Inflammation Markers Fell, but Cardiovascular Events Did Not: Phase 3 Ziltivekimab Trial Misses Its Endpoint

The link between cardiovascular disease and chronic inflammation has long been supported by extensive research, but whether lowering inflammation markers can actually prevent myocardial infarction or stroke remains a more stringent clinical test. Novo Nordisk announced that the experimental antibody ziltivekimab failed to clear this threshold in the large Phase 3 ZEUS trial.

ZEUS enrolled more than 6,300 adults with established atherosclerotic cardiovascular disease, chronic kidney disease, and systemic inflammation. Participants had high-sensitivity C-reactive protein (hsCRP) levels of at least 2 milligrams per liter and, in addition to existing standard treatment, were randomly assigned to receive a once-monthly 15-milligram subcutaneous injection of ziltivekimab or placebo; the trial used a double-blind, placebo-controlled design.

The study’s primary endpoint was the time to the first occurrence of a three-point major adverse cardiovascular event, comprising cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The results showed a hazard ratio of 0.99 for ziltivekimab versus placebo, with a 95% confidence interval of 0.88 to 1.11, meaning the risks were nearly identical between the two groups and the treatment did not demonstrate a statistically significant protective effect.

What makes the result particularly noteworthy is that the drug did produce a biological effect. Ziltivekimab binds to the pro-inflammatory cytokine IL-6; the company said treatment did lower free IL-6 and hsCRP, indicating that the drug engaged its intended target and inhibited the associated pathway. However, the improvement in biomarkers did not translate into fewer major cardiovascular events, also reminding researchers that although hsCRP can reflect the degree of inflammation, it may not be sufficient on its own as a surrogate marker of efficacy.

In terms of safety, the overall rates of adverse events and serious adverse events were similar between the two groups, and there was no difference in all-cause mortality. However, the proportion of serious infections was higher in the ziltivekimab group, consistent with the mechanism by which IL-6 inhibition may weaken some immune defenses. The company has so far released only topline results and has not disclosed the specific number of infection events, individual secondary endpoints, or patient subgroup analyses. Full data are expected to be presented at a scientific meeting in 2026.

### Background

The neutral result from ZEUS does not directly disprove the role of inflammation in cardiovascular disease, nor does it establish that all anti-inflammatory strategies will fail. What it answers more clearly is that, in this group of patients with atherosclerosis, chronic kidney disease, and elevated hsCRP, monthly IL-6 inhibition changed laboratory markers but was still insufficient to reduce three-point major adverse cardiovascular events. Different disease stages, patient selection, and inflammatory pathways may produce different outcomes and still require separate validation.

Novo Nordisk plans to continue two other cardiovascular outcomes trials of ziltivekimab: HERMES focuses on heart failure, while ARTEMIS enrolls patients following acute myocardial infarction. Results from both are expected in the first half of 2027. The failure of ZEUS will cause the company to recognize a non-cash impairment in the third quarter of 2026 but will not affect its previously announced full-year adjusted operating profit outlook. For this drug and similar development strategies, whether the next round of trials can identify benefits in different clinical settings will be more critical than simply demonstrating another reduction in inflammation markers.