IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial

Roles of Macrophages in Atherogenesis

“…A phase II clinical trial demonstrating ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, markedly reduced multiple biomarkers of systemic inflammation and thrombosis including hsCRP, fibrinogen, SAA, sPLA2, and Lp(a). Thus, the direct inhibition of IL-6 might have the potential to maximize anti-inflammatory atherosclerotic benefits (Ridker et al, 2021). Since IL-6 is a pleiotropic cytokine, depending on the target cell type, it can exhibit both pro-and anti-inflammatory properties.…”

Emerging Anti-Atherosclerotic Therapies

“…The aforementioned clinical trial (CANTOS) have indicated that the IL-6 signaling pathway decreased cardiovascular event rates independent of LDL lowering [102]. In this trial, the observed clinical benefit was directly associated with the extent of downstream IL-6 reduction, which implies that IL-6 may be the primary target for atheroprotection [104]. The role of IL-6 signaling in the development of various forms of atherosclerosis (MI, PAD, and aortic aneurysm formation) was confirmed by GWAS and PHEWAS data.…”

“…Ziltivekimab was demonstrated to be well tolerated and there were no serious injection-site reactions. Apart from hsCRP levels, dose-dependent reductions were also found for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a) (from 16.4% to 25.0% in all treatment groups) [104]. The use of ziltivekimab slightly increased apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 (APOA1).…”

“…The role of IL-6 signaling in the development of various forms of atherosclerosis (MI, PAD, and aortic aneurysm formation) was confirmed by GWAS and PHEWAS data. The safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder remain unknown, and therefore a randomized, doubleblind, placebo-controlled phase 2 RESCUE trial focused on these issues [104]. This trial assessed the effects of ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand with extended half-life technology, on multiple biomarkers of inflammation and thrombosis in patients at high cardiovascular risk with moderate to severe chronic kidney disease (CKD) and elevated hsCRP.…”

“…Ziltivekimab has earlier completed two earlystage trials in chronic kidney disease patients in which its administration reduced the levels of C-reactive protein (CRP). Participants in the RESCUE trial were randomized (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab in a dose of 7.5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks [104]. Ziltivekimab was found to significantly decrease various biomarkers of systemic inflammation and thrombosis involved in the stimulation of the atherothrombotic process development [101].…”