Novo Nordisk's Ziltivekimab Fails to Cut Cardiovascular Events in Phase 3 ZEUS Trial
The IL-6 inhibitor lowered inflammation markers but did not reduce heart attacks, strokes or cardiovascular deaths versus placebo in more than 6,300 patients, the company said.
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These results come from a Phase 3 trial, the large trial usually needed before approval.
Key points
- Novo Nordisk said on July 31 that ziltivekimab did not reduce major adverse cardiovascular events versus placebo in the Phase 3 ZEUS trial (hazard ratio 0.99; 95% CI 0.88 to 1.11).
- Overall adverse event rates were similar to placebo, but more patients on ziltivekimab had serious infections; there was no difference in all-cause mortality.
- Two other outcomes trials, HERMES in heart failure and ARTEMIS after heart attack, will continue, and Novo expects a non-cash impairment charge in the third quarter.
Novo Nordisk's experimental anti-inflammatory drug ziltivekimab did not reduce the risk of major adverse cardiovascular events (MACE) compared with placebo in the Phase 3 ZEUS trial, the company announced on July 31. The trial enrolled people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and inflammation.
Ziltivekimab is a fully human monoclonal antibody that targets the IL-6 ligand, a pro-inflammatory cytokine. In ZEUS, it produced the expected reductions in free IL-6 and high-sensitivity C-reactive protein (hsCRP), Novo said, but that did not translate into fewer cardiovascular events: the hazard ratio for the primary endpoint was 0.99 (95% confidence interval 0.88 to 1.11). The results are company-reported headline data.
The trial
ZEUS was a double-blind, placebo-controlled, event-driven outcomes trial that enrolled more than 6,300 people with ASCVD, CKD and hsCRP of at least 2 mg/L. It tested once-monthly subcutaneous ziltivekimab 15 mg against placebo, on top of standard care. MACE was defined as cardiovascular death, non-fatal heart attack or non-fatal stroke.
Overall rates of adverse events and serious adverse events were similar between the two groups. A higher proportion of patients on ziltivekimab had serious infections, which Novo described as consistent with IL-6 inhibition, and no difference in all-cause mortality was observed, Healio reported. In the earlier RESCUE trial, ziltivekimab significantly reduced hsCRP and other inflammatory markers, according to Healio.
"Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population," said Martin Holst Lange, Novo Nordisk's chief scientific officer and head of research and development. "While ziltivekimab did not achieve the MACE benefit we had hoped for, this does not change our strategic commitment to cardiovascular disease."
What comes next
Two other cardiovascular outcomes trials of ziltivekimab will continue: HERMES, in people with heart failure, and ARTEMIS, in people following an acute heart attack. Both are expected to read out in the first half of 2027, the company said. Full ZEUS results will be presented at a scientific meeting later in 2026.
Novo said the outcome will not affect its previously communicated adjusted operating profit outlook for 2026 but will result in a non-cash impairment charge in the third quarter of 2026. The company is also developing ziltivekimab for acute myocardial infarction and heart failure with preserved ejection fraction.
Sources
- Novo Nordisk provides update on the ZEUS phase 3 trial in people with ASCVD, CKD and inflammation, Novo Nordisk, July 31, 2026
- Ziltivekimab reduces inflammation, not MACE risk in patients with atherosclerosis, CKD, Healio, July 31, 2026