Ziltivekimab, a human monoclonal antibody directed against the interleukin (IL)-6 ligand, markedly reduces biomarkers of thrombosis and inflammation related to atherosclerosis, according to findings published in The Lancet. This data will be used as the basis for a large-scale trial concerning cardiovascular outcomes in patients with increased high-sensitivity C-reactive protein (CRP), chronic kidney disease, and established cardiovascular disease treated with ziltivekimab.

Anticytokine and anti-inflammatory therapies can reduce the rates of cardiovascular events. IL-6 may be a causal mediator of this process. IL-6 is a pivotal factor in atherothrombosis.

The efficacy and safety of IL-6 inhibition among patients with high atherosclerotic risk and without systemic inflammatory disorders are largely unknown. For that reason, investigators designed RESCUE, a randomized, double-blind phase 2 trial to assess whether ziltivekimab would effectively and safely reduce thrombotic and inflammatory biomarkers among patients with high cardiovascular risk (ClinicalTrials.gov, NCT03926117).


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The patient population selected to participate in RESCUE included adults with high cardiovascular risk, elevated high-sensitivity CRP, and chronic kidney disease. They were chosen because they had substantially unmet clinical needs and had been shown to experience cardiovascular event reduction benefits from inflammation inhibition.

Participants were randomly assigned 1:1:1:1 to the subcutaneous administration of placebo or 7.5 mg, 15 mg, or 30 mg ziltivekimab every 4 weeks for up to 24 weeks. The primary study outcome was the percentage change in high-sensitivity CRP from baseline after 12 weeks of ziltivekimab treatment vs placebo. Safety and additional biomarker data were collected over a total of 24 weeks of treatment. The researchers performed primary analyses in the intention-to-treat population, and assessed safety in all participants receiving at least 1 dose of the assigned treatment.

A total of 264 participants were included in RESCUE, and 66 were randomly assigned to each of the 4 treatment groups. After 12 weeks of treatment, median high-sensitivity CRP levels were reduced by 77% in the 7.5-mg ziltivekimab group, 88% in the 15-mg group, and 92% in the 30-mg group compared with 4% for the placebo group, making the median pairwise differences in percentage change between the ziltivekimab and placebo groups, after aligning for strata, -66.2% for the 7.5-mg group, -77.7% for the 15-mg group, and -87.8% for the 30-mg group (all P <.0001). These effects remained stable throughout the 24-week treatment period.

The researchers observed a significant reduction in lipoprotein(a) for all treatment groups (16.4% to 25.0%), and small dose-dependent increases in apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 (APOA1) meant that no substantive shifts were observed in either the ratio of total cholesterol to HDL cholesterol or in the ratio of APOB to APOA1.

The ziltivekimab group showed increased triglycerides compared with placebo, but no differences were observed respecting estimated glomerular filtration rate or the urine albumin to creatinine ratio.

Ziltivekimab was well-tolerated overall, and there were no serious injection-site reactions, no sustained grade 3 or 4 neutropenia, and no thrombocytopenia.

Study limitations include a modest sample size and duration of therapy. COVID-19 safety concerns prevented investigators from maintaining face-to-face visits for all participants through the secondary 24-week endpoint and caused them to terminate the study before formal completion.

Nevertheless, these findings provide some evidence that IL-6 inhibition with ziltivekimab reduces thrombotic and inflammatory biomarkers in patients with high cardiovascular risk and chronic kidney disease.

“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,” the study researchers stated.

Disclosure: This clinical trial was supported by Corvidia Therapeutics with input from Novo Nordisk. Please see the original reference for a full list of authors’ disclosures.

Reference

Ridker PM, Devalaraja M, Baeres FMM, et al; RESCUE Investigators. 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 14, 2021. doi:10.1016/S0140-6736(21)00520-1