Vadadustat for treating anemia in dialysis-dependent CKD

Vadadustat once daily, but not 3 times weekly, was noninferior to darbepoetin alfa in correcting hemoglobin levels in CKD patients on dialysis, after conversion from prior erythropoiesis-stimulating therapy for anemia. Safety profiles were similar across treatment groups.

This summary is based on the publication of Kooienga L, Burke S, Kathresal A, et al. - Safety and Efficacy of Vadadustat Once-Daily and 3-Times-Weekly in Dialysis-Dependent Chronic Kidney Disease Patients with Anemia. Kidney360. 2024 Sep 4 [Online ahead of print]. doi: 10.34067/KID.0000000567

Introduction and methods

Background

As CKD progresses, more patients develop anemia [1]. One of the treatment options is parenteral administration of erythropoiesis-stimulating agents (ESAs), but this requires refrigeration and is associated with increased CV morbidity and mortality [2-4]. Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has been approved for treating anemia in patients with CKD [5-7]. The global INNO₂VATE trials among patients with dialysis-dependent CKD showed vadadustat once daily (starting dose: 300 mg) was noninferior to darbepoetin alfa with regard to the correction and maintenance of hemoglobin levels and CV safety outcomes [8]. In these trials, some patients who were switched from an ESA to vadadustat—particularly those receiving high-dose ESAs at baseline—experienced an initial hemoglobin decline, which resolved after the dose was increased.

Aim of the study

The study aim was to investigate the efficacy and safety of vadadustat (dosed once daily or 3 times weekly) versus darbepoetin alfa in patients with dialysis-dependent CKD who were previously on ESA therapy.

Methods

In the MO₂DIFY trial, an open-label, active-controlled, noninferiority, phase 3b RCT, 319 patients were enrolled who were receiving chronic, outpatient in-center hemodialysis 3 times weekly for end-stage kidney disease for ≥12 weeks prior to screening, had taken an approved ESA for ≥8 weeks prior to screening, and had low hemoglobin levels (US: 8-11 g/dL; Europe: 9-12 g/dL). The study consisted of a screening period (8 weeks), conversion period (0–20 weeks), maintenance period (20–52 weeks), and safety follow-up period (4 weeks). Participants were stratified by geographical region (US vs. Europe) and mean baseline weekly darbepoetin alfa dose (or ESA equivalent; i.e., low ESA dose (≤0.45 μg/kg per week) vs. high ESA dose (0.46–1.50 μg/kg per week)). Next, they were randomized in a 1:1:1 ratio to oral vadadustat once daily, oral vadadustat 3 times weekly, or intravenous or subcutaneous darbepoetin alfa. The vadadustat starting dose was 300 mg once daily or 600 mg 3 times weekly for the low baseline ESA-dose group and 450 mg once daily or 750 mg 3 times weekly for the high baseline ESA-dose group. Both vadadustat and darbepoetin alfa doses were titrated using protocol-specified algorithms to maintain target hemoglobin levels (US: 10-11 g/dL; Europe: 10-12 g/dL).

Outcomes

The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the prespecified primary evaluation period (20–26 weeks). The key secondary efficacy endpoint was the mean change in hemoglobin level from baseline to the secondary evaluation period (46–52 weeks). Other endpoints included the proportion of patients requiring ESA rescue (when hemoglobin <9.5 g/dL or darbepoetin alfa dose increase ≥50%). Safety assessment included the incidence of treatment-emergent adverse events, serious treatment-emergent adverse events, and adverse events of special interest.

Main results

Efficacy

• The least-squares (LS) mean change in hemoglobin level from baseline to 20–26 weeks (i.e., primary efficacy endpoint) was 0.07 g/dL (95%CI: –0.17 to 0.31) in patients treated with vadadustat once daily and 0.34 g/dL (95%CI: 0.11 to 0.57) in those receiving darbepoetin alfa. This corresponded with a LS mean treatment difference of –0.27 g/dL (95%CI: –0.55 to 0.01), with the lower limit of the 95%CI being above the prespecified noninferiority threshold of –0.75 g/dL.

• For vadadustat 3 times weekly, the mean change in hemoglobin level from baseline to 20–26 weeks was –0.19 g/dL (95%CI: –0.41 to 0.04). Hence, the LS mean treatment difference between vadadustat 3 times weekly and darbepoetin alfa was –0.53 g/dL (95%CI: –0.80 to –0.25), which did not meet the lower bound noninferiority threshold.

• As mean hemoglobin levels were consistently lowest in patients receiving vadadustat 3 times weekly, subgroup analyses stratified by ESA dose at baseline were performed. These analyses demonstrated the LS mean change in hemoglobin level from baseline to 20–26 weeks was lower in patients who were treated with a low ESA dose at baseline and therefore received a vadadustat starting dose of 600 mg compared with those treated with a high baseline ESA dose and received a vadadustat starting dose of 750 mg (–0.28 g/dL; 95%CI: –0.50 to –0.06 vs. 0.24 g/dL; 95%CI: –0.32 to 0.80). Similar results were observed for patients in the vadadustat once-daily group.

• The LS mean treatment difference in hemoglobin change from baseline to 46–52 weeks (i.e., key secondary efficacy endpoint) between vadadustat once daily and darbepoetin alfa was –0.40 (95%CI: –0.79 to –0.02) and that between vadadustat 3 times weekly and darbepoetin alfa was –0.42 (95%CI: –0.81 to –0.02). In both cases, the lower limit of the 95%CI exceeded the noninferiority margin.

• The proportion of patients receiving any ESA rescue medication during the primary evaluation period was 7.6% in the vadadustat once-daily group, 9.8% in the vadadustat 3-times-weekly group, and 15.6% in the darbepoetin alfa group. The patient proportions during the secondary evaluation period were 1.5%, 1.5%, and 12%, respectively.

Safety

• The frequency of any treatment-emergent adverse event was 85% in the vadadustat once-daily group, 85% in the vadadustat 3-times-weekly group, and 81% in the darbepoetin alfa group.

• The incidence of study drug–related treatment-emergent adverse events was 12%, 16%, and 0%, respectively. These events included gastrointestinal disorders (mostly diarrhea).

• The frequency of serious treatment-emergent adverse events was similar in the 3 treatment groups (~45%), and these mainly comprised infections and infestations, and cardiac disorders.

• The mortality rate was 11% in the vadadustat once-daily group, 9% in the vadadustat 3-times-weekly group, and 6% in the darbepoetin alfa group, but none of the deaths were considered to be related to the study drug.

Conclusion

In the open-label noninferiority trial MO₂DIFY, vadadustat once daily, but not 3 times weekly, was noninferior to darbepoetin alfa with regard to the primary efficacy endpoint of hemoglobin change from baseline to 20–26 weeks in patients with dialysis-dependent CKD, after conversion from prior ESA therapy for anemia. Patients receiving vadadustat once daily or 3 times weekly seemed to have a lower chance of needing ESA rescue than those on darbepoetin alfa. Overall, vadadustat had a similar safety profile as darbepoetin alfa, except for a higher incidence of gastrointestinal disorders. The authors conclude that “[v]adadustat offers a convenient oral alternative for the treatment of anemia in patients with [dialysis-dependent] CKD, circumventing the limitations of parenteral or subcutaneous routes and providing an important option when iron supplementation and ESA treatment prove inadequate.”

Find this article online at Kidney360.

References

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