Ziltivekimab did not reduce the risk of major adverse
The interleukin-6 (IL-6) inhibitor demonstrated target engagement, reflected by expected reductions in free IL-6 and high-sensitivity C-reactive protein (hsCRP), yet this biological effect did not translate into a reduction in MACE, defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke. Full results are scheduled for presentation at an upcoming scientific meeting in 2026.
"ZEUS was designed to test whether inhibition of the IL-6 pathway could translate reductions in cardiovascular inflammation into fewer major cardiovascular events," said Martin Holst Lange, executive vice president, chief scientific officer, and head of Research and Development at Novo Nordisk. "Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population."
Ziltivekimab is a fully human monoclonal antibody targeting the IL-6 ligand, a pro-inflammatory cytokine, with the goal of reducing cardiovascular inflammation.
No. The HERMES trial in heart failure and the ARTEMIS trial following acute myocardial infarction remain ongoing and are expected to read out in the first half of 2027.
ZEUS was a double-blind, placebo-controlled, event-driven cardiovascular outcomes trial enrolling more than 6300 people with ASCVD, CKD, and CV inflammation, defined by hsCRP levels of 2 mg/L or higher. Participants received once-monthly subcutaneous ziltivekimab 15 mg or placebo on top of standard of care. The phase 3 trial followed the phase 2 RESCUE study, in which ziltivekimab produced dose-dependent reductions in hsCRP of up to 92% versus 4% with placebo in patients with moderate to severe CKD and elevated hsCRP, providing the biomarker rationale for testing cardiovascular outcomes in ZEUS.2
The primary endpoint was time to first occurrence of 3-point MACE, analyzed by Cox regression in the full analysis set. Ziltivekimab showed no reduction in MACE risk compared with placebo (HR, 0.99; 95% CI, 0.88-1.11).1 The result held despite ziltivekimab producing the anticipated pharmacodynamic effect on the IL-6 pathway, according to Novo Nordisk, which noted expected reductions in free IL-6 and hsCRP consistent with target engagement. The lack of separation on the primary endpoint indicates inflammation reduction via IL-6 inhibition did not translate into a measurable cardiovascular benefit in this population.
Overall rates of adverse events and serious adverse events were similar between the ziltivekimab and placebo arms, Novo Nordisk reported. Consistent with IL-6 pathway inhibition, a higher proportion of participants treated with ziltivekimab experienced serious infections compared with placebo. No difference in all-cause mortality was observed between arms.
Novo Nordisk stated the ZEUS outcome will not affect the company's previously communicated adjusted operating profit outlook for 2026, though it will result in a non-cash impairment charge in the third quarter of 2026. The company reiterated its safety characterization is based on topline data pending full presentation, and additional granularity on adverse event rates and discontinuations is expected when full trial results are shared later this year.
Two additional cardiovascular outcomes trials investigating ziltivekimab remain ongoing: HERMES, in people with heart failure, and ARTEMIS, in people following an acute myocardial infarction. Novo Nordisk said both trials are anticipated to read out in the first half of 2027, and the ZEUS findings will inform the company's broader cardiovascular research program despite the missed primary endpoint.
