Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Pergola Pablo E. , Devalaraja Matt , Fishbane Steven , Chonchol Michel , Mathur Vandana S. , Smith Mark T. , Lo Larry , Herzog Kurt , Kakkar Rahul , Davidson Michael H. 
Published: December 2020

Significance Statement
Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation mediated by IL-6–induced expression of hepcidin, an iron regulatory hormone. Reducing ESA usage to decrease ESA-related cardiovascular risk, especially with high ESA doses, is a clinical goal of nephrologists. In this randomized, phase 1/2 trial in patients with inflammation on hemodialysis, the authors show that ziltivekimab, a novel anti–IL-6 ligand antibody, reduced markers of inflammation, decreased ESA usage, and increased serum albumin, which might lead to a reduction in overall cardiovascular risk. Because current anemia treatments do not reduce inflammation, the availability of an anti-inflammatory therapy that also improves iron utilization and reduces the need for escalating doses of ESAs could represent an important advancement in the care of patients on hemodialysis.

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