -0.33 g/dL (-0.56, -0.09) for the combined vadadustat-treated group. During the secondary evaluation period, the mean Hb level for the combined vadadustat group was 10.03 (0.066) g/dL vs 10.28 (0.076) g/dL for the Mircera group.

As for safety, treatment-emergent adverse events (TEAEs) occurred in 78.7% of patients in the combined vadadustat-treated group vs 75.3% of patients in the Mircera group. The most common TEAEs reported for vadadustat- and Mircera-treated patients were COVID-19 (14.6% vs 16.0%), diarrhea (12.3% vs 8%) and hyperkalemia (9% vs 10.7%).

“The FO₂CUS study demonstrated that vadadustat managed hemoglobin levels in patients on hemodialysis when administered 3 times a week, which we believe is important as the dosing schedule aligns with dialysis visits and has the potential, if approved, to provide an oral alternative to the standard of care,” said Steven K. Burke, MD, Senior Vice President, Research & Development and Chief Medical Officer of Akebia.

In March 2023, Akebia received a Complete Response Letter regarding the application for vadadustat for the treatment of anemia due to CKD. In the letter, the FDA noted conflicting data related to the primary safety endpoint of major adverse cardiovascular events (MACE), as well as other safety concerns, and had requested new trial data to address these issues. In response, the Company filed a Formal Dispute Resolution Request and is awaiting a response to its appeal.