Novo Nordisk has said its Phase 3 ZEUS cardiovascular outcomes trial failed to show that ziltivekimab reduced the risk of major adverse cardiovascular events (MACE) compared with placebo.

 

This is despite demonstrating the expected biological effects on inflammation.

 

The company reported that while ziltivekimab achieved target engagement and successfully inhibited the IL-6 pathway—as shown by expected reductions in free IL-6 and high-sensitivity C-reactive protein (hsCRP)—the treatment did not lower the risk of MACE in people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and inflammation. 

 

The study reported a hazard ratio of 0.99 versus placebo.

 

ZEUS was a randomized, double-blind, placebo-controlled Phase 3 trial involving more than 6,300 participants with ASCVD, CKD and inflammation, defined by hsCRP levels of at least 2 mg/L. The trial evaluated once-monthly ziltivekimab 15 mg against placebo, with the primary endpoint measuring the incidence of MACE, defined as cardiovascular death, non-fatal heart attack or non-fatal stroke.

 

“ZEUS was designed to test whether inhibition of the IL-6 pathway could translate reductions in cardiovascular inflammation into fewer major cardiovascular events. Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population,” said Martin Holst Lange, executive vice president, chief scientific officer and head of Research and Development at Novo Nordisk. 

 

“While ziltivekimab did not achieve the MACE benefit we had hoped for, this does not change our strategic commitment to cardiovascular disease. The study provides important scientific evidence that will inform our ongoing cardiovascular research and the development of treatments for patients who continue to face substantial unmet need.”

 

Safety findings were broadly consistent with previous observations. Overall rates of adverse events and serious adverse events were similar between the ziltivekimab and placebo groups. However, consistent with IL-6 inhibition, serious infections occurred more frequently in patients receiving ziltivekimab. The trial found no difference in all-cause mortality between the two groups.

 

Novo Nordisk said the disappointing ZEUS outcome will not affect its previously announced adjusted operating profit outlook for 2026, although the company expects to record a non-cash impairment charge in the third quarter of 2026.