Novo Nordisk: ZEUS phase 3 finds no MACE reduction with ziltivekimab

Primary results

ZEUS was a double‑blind, placebo‑controlled, event‑driven phase 3 trial that enrolled over 6,300 people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and elevated inflammation (hsCRP ≥2 mg/L). The trial compared once‑monthly subcutaneous ziltivekimab 15 mg versus placebo on top of standard of care. The primary endpoint was time to first occurrence of 3‑point MACE (CV death, non‑fatal myocardial infarction or non‑fatal stroke); the hazard ratio versus placebo was 0.99 (95% CI 0.88 to 1.11), showing no MACE risk reduction.

Biological activity

Ziltivekimab demonstrated target engagement and inhibition of the IL‑6 pathway, with expected reductions in free IL‑6 and high‑sensitivity C‑reactive protein (hsCRP). Despite these biomarker effects, the reductions did not translate into fewer major adverse cardiovascular events in the studied population.

Safety profile

Overall rates of adverse events and serious adverse events were similar between ziltivekimab and placebo. Consistent with IL‑6 pathway inhibition, a higher proportion of people treated with ziltivekimab experienced serious infections. No difference in all‑cause mortality was observed.

Next steps and financial note

The two ongoing cardiovascular outcomes trials of ziltivekimab—HERMES (heart failure) and ARTEMIS (post‑acute myocardial infarction)—will continue and are anticipated to read out in the first half of 2027. Novo Nordisk stated the ZEUS outcome will not change its previously communicated adjusted operating profit outlook for 2026 but will result in a non‑cash impairment charge in Q3 2026. Full ZEUS results will be presented at a scientific meeting in 2026.