Ziltivekimab, a novel human IgG1, k antibody directed against IL-6 ligand, may improve inflammation and hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in patients receiving maintenance hemodialysis (HD), according to new study findings.
In a double-blind phase 1/2 trial, investigators identified patients on HD with rs855791, the most common single nucleotide polymorphism of the TMPRSS6 gene, and elevated IL-6 levels (more than 4 pg/mL). Baseline hemoglobin levels ranged from 8.5 to 11.0 g/dL. The team randomly assigned 61 patients to receive intravenous ziltivekimab (doses of 2, 6, or 20 mg) or placebo every 2 weeks for 12 weeks during HD sessions. ESA dose adjustments were allowed after 4 weeks.
Median ESA use per patient significantly decreased by 15,000, 15,000, and 33,000 IU per week in the 2-, 6-, and 20-mg ziltivekimab groups, respectively, compared with no change in the placebo group, Pablo E. Pergola, MD, of Renal Associates, PA, in San Antonio, Texas, and colleagues reported in the Journal of the American Society of Nephrology. The erythropoietin resistance index (ERI) likewise significantly decreased dose dependently (-5.6, -5.8, -10.5 U/kg per g/dL hemoglobin) over the treatment period.
Inflammation significantly improved with ziltivekimabfrom baseline to the end of treatment, with declines observed in high-sensitivity C-reactive protein (median percentage change -74.8%, -91.7%, and 98.1% for the 2-, 6- and 20-mg doses, respectively, compared with -4.5% for placebo); , serum amyloid A (median percentage change -63.3%, 70.4%, and -83.1% for the 3 ziltivekimab doses, respectively, compared with no change with placebo); and fibrinogen (-19.8%,-41.3%, and -41.1% for the 3 ziltivekimab doses, respectively, compared with a mean increase of 4.6 mg/dL in the placebo group),
In addition, ziltivekimab treatment significantly increased serum albumin (0.1, 0.2, 0.3 g/dL), serum iron (24.3, 26.9, 31.0 µg/dL), total iron binding capacity (TIBC; 10.6, 17.3, 33.2 µg/dL), and transferrin saturation (TSAT; 6.4%, 9.2%, 9.0%) at each dose, respectively.
Dr Pergola’s team observed, “Current anemia treatments do not reduce inflammation; “advancement of an anti-inflammatory therapy that improves iron utilization and reduces the need for escalating doses of ESAs would be a paradigm shift in the care of patients on hemodialysis.” The study did not evaluate other factors associated with ESA hyporesponsiveness, such as hyperparathyroidism or vitamin-D deficiency.
In an accompanying editorial, Daniel W. Coyne, MD, of Washington University, and Robert Fleming, MD, of St. Louis University, both in St. Louis, Missouri, agreed:
“Ziltivekimab or other IL-6 signaling disruption may be a way to move beyond our stagnant anemia management of ESA therapy and parenteral iron, and finally target inflammation directly.”
With respect to safety, 20 patients experienced a serious adverse event, including 3 receiving placebo, and 4, 7, and 6 patients receiving 2-, 6-, and 20-mg ziltivekimab, respectively. Four patients taking ziltivekimab died during the study, including 2 from sepsis and 2 from cardiovascular causes. No dose-limiting toxicity was reported, and no patient experienced neutropenia. A third of patients taking 20-mg ziltivekimab discontinued therapy after 12 weeks, and 58% reduced their dose by about half. Additional safety data from future, well-powered trials are needed.
Disclosure: This clinical trial was supported by Corvidia Therapeutics. Please see the original reference for a full list of authors’ disclosures.
Pergola PE, Devalaraja M, Fishbane S, et al. Ziltivekimab for treatment of anemia of inflammation in patients on hemodialysis: Results from a phase ½ multicenter, randomized, double-blind, placebo-controlled trial. J Am Soc Nephrol. 2021;32(1):211-222. doi:10.1681/ASN.2020050595
Coyne DW, Fleming R. Will targeting interleukin-6 in the anemia of CKD change our treatment paradigm? J Am Soc Nephrol. doi:10.1681/ASN.2020101476