Inflammation Has Little to No Effect on Safety, Effectiveness of Roxadustat for Anemia in CKD

Weiru Zhang, PhD
Credit: Central South University

Inflammation had little to no effect on the safety and efficacy of roxadustat for the treatment of anemia in patients with chronic kidney disease (CKD), according to a new study.

A systematic review and meta-analysis of more than half a dozen studies, results indicate roxadustat had a similar safety and efficacy profile across the spectrum of C-reactive protein (CRP) levels examined within the studies, with further analysis suggesting efficacy similar to erythropoiesis-stimulating agents (ESAs) even among those with CRP beyond the upper limit of normal without need for dose escalation.

“This finding has implications for advancing research focused on the efficacy of [hypoxia-inducible factor-prolyl hydroxylase inhibitors] in patients with CKD experiencing an inflammatory state,” wrote investigators.¹

Associated with increased risk of multiple comorbidities and posing a significant threat to quality of life, as well as overall survival, the optimal diagnosis and management anemia among patients with CKD stands to provide a substantial benefit for this patient population. A 2020 review of more than 190 studies on the topic found risk of mortality among patients on dialysis was 17 to 56% greater if their hemoglobin levels were 12 g/dL or less.

With approximately 25% of US individuals with stage 3-5 CKD dealing with anemia, a team led by Weiru Zhang, PhD, of the National Clinical Research Center for Geriatric Disorders at Ziangya Hospital, sought to determine whether inflammation might play a role in the safety and efficacy of roxadustat in management of anemia relative to ESAs through a systematic review and meta-analysis of available randomized controlled trials.^1,3

A first-in-class hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI), roxadustat is marketed by FibroGen and has received approvals for use in the treatment of anemia in both dialysis-dependent and non-dialysis-dependent CKD from regulatory authorities in China, India, and Japan. However, the US Food and Drug Administration declined to approve the agent’s New Drug Application in August 2021. According to FibroGen, the FDA requested an additional clinical study of the agent prior to resubmission.^3,4

For their systematic review and meta-analysis, investigators performed a search of the PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. Limiting their search to randomized controlled trials of for renal anemia treatment, investigators identified 7 studies from 6 publications for inclusion.¹

Among these 7 studies, 4 were included in the comparison of those with CRP levels equal to or greater than the upper limit of normal to those with CRP levels less than the upper limit of normal, which yielded a population of 524 individuals. Of note, all of these patients received roxadustat as the primary intervention. The other 3 studies examined the efficacy of roxadustat against ESAs and yielded a population of 1399 individuals.¹

The primary outcome of interest for the meta-analysis was the mean difference in changes in hemoglobin concentration before and after treatment across groups stratified by CRP levels. Investigators defined CRP groups as being greater than or equal to the upper limit of normal and less than the upper limit of normal. Investigators also noted plans to further assess the effects of HIF-PHIs and ESAs among those with CRP equal to or greater than the upper limit of normal.¹

Upon analysis, results indicated there was no significant difference in hemoglobin between patients with CRP equal to or greater than the upper limit of normal and CRP less than the upper limit of normal at baseline (MD, 0.00; 95% Confidence Interval [CI], -0.32 to 0.33, P = .99). Further analysis comparing the effect of roxadustat relative to ESAs, results suggested there was no significant difference in hemoglobin between patients treated with ESAs and HIF-PHIs (MD, 0.24; 95% CI, -0.08 to 0.56; P = .14).¹

Investigators highlighted increases in ESA dose over time was observed across various studies, with this most prominent among those with a CRP equal to or greater than the upper limit of normal. In contrast, investigators observed doses of roxadustat remained constant over time and were not influenced by baseline CRP levels.¹

Investigators called attention to specific limitations within their study to consider before overinterpretation of results. These limitations included quality of studies included, reliability of results being impacted by variations in study design, and relative variability in hemoglobin levels.¹

“Our systematic review reveals that roxadustat demonstrates consistent efficacy across different CRP levels. Particularly noteworthy is its ability to maintain efficacy comparable to ESA in the CRP [equal to or greater than the upper limit of normal] group without the need for dose escalation,” investigators added.¹

References:

1. _{^{Luo X, Li G, Yang H, et al. Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials. BMC Nephrol. 2024;25(1):47. Published 2024 Feb 5. doi:10.1186/s12882-024-03474-5}}
2. _{^{Palaka E, Grandy S, van Haalen H, McEwan P, Darlington O. The Impact of CKD Anaemia on Patients: Incidence, Risk Factors, and Clinical Outcomes-A Systematic Literature Review. Int J Nephrol. 2020;2020:7692376. Published 2020 Jul 1. doi:10.1155/2020/7692376}}
3. _{^{Kovesdy CP, Davis JR, Duling I, Little DJ. Prevalence of anaemia in adults with chronic kidney disease in a representative sample of the United States population: analysis of the 1999-2018 National Health and Nutrition Examination Survey. Clin Kidney J. 2022;16(2):303-311. Published 2022 Nov 12. doi:10.1093/ckj/sfac240}}
4. _{^{Astellas Pharma US. Astellas receives European Commission approval for first-in-class EVRENZOTM (roxadustat) for adult patients with symptomatic anemia of chronic kidney disease. Astellas Pharma US, Inc. | News Room. August 19, 2021. Accessed February 7, 2024. https://newsroom.astellas.us/2021-08-19-Astellas-Receives-European-Commission-Approval-for-First-in-Class-EVRENZO-TM-roxadustat-for-Adult-Patients-with-Symptomatic-Anemia-of-Chronic-Kidney-Disease.}}