In ZEUS, ziltivekimab reduced IL-6 and hsCRP without reducing the risk of myocardial infarction, stroke, or cardiovascular death
In ZEUS, ziltivekimab reduced IL-6 and hsCRP without reducing the risk of myocardial infarction, stroke, or cardiovascular death
On 31 July, Novo Nordisk reported the results of the phase III ZEUS trial. In 6 385 patients, ziltivekimab reduced free IL-6 and hsCRP, a measure of C-reactive protein that rises during inflammation. The risk of a first major cardiovascular event was nearly identical in the treatment and placebo groups, with a hazard ratio of 0.99.
ZEUS tested whether suppressing IL-6 signaling changes the clinical course of vascular disease. IL-6 is an immune system protein involved in the inflammatory response. hsCRP measures inflammation-related increases in C-reactive protein in the blood. Ziltivekimab binds IL-6, and the trial tested whether this intervention would reduce the number of serious cardiovascular events.
The trial enrolled people with atherosclerotic vascular disease, chronic kidney disease, and hsCRP of at least 2 mg/L. According to the ZEUS registry, 6 385 participants were randomly assigned to receive monthly subcutaneous injections of ziltivekimab or placebo for up to four years, in addition to usual treatment.
The primary outcome was the time to the first of three events: death from a cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. In the Novo Nordisk release, the hazard ratio for this composite outcome was 0.99, with a 95 percent confidence interval from 0.88 to 1.11. A value of 1 on this scale means that the event rate was the same in both groups. The ZEUS result was almost exactly at that point.
The antibody reduced free IL-6 and hsCRP in the blood, but this did not reduce the number of myocardial infarctions, strokes, or cardiovascular deaths among people with established vascular disease. Interest in this target also came from genetic data. In an analysis of IL6R variants, some variants were associated with lower cardiovascular mortality. That genetic association did not test monthly IL-6 blockade in these patients. ZEUS tested that specific intervention.
The company also reported that serious infections were more common among participants who received ziltivekimab. The overall incidence of adverse events was comparable between the groups, and no difference in all-cause mortality was found.
In aging research, a reduction in a blood marker of inflammation cannot by itself be considered a clinical benefit. In ZEUS, the markers changed, but the prespecified patient outcome, the first major cardiovascular event, did not.