Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE)

Abstract

Significance statement: Systemic inflammation in CKD can lead to anemia. Ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, has been shown to reduce systemic inflammation in patients with CKD. It has also been shown to increase serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to treatment with erythropoiesis-stimulating agents. This exploratory analysis of the RESCUE clinical trial found that among patients with CKD stage 3-5 and systemic inflammation, ziltivekimab treatment significantly increased hemoglobin (Hb) levels after 12 weeks compared with placebo. Ziltivekimab was also associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation. No major safety concerns were reported. Further clinical trials are warranted to study ziltivekimab's potential for anemia management in patients with CKD.

Background: In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to assess the effect of ziltivekimab on Hb and iron homeostasis in this patient population.

Methods: This was an analysis of exploratory end points from the RESCUE trial ( NCT03926117 ), which included 264 adults with CKD stage 3-5 and high-sensitivity C-reactive protein ≥2 mg/L. Participants received placebo or subcutaneous ziltivekimab (7.5, 15, or 30 mg) (1:1:1:1) once every 4 weeks, up to 24 weeks. End points for this analysis were changes in Hb and biomarkers of iron homeostasis from baseline to week 12.

Results: The trial was terminated early due to the coronavirus disease 2019 pandemic, and thus, data up to week 12 are presented. Hb levels significantly increased from baseline to week 12 with ziltivekimab 7.5, 15, and 30 mg (treatment differences versus placebo: +0.57 g/dl [95% confidence interval, 0.27 to 0.86], +1.05 g/dl [0.76 to 1.33], and +0.99 g/dl [0.70 to 1.28], respectively, all P < 0.001). Ziltivekimab was associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation from baseline to week 12 ( P < 0.05 versus placebo for all doses and comparisons). Cases of sustained thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia were infrequent and similar across all groups.

Conclusions: Anti-inflammatory therapy with ziltivekimab improved the markers of anemia and iron homeostasis in people with stage 3-5 CKD and systemic inflammation, suggesting a possible role in anemia management.

Trial registration: ClinicalTrials.gov NCT03926117 NCT02868229.

Graphical abstract

Figure 1

RESCUE CONSORT diagram. ^aOne participant did not attend a visit after 12 weeks but did complete the 24 weeks of treatment. “No follow-up” is defined as participants who withdrew consent and refused all further follow-up. “Passive follow-up” is defined as participants who withdrew consent and did not participate further with the trial procedures but consented to some follow-up. “Randomization error” is defined as participants who were randomized in error because they violated inclusion/exclusion criteria; these patients should not have been randomized and did not receive any treatment. COVID-19, coronavirus disease 2019. This figure was first published in Ridker PM et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2021;397:2060–9, copyright Elsevier (2021), and reproduced with permission.

Figure 2

Mean Hb levels for the pooled ziltivekimab groups versus placebo over time (intention-to-treat population). ^aPrespecified time point. Data are presented as mean values and SDs (error bars). Ziltivekimab data include the pooled 7.5, 15, and 30 mg doses; n values for the placebo and ziltivekimab 7.5, 15, and 30 mg treatment groups at week 12 in the overall population were 57, 53, 60, and 57 participants. n values shown below the graph are for participants contributing to the analysis at the time point indicated. Hb, hemoglobin.