Heart researchers unpack neutral findings from ZEUS, an anti-inflammatory clinical trial

The ZEUS trial found that ziltivekimab, a monoclonal antibody targeting the IL-6 ligand, substantially reduced inflammatory biomarkers but did not reduce cardiovascular events in patients with atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation, MedPage Today reported. Over a median follow-up of 33 months, a primary endpoint event occurred in 561 patients (17.6%) in the ziltivekimab group and 565 patients (17.7%) in the placebo group, for a hazard ratio of 0.99 (95% CI 0.88-1.11, P=0.84). The primary composite endpoint included death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

The trial enrolled 6,376 patients globally in a double-blind, randomized, placebo-controlled design, with 3,184 assigned to ziltivekimab and 3,192 to placebo. Participants had established ASCVD, CKD, and cardiovascular inflammation defined as an hs-CRP level above 2 mg per liter. The dose was 15 mg given subcutaneously once a month.

Despite the neutral primary result, the drug produced substantial biomarker reductions: a 76% placebo-adjusted change from baseline in free interleukin-6 and a 64% placebo-adjusted change in high-sensitivity C-reactive protein, reported Paul M. Ridker of Harvard Medical School and Mass General Brigham Hospital at the American Heart Association annual meeting in Chicago. The results were published simultaneously in the New England Journal of Medicine. Topline results were released in July 2026.

Ridker said high levels of inflammation remained linked to events, with increasing tertiles of CRP and IL-6 predicting higher risk of the primary endpoint and of all-cause death. He contrasted ZEUS with prior trials including CANTOS with canakinumab, plus LoDoCo2 and COLCOT using colchicine, which showed anti-inflammatory therapy can reduce event rates in stable coronary disease. ZEUS patients had significant CKD, more diabetes and heart failure, and an all-cause mortality rate twice as high as CANTOS, suggesting late-stage, non-modifiable disease. "The horse may already have been out of the barn," Ridker said.

AHA discussant Priscilla Hsue of the University of California San Francisco asked whether the drug was given too late, targeted the wrong molecule, or pursued the wrong downstream strategy. She stressed that inflammation still matters and that the need for science, mechanistic studies, and trials is more important in 2026 than ever.

Safety findings showed serious adverse events were equal between groups at 54.6% for ziltivekimab and 54.8% for placebo. Serious infections occurred in 20.4% versus 17.9%, a significant difference, and venous thromboembolism was significantly higher with treatment at 1.6% versus 0.6%. A similar lack of treatment effect was seen on secondary endpoints, including a 4-point MACE endpoint, composite kidney and heart failure endpoints, and all-cause mortality.

Other ziltivekimab trials are continuing or have been halted. HERMES, in heart failure with midrange or preserved ejection fraction, has been halted due to futility, while ARTEMIS in acute coronary ischemia has been allowed to continue. BioSpace reported that Novo ended several studies after the ZEUS failure, including Phase 3 HERMES and ATHENA, but ARTEMIS continues with patients who have had a heart attack and who have less chronic kidney disease and heart failure than the ZEUS population. Investigators suggested ziltivekimab may find a niche in less sick patients with modifiable earlier-stage disease.