Ziltivekimab May Help Anemia Management in CKD Patients

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A new study demonstrated hemoglobin levels significantly increased with ziltivekimab, showing the monoclonal antibody has the potential to serve as a new treatment method for anemia.

Ziltivekimab, a human monoclonal antibody against IL-6 ligand, improved anemia, systemic inflammation and iron homeostasis in patients with stage 3 – 5 chronic kidney disease (CKD), according to a new study.1

Approximately 15% of patients with CKD have anemia—30-50% of patients with kidney failure treated by chronic dialysis have high levels of the biomarkers of inflammation, including IL-6 and high-sensitivity C-reactive protein. High levels of C-reactive proteins are associated with the development of anemia in earlier stages of CKD. Previous research found a reduction of high-sensitivity C-reactive production—and thus a reduction in inflammation— may prevent the onset of anemia.

Moreover, systemic inflammation can affect iron homeostasis through the upregulation of proinflammatory cytokines, like IL-6, which can increase hepcidin levels. Higher hepcidin levels may lead to functional iron deficiency and anemia in patients with CKD. A previous phase 1/2 trial found ziltivekimab significantly reduced inflammatory biomarkers and increased serum albumin in patients treated by dialysis with inflammation, but it had not explored the antibody’s effect on hemoglobin and iron homeostasis, nor patients specifically diagnosed with CKD.

In RESCUE, a new randomized, double-blind, placebo-controlled phase 2 trial, the investigators, led by Pablo Pergola, MD, PhD, from Renal Associates P.A. in San Antonio, Texas, sought to evaluate the effect of ziltivekimab on hemoglobin and iron homeostasis in adults with stage 3 – 5 CKD and high-sensitivity C-reactive protein ≥2 mg/L.

“Ziltivekimab was associated with significantly increased levels of [hemoglobin] from baseline to week 12 versus placebo,” the investigators wrote. “The levels of biomarkers of iron metabolism (serum iron, TIBC, and transferrin saturation) also increased from baseline with ziltivekimab compared with placebo, suggesting a potential role for anti-inflammatory therapy in the treatment of anemia in CKD.”

Participants were eligible if they were aged ≥18 years old, had an eGFR >10 and <60 ml/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration 2009 creatinine equation, and systemic inflammation with a high-sensitivity C-reactive protein level of ≥ 2 mg/L. The team selected participants from June 17, 2019 – January 14, 2020, with 48.9% of participants female (n = 129) and a mean age of 66.4 years old. The sample had 29.2% (n = 77) of patients with CKD stage 3a, 40.9% (n = 108) stage 3b, 22.7% (n = 60) stage 4, and 5.7% (n = 15) stage 5, as well as a mean hemoglobin of 12.2 – 12.5 g/dl.

Afterward, the team randomized 264 patients into receiving either placebo or ziltivekimab (doses 7.5, 15, or 20 mg) every 4 weeks, up to 12 weeks. The team measured changes in hemoglobin and biomarkers of iron homeostasis from baseline to end-of-study. RESCUE was going to last 24 weeks, but the trial ended early due to COVID-19.

From baseline to week 12, hemoglobin levels significantly increased with ziltivekimab 7.5 mg (+0.57 g/dl; 95% CI, 0.27 – 0.86), 15 mg (+1.05 g/dl; 0.76 – 1.33), and 30 mg (+0.99 g/dl; 0.70 – 1.28) (P <.001). Ziltivekimab was also linked with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation (P <.05).Participants had infrequent cases of thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia in every group.

Ziltivekimab was linked with a significant increase in hemoglobin levels from baseline to week 12, compared to placebo. The mean changes in hemoglobin were -0.22 g/dl for placebo, as well as 0.34 g/dl for ziltivekimab 7.5 mg (0.57; 95% CI, 0.27 – 0.86, P <.001), 0.82 g/dl for 15 mg (1.05; 95% CI, 0.76 – 1.33, P <.001), and 0.77 g/dl for ziltivekimab 30 mg (0.99; 95% CI, 0.70 –1.28, P <.001).

The team also observed a decrease in hepcidin levels over the 12-week treatment. The greater the ziltivekimab dose, the greater the hepcidin reduction. Despite the decrease in hepcidin levels, changes were not statistically significant compared to the placebo group.

“It can be postulated that these reductions were physiologically meaningful because the reduction in hepcidin levels would explain the observed effects on iron metabolism and ultimately on [hemoglobin] levels,” the investigators wrote.

Ziltivekimab was overall well-tolerated with no major adverse events. Cases of AKI, anemia, and iron deficiency anemia were low in all groups. The team observed 1 case of sustained grade 2 neutropenia in the ziltivekimab 7.5 mg group, but there were no cases of grade 4 or 4 neutropenia. They also did not observe grade 2 – 4 sustained thrombocytopenia.

“These findings suggest that ziltivekimab has the potential to improve anemia in patients with CKD stage 3–5, via the inhibition of IL-6,” the investigators wrote. “Together with the results from the phase 1/2 trial, the results of this analysis suggest a new therapeutic approach for treating anemia in patients with CKD.”

Investigators are currently working on the ongoing phase 3 trial, ZEUS, investigating the effect of ziltivekimab 15 mg compared with placebo. The trial contains 6200 participants with stage 3 – 4 CKD, elevated high-sensitivity C-reactive proteins, and who are at high risk of cardiovascular events.

“It’s only launching around the world right now,” Paul M. Ridker, MD, of Brigham and Women’s Hospital and Harvard Medical School and co-author of the ZEUS trial, told HCPLive in 2022.2 “It’ll ultimately be in about 16 – 17 countries—we’re in the middle of country launches as we speak—investigators are just getting used to the protocol.”


  1. Pergola PE, Davidson M, Jensen C, et al. Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE). J Am Soc Nephrol. Published online December 13, 2023. doi:10.1681/ASN.0000000000000245
  2. Kunzmann, K. A Preview of the Ziltevekimab ZEUS Clinical Trial. HCPLive. April 6, 2022. Accessed December 14, 2023.