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

J Am Soc Nephrol. 2021 Jan;32(1):211-222. doi: 10.1681/ASN.2020050595. Epub 2020 Dec 3.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anemia / complications
  • Anemia / drug therapy*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers / metabolism
  • Cardiovascular Diseases / metabolism
  • Double-Blind Method
  • Female
  • Hematinics / therapeutic use
  • Hepcidins / metabolism
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Interleukin-6 / antagonists & inhibitors
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / therapy*
  • Ligands
  • Male
  • Middle Aged
  • Renal Dialysis / adverse effects*
  • Serum Albumin / metabolism
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Hematinics
  • Hepcidins
  • Interleukin-6
  • Ligands
  • Serum Albumin
  • ziltivekimab

Associated data

  • ClinicalTrials.gov/NCT02868229