Authors’ Reply

Journal of the American Society of Nephrology, vol. 31, pp. 2738–2740

Abstract

The following is in response to a letter to the editor submitted by Tanaka et al. concerning the recently published article titled “Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan.”1 In their letter, Tanaka et al. cite several concerns regarding the effects of roxadustat versus darbepoetin alfa (DA) in patients with inflammation, defined according to high-sensitivity C-reactive protein (hs-CRP). The specific concerns cited by Tanaka et al. are as follows: (1) that the study did not aim to compare the efficacy of study drugs in patients with inflammation, and the small sample of patients with high hs-CRP will not allow for further statistical analysis; (2) that the changes in hs-CRP during the treatment period were not considered; (3) that, in patients with high hs-CRP, the hemoglobin (Hb) levels during the evaluation period in the DA group seemed slightly higher than those in the roxadustat group; and (4) that, in the study, the mean Hb level and the rate of increase in Hb at week 4 were higher in the roxadustat group than in the DA group. To evaluate the effect of roxadustat in patients with inflammation, a post hoc (not prespecified) subgroup analysis of average Hb levels and the allocated doses of the study drug (per administration, by visit) was conducted using hs-CRP (i.e., <3.000 mg/L and ≥3.000 mg/L) as a factor, where the threshold 3.000 mg/L represents the upper limit of normal in the hs-CRP range. Regarding the first point of Tanaka et al.’s letter, we agree that a comparison of the efficacy of study drugs in patients with inflammation was not the primary objective of this study, and the small sample of patients with high hs-CRP will not allow for concrete conclusions. The manuscript carefully states that observations relating to hs-CRP merely provide preliminary evidence that the dose requirement of roxadustat may not be affected by inflammation to the same extent that the dose requirement of erythropoiesis-stimulating agents was. We go on to say that further investigation is required before any firm conclusions can be made regarding the relationship between roxadustat dosing and inflammation. Nevertheless, this analysis focuses on an important potential clinical difference between roxadustat and DA. Regarding the second point of Tanaka et al.’s letter, we agree that the changes in hs-CRP during the study were not presented in the manuscript. However, median hs-CRP was stable for both treatment groups and for both subgroups (low versus high hs-CRP) during the study. In the third point of the letter, Tanaka et al. suggest that, in patients with high hs-CRP, the Hb levels during the evaluation period in the DA group seemed slightly higher than those in the roxadustat group. In this study, data suggest that the average Hb levels at weeks 18–24 in the DA group were similar to those in the roxadustat group. Among patients with hs-CRP <3.000 mg/L, the mean (SD) change of average Hb from baseline to weeks 18–24 was −0.03 g/dl (0.79) and −0.03 g/dl (0.88) in the roxadustat and DA groups, respectively. Among patients with hs-CRP ≥3.000 mg/L, the mean (SD) change of average Hb from baseline to weeks 18–24 was −0.13 g/dl (0.81) and −0.18 g/dl (0.94) in the roxadustat and DA groups, respectively (see Figure 3 in the article1). Regarding the fourth point of Tanaka et al.’s letter, the mean Hb level and the rate of increase in Hb level at 4 weeks were higher in the roxadustat group than in the DA group and, because of this, it is expected that the dose of roxadustat would be reduced later in the study (see Figure 4 in the article1). In this study, there is no difference in trends regarding the doses required to maintain target Hb between patients with low or high hs-CRP in the roxadustat group. However, the dosing patterns in patients in the DA arm, with low versus high hs-CRP, appeared to be different, which we thought would be interesting to readers. It is important to note that this subgroup analysis mainly focused on doses used in the maintenance period (i.e., weeks 18–24); as such, the influence of initial conversion doses is limited, especially when considering that dose adjustments were conducted after week 4. Moreover, the Hb levels in the maintenance period (i.e., weeks 18–24) were similar among subgroups in both treatment groups, regardless of initial Hb increase in the early treatment period. Importantly, the aim of the analysis was not to discuss the absolute volume of the dose in each hs-CRP subgroup at each visit, but rather to consider dosing trends in each hs-CRP subgroup. Although we readily agree that firm conclusions cannot be drawn at this point, it should be noted that the relationship between roxadustat dosing and inflammation levels has been examined in previous studies. In a phase-2 study, Chen et al.3 reported that treatment with roxadustat significantly decreased the levels of hepcidin, a marker shown to be associated with iron deficiency and increased inflammation,2 in both patients who were dialysis dependent and those who were not dialysis dependent. Another phase-2 study comparing epoetin alfa with roxadustat demonstrated that hs-CRP levels were correlated with higher pre-enrollment doses of epoetin alfa, whereas, in the same study after a 19-week treatment, no association between the roxadustat dose required to maintain target Hb levels and hs-CRP levels was observed in the last 7 weeks of treatment.4 Likewise, in a phase-3 study, Chen et al.5 reported that, in a comparison of subgroups of patients stratified by CRP, roxadustat resulted in a greater change from baseline in the Hb level, compared with epoetin alfa. Moreover, Chen et al.5 reported that roxadustat doses between normal and high CRP subgroups were similar, whereas patients with high CRP in the epoetin alfa group required higher epoetin alfa doses. We conclude by suggesting that the ability of roxadustat to maintain target Hb levels in the presence of inflammation, at comparable doses in the absence of inflammation, may represent an advantage of roxadustat compared with ESA treatment. Rather than presenting a conclusion, the aim of this manuscript was to present a forward-thinking statement that may help shape future studies. We agree that any subgroup analysis of a randomized controlled trial should be interpreted with caution. Data Sharing Statement Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas-sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx. Disclosures Y. Majikawa and Y. Yamaguchi are employees of Astellas Pharma, Inc. M. Reusch is an employee of Astellas Pharma Europe B.V. All remaining authors have nothing to disclose. Funding This study was funded by Astellas Pharma. T. Akizawa reports receiving personal fees from Astellas, Bayer Yakuhin Ltd., GlaxoSmithKline, JT Pharmaceuticals, Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin, and Chugai Pharmaceutical Co. Ltd., during the conduct of the study.

Authors 4

1. Tadao Akizawa corresponding

   SHOWA Medical University

   Affiliation as printed

   Department of Nephrology, Showa University School of Medicine, Tokyo, Japan

2. Manabu Iwasaki

   Yokohama City University

   Affiliation as printed

   Department of Data Science, Yokohama City University, Yokohama, Japan

3. Yusuke Yamaguchi

   Astellas Pharma (Japan)

   Affiliation as printed

   Japan-Asia Data Science, Development, Astellas Pharma, Inc., Tokyo, Japan

4. Yoshikatsu Majikawa

   Astellas Pharma (Japan)

   Affiliation as printed

   Japan-Asia Clinical Development 2, Development, Astellas Pharma, Inc., Tokyo, Japan