Vadadustat Response Influenced by Patient Background in Anemia from CKD

A post-hoc subgroup analysis of two phase 3 randomized trials in Japan, investigating vadadustat for anemia associated with chronic kidney disease (CKD), revealed independent factors associated with a better patient response.¹

The analysis focused on patients with anemia and either nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD enrolled in the two trials, to determine the patient background variables affecting the vadadustat resistance index (VRI), a composite measure of maintenance doses and hemoglobin levels.

Ultimately, Tokyo-based investigators reported the vadadustat treatment response was higher among those with factors including high baseline hemoglobin and low baseline estimated glomerular filtration rate (eGFR) in the NDD-CKD trial, and those with high baseline C-reactive protein (CRP) and low baseline erythropoiesis-stimulating agent resistance index (ERI) in the HDD-CKD trial.

“These results would be expected to provide useful information leading to an appropriate dose modification for vadadustat,” wrote the investigative team, led by Masaomi Nangaku, MD, PhD, Graduate School of Medicine, The University of Tokyo.

Standard-of-care treatment for renal anemia had previously been injectable erythropoiesis-stimulating agents (ESAs).² The onset of oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors has transformed the clinical armamentarium. Recent phase 3 trials, based in Japan, revealed the noninferiority of vadadustat, an oral HIF-PH, to darbepoetin alfa, an ESA, in the maintenance of hemoglobin levels among patients with anemia and NDD-CKD or HDD-CKD.^3,4

Multiple subgroup analyses were performed on the impact of patient background on treatment efficacy. Still, Nangaku and colleagues cited the use of two separate indicators (dose and hemoglobin level) as impacting the interpretation of the results.¹ As a result, the team performed a multivariate analysis to assess the efficacy of vadadustat, using the VRI, to determine the factors affecting treatment response in the two phase 3 studies.

Across both trials, the primary endpoint was the mean hemoglobin level at weeks 20–24 of vadadustat treatment. For this post-hoc analysis, the primary endpoint was set to be equivalent to the VRI at weeks 20–-24, stratified by patient background. The index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) divided by the mean hemoglobin (g/dL).

Among 151 and 162 patients in the vadadustat cohorts in the NDD-CKD and HDD-CKD studies, 136 and 140, respectively, were enrolled into the posthoc analysis and divided into subgroups. Participants had a mean age of 71.4 and 65.5 years, and a mean baseline hemoglobin level of 10.46 g/dL and 10.73 g/dL, in the NDD-CKD and HDD-CKD studies, respectively.

Upon multivariate analysis, in patients with NDD-CKD, high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease, glomerulonephritis, or vasculitis, were independent factors associated with better response to vadadustat. Among individuals with HDD-CKD, multivariate analysis revealed male sex, high baseline CRP, and low baseline ERI as independent factors associated with a better vadadustat treatment response.

Low ferritin levels, indicating lower levels of stored iron, negatively impacted responsiveness to vadadustat in the NDD-CKD cohort, but were not considered an independent factor affecting response in HDD-CKD, as the VRI were found to increase with decreasing week-20–24 ferritin levels.

As all patients switched from ESAs to vadadustat, Nangaku and colleagues noted the hemoglobin levels were maintained from baseline to 24 weeks in patients with HDD-CKD. However, for those with NDD-CKD, hemoglobin levels increased by approximately 1 g/dL, indicating the level of stored iron could affect vadadustat response.

“The present results are consistent with the reports that iron supplementation was associated with a lower ESA dose and an augmented hemoglobin response by HIF-PH inhibitor,” Nangaku and colleagues wrote. “Therefore, especially during the hemoglobin elevation phase, appropriate iron supplementation may be essential from the viewpoint of vadadustat responsiveness.”

References

1. _{Nangaku M, Ueta K, Nishimura K, Sasaki K, Hashimoto T. Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies. Clin Exp Nephrol. Published online March 26, 2024. doi:10.1007/s10157-023-02432-z}
2. _{Walter K, Campbell P. DAPRODUSTAT receives FDA approval for anemia caused by CKD on dialysis. HCP Live. February 2, 2023. Accessed March 27, 2024. https://www.hcplive.com/view/fda-daprodustat-patients-anemia-ckd-dialysis.}
3. _{Nangaku M, Kondo K, Kokado Y, et al. Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD. J Am Soc Nephrol. 2021;32(7):1779-1790. doi:10.1681/ASN.2020091311}
4. _{Nangaku M, Kondo K, Ueta K, et al. Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant. 2021;36(9):1731-1741. doi:10.1093/ndt/gfab055}