Novo Nordisk’s Phase III ZEUS trial found ziltivekimab failed to reduce 3-point MACE despite suppressing IL-6 inflammation in ASCVD and CKD patients.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Novo Nordisk reported that its investigational anti-inflammatory monoclonal antibody ziltivekimab failed to meet the primary endpoint in the pivotal Phase III ZEUS cardiovascular outcomes trial (NCT05021835). The therapy did not reduce the risk of 3-point major adverse cardiovascular events (3-point MACE), defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, compared with placebo in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and persistent systemic inflammation. The primary analysis showed a hazard ratio of 0.99 (95% CI: 0.88–1.11), indicating no significant difference between treatment groups.
IL-6 Ligand Inhibition Reduced Inflammation but Not Cardiovascular Risk
Ziltivekimab is an investigational, fully human monoclonal antibody that directly targets the IL-6 ligand, preventing downstream IL-6 inflammatory signaling. Unlike therapies that block the IL-6 receptor, ziltivekimab neutralizes the circulating cytokine itself. The drug is being developed for cardiovascular disease, acute myocardial infarction (AMI), and heart failure with preserved ejection fraction (HFpEF).
Chronic inflammation remains an important contributor to residual cardiovascular risk despite advances in lipid-lowering therapies. Elevated high-sensitivity C-reactive protein (hsCRP) is a well-established marker of this inflammatory burden and has emerged as a therapeutic target in cardiovascular medicine.
In ZEUS, ziltivekimab achieved the expected biological effects, producing marked reductions in free IL-6 and hsCRP, confirming effective inhibition of the IL-6 pathway. However, these reductions did not translate into fewer cardiovascular events, suggesting that suppressing IL-6-driven inflammation alone may be insufficient to improve outcomes in this high-risk patient population.
ZEUS Evaluated More Than 6,300 High-Risk Patients
ZEUS was a randomized, double-blind, placebo-controlled, event-driven Phase III cardiovascular outcomes trial that enrolled more than 6,300 adults with established ASCVD, CKD, and persistent inflammation, defined by hsCRP levels of at least 2 mg/L.
Participants received once-monthly subcutaneous ziltivekimab 15 mg or placebo in addition to standard of care. The study evaluated whether long-term IL-6 inhibition could reduce the incidence of 3-point MACE in patients with significant residual inflammatory risk.
Overall adverse event and serious adverse event rates were comparable between treatment groups. Consistent with IL-6 pathway inhibition, serious infections occurred more frequently among patients receiving ziltivekimab than placebo. No difference in all-cause mortality was observed.
ZEUS Adds to the Understanding of Cardiovascular Inflammation
Martin Holst Lange, executive vice president, chief scientific officer and head of Research and Development at Novo Nordisk, said ZEUS tested whether suppressing IL-6-mediated inflammation could translate into meaningful reductions in cardiovascular events.
He noted that while ziltivekimab demonstrated the expected biological activity, those effects did not produce the hoped-for clinical benefit. Lange added that the findings strengthen the scientific understanding of inflammatory cardiovascular disease and will help guide the company’s ongoing cardiovascular research despite the negative outcome.
Development Continues in Heart Failure and Acute Myocardial Infarction
Novo Nordisk will continue the two ongoing Phase III cardiovascular outcomes studies evaluating ziltivekimab. The HERMES trial (NCT05636176) is investigating the therapy in patients with heart failure with preserved ejection fraction (HFpEF), while the ARTEMIS trial (NCT06118281) is evaluating its use following acute myocardial infarction (AMI). Both studies are expected to report results during the first half of 2027.
The company said the ZEUS results will not affect its previously communicated adjusted operating profit outlook for 2026. However, the trial outcome will lead to a non-cash impairment charge in the third quarter of 2026 related to the ziltivekimab program following the ZEUS results. Full findings from the ZEUS trial will be presented at a scientific meeting later in 2026.
Reference
Novo Nordisk provides update on the ZEUS phase 3 trial in people with ASCVD, CKD and inflammation
About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.