Novo Nordisk's ziltivekimab failed to reduce cardiovascular events in the phase 3 ZEUS trial despite confirmed IL-6 target engagement.
Novo Nordisk reported headline results from the ZEUS cardiovascular outcomes
"Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population," said
ZEUS was a double-blind, placebo-controlled trial enrolling more than 6300 people with ASCVD, CKD, and inflammation, defined as high-sensitivity C-reactive protein (hsCRP) levels of 2 mg/L or higher.1,2 The trial evaluated once-monthly subcutaneous ziltivekimab, 15 mg, versus placebo on top of standard of care, with MACE, defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke, as the primary endpoint.1,2
Ziltivekimab produced expected reductions in free interleukin-6 (IL-6) and hsCRP, confirming target engagement, but this biological effect did not translate into a reduction in MACE risk relative to placebo.1 Full results from the trial are expected to be presented at a scientific meeting later in 2026.
Overall rates of adverse events and serious adverse events were similar between the ziltivekimab and placebo groups, according to the company. A higher proportion of people treated with ziltivekimab experienced serious infections compared with placebo, a finding the company said is consistent with IL-6 pathway inhibition. No difference in all-cause mortality was observed between groups.1
Two additional ongoing cardiovascular outcomes trials of ziltivekimab are continuing: HERMES, in people with heart failure, and ARTEMIS, in people following an acute heart attack; both are anticipated to read out in the first half of 2027.1 Novo Nordisk said the ZEUS outcome will not affect its previously communicated adjusted operating profit outlook for 2026 but will result in a non-cash impairment charge in the 3rd quarter of 2026.1
ZEUS is among a small number of large, dedicated cardiovascular outcomes trials to test whether direct IL-6 pathway inhibition can translate anti-inflammatory biomarker changes into a reduction in cardiovascular events, rather than relying on hsCRP or IL-6 reduction as surrogate measures of benefit. The dissociation between confirmed target engagement. The absence of a MACE benefit in ZEUS adds to an evolving body of outcomes data that developers of anti-inflammatory
The result also highlights a recurring challenge in cardiovascular drug development, which is that demonstrating a drug’s ability to engage its intended biological target, as ziltivekimab did through reductions in free IL-6 and hsCRP, does not by itself establish that the drug will change hard clinical outcomes, such as death, heart attack, or stroke. Ziltivekimab is a fully human monoclonal antibody that targets the IL-6 ligand, a pro-inflammatory cytokine, and remains in development for other indications, including acute myocardial infarction and heart failure with preserved ejection fraction, through the ongoing HERMES and ARTEMIS trials.
