Ziltivekimab, a novel interleukin-6 ligand monoclonal antibody, reduces inflammation in patients with chronic kidney disease (CKD) and atherosclerosis, according to new study findings published in The Lancet.
In the RESCUE trial, 264 patients with an estimated glomerular filtration (eGFR) rate of less than 60 mL/min/1.73 m2 (but higher than 10 mL/min/1.73 m2) and high-sensitivity C-reactive protein (hs-CRP) of at least 2 mg/L were randomly assigned to subcutaneous placebo or ziltivekimab 7.5 mg, 15 mg, or 30 mg every 4 weeks. Patients were at high atherosclerotic risk and free of systemic inflammatory disorders.
At 12 weeks, median hs-CRP levels had declined 77% in the 7.5 mg group, 88% in the 15 mg group, and 92% in the 30 mg group, compared with 4% in the placebo group – all significant differences favoring ziltivekimab, Paul M Ridker, MD, MPH, of the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital in Boston, Massachusetts, and collaborators reported. Nearly all patients in the 30 mg group had hs-CRP reductions of at least 50% or on-treatment hs-CRP levels less than 2 mg/L at 12 weeks.
Ziltivekimab also dose-dependently reduced fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a).
With respect to safety, ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio as other IL-6 ligand inhibitors do, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia,” the investigators reported.
The team is making plans to further investigate ziltivekimab.
“Beyond aggressive lipid lowering, future treatment of atherosclerosis will probably include targeted anti-inflammatory therapy that inhibits the IL-1 to IL-6 pathway of innate immunity,” Dr Ridker’s team wrote. “On the basis of these phase 2 efficacy and safety data, a large-scale cardiovascular outcomes trial of ziltivekimab will be conducted among patients with chronic kidney disease, increased CRP, and established cardiovascular disease.”
In an accompanying editorial, Mette Christoffersen, MSc, and Anne Tybjaerg-Hansen, MD, DMSc, of Copenhagen University Hospital in Denmark, pointed out that a 25% lowering of lipoprotein(a) as observed in the RESCUE trial might contribute to a reduction in atherothrombotic events in patients with CKD even without improving eGFR or urine albumin-to-creatinine ratio.
Disclosure: This research was supported by Novo Nordisk. Please see the original references for a full list of authors’ and editorialists’ disclosures.
Ridker PM, Devalaraja M, Baeres FM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. Published online May 17, 2021. doi:10.1016/S0140-6736(21)00520-1
Christoffersen M, Tybjaerg-Hansen A. Targeting IL-6 in patients at high cardiovascular risk. Lancet. Published online May 17, 2021. doi:10.1016/S0140-6736(21)00985-5