Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation.

Methods: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies.

Results: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin.

Conclusions: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy.

Clinical trial registry name and registration number: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Keywords: anemia; cardiovascular disease; chronic kidney disease; erythropoietin stimulating agents; hemodialysis; inflammation.

Graphical abstract

Figure 1.

Patient flow through the study. Safety population included all randomized patients. Pharmacodynamic population included 53 patients: placebo (n=12), 2-mg ziltivekimab (n=16), 6-mg ziltivekimab (n=13), and 20-mg ziltivekimab (n=12). ^†Reasons for screen failures were classified as follows: did not have hemoglobin concentration ≥8.5 and ≤11.0 g/dl before randomization (n=42), did not have serum IL-6 ≥4 pg/ml at screening (n=25), was not genotype positive (GG or AG) (n=24), had a positive tuberculosis test at screening (n=13), hospitalization or outpatient procedures within 2 weeks before screening (n=12), and other (n=91). ^‡One of the patients whose discontinuation was formally classified as withdrawal of consent was described by the site as discontinuing the study drug due to low platelets.

Figure 2.

Median percentage changes from baseline to end of treatment in hsCRP, SAA, and fibrinogen concentrations among patients undergoing hemodialysis receiving placebo or 2-, 6-, and 20-mg ziltivekimab (n=53). *P<0.05 versus placebo.

Figure 3.

Changes in hemoglobin concentrations and percentage changes in the ERI from baseline to week 4 and weeks 10–12 among patients undergoing hemodialysis receiving placebo or 2-, 6-, and 20-mg ziltivekimab (n=53). Panel A presents results for hemoglobin concentrations and Panel B presents results for the ESA Resistance Index. Data for ERI are shown as median (IQL) because values from one or more of the visits were non-normally distributed. SI conversion for hemoglobin, multiply by ten for grams per liter. IQL, interquartile limits. *P<0.05 versus placebo; ^†P-DR<0.05 for hemoglobin, week 4; P-DR<0.01 for ERI, for both time points.

Figure 4.

Baseline and week-12 albumin concentrations among patients undergoing hemodialysis receiving placebo or 2-, 6-, and 20-mg ziltivekimab (n=53). SI conversion, multiply by ten for grams per liter. *P<0.05 for 20-mg ziltivekimab versus placebo in the change from baseline; P-DR<0.001.