Inflammatory Markers Fall, Cardiovascular Risk Unchanged: Ziltivekimab Phase 3 Trial Fails

Reducing inflammatory signals in the blood does not necessarily prevent myocardial infarction or stroke. Novo Nordisk announced topline results from the phase 3 ZEUS trial. Although the investigational monoclonal antibody ziltivekimab inhibited the interleukin-6 (IL-6) pathway and lowered high-sensitivity C-reactive protein (hsCRP), it was no better than placebo at preventing major cardiovascular events that truly matter to patients, dealing a setback to the strategy of using anti-inflammatory therapies to reduce residual cardiovascular risk.

ZEUS was a multinational, double-blind, placebo-controlled, event-driven trial that randomized 6,376 patients with established atherosclerotic cardiovascular disease, chronic kidney disease, and hsCRP of at least 2 milligrams per liter. In addition to existing standard-of-care treatment, participants received a monthly subcutaneous injection of 15 milligrams of ziltivekimab or placebo. The primary endpoint was three-point major adverse cardiovascular events, comprising cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

The results showed a hazard ratio of 0.99 for ziltivekimab versus placebo, with a 95% confidence interval of 0.88 to 1.11, meaning that the risk of primary events was nearly identical in the two groups. The drug did reduce free IL-6 and hsCRP, showing that it engaged its intended target. However, the biomarker changes did not translate into clinical benefit, again underscoring that surrogate markers cannot replace cardiovascular outcomes trials.

These patients had been considered a high-risk population most likely to benefit. The trial design paper showed that participants had a mean age of 69.5 years, 65.7% had diabetes, 41.3% had heart failure, and the mean estimated glomerular filtration rate was only 44.5 mL/min/1.73 m². Chronic kidney disease is often accompanied by systemic inflammation and high cardiovascular risk, so ZEUS tested not only the anti-inflammatory hypothesis but also prespecified secondary endpoints including expanded cardiovascular events, heart failure events, all-cause mortality, and a kidney composite outcome. These results have not yet been fully reported.

Regarding safety, Novo Nordisk said the overall rates of adverse events and serious adverse events were similar between the two groups, with no difference in all-cause mortality. However, serious infections occurred at a higher rate in the ziltivekimab group, consistent with the potential risks of suppressing IL-6 immune signaling. The company has not yet provided the actual number of events, types of infections, or data for individual secondary endpoints, so the risks and any potential localized benefits cannot yet be fully assessed.

The failure of ZEUS has not halted the overall development program. Novo Nordisk plans to continue the HERMES and ARTEMIS cardiovascular outcomes trials, which focus on patients with heart failure and patients following acute myocardial infarction, respectively, with readouts expected in the first half of 2027. Whether different disease stages and inflammatory environments produce different responses will be key to determining whether IL-6 inhibition still has a clinical role.

The company expects to present the full ZEUS results at a scientific meeting in 2026. The trial’s failure does not affect its adjusted operating profit outlook for 2026, but it will recognize a non-cash impairment in the third quarter. The clearest message at this stage is that ziltivekimab can alter inflammatory biology but did not change the primary cardiovascular outcome in this group of patients with concomitant cardiovascular and kidney disease. Whether an identifiable subgroup may benefit remains subject to full analysis and cannot be inferred from the topline data.