Novo Nordisk's ziltivekimab falls short to reduce cardiovascular events in phase 3 trial

Novo Nordisk's ziltivekimab, an antibody designed to fight inflammation-driven heart disease, failed to reduce the risk of major cardiovascular events compared with placebo in the phase 3 ZEUS trial, according to a company news release.

The ZEUS trial enrolled more than 6,300 people who had atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and signs of inflammation. Researchers measured inflammation using a blood marker called high-sensitivity C-reactive protein (hsCRP), and participants needed a level of at least 2 milligrams per liter to qualify. Participants received once-monthly injections of either ziltivekimab or a placebo, on top of their usual care.

Ziltivekimab is an antibody that targets interleukin-6 (IL-6), a protein involved in inflammation. The trial's main goal was to see whether the drug could reduce major adverse cardiovascular events, or MACE. This measure combines cardiovascular death, non-fatal heart attack and non-fatal stroke.

Unlike statins and blood pressure medications, which target cholesterol and blood pressure, ziltivekimab was designed to address inflammation as a separate driver of heart attacks and strokes, a pathway with few approved treatments.

According to clinical trial data, ziltivekimab lowered levels of free IL-6 and hsCRP, as expected, and showed the drug was working as designed to block the IL-6 pathway. However, that biological effect did not translate into fewer cardiovascular events.

The risk of MACE was statistically no different between the ziltivekimab group and the placebo group, resulting in the trial missing its main goal. It was also found that rates of adverse events and serious adverse events (AEs and SAEs) were similar between the two groups. However, more people who received ziltivekimab developed serious infections than those who received a placebo.

In addition, there was no difference in deaths from any cause between the groups. The higher rate of serious infections is also consistent with other therapies that target IL-6, since blocking that pathway can also weaken the body's normal response to infection.

“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,” Martin Holst Lange, executive vice president, chief scientific officer and head of research and development at Novo Nordisk, said in the release. “While ziltivekimab did not achieve the MACE benefit we had hoped for, this does not change our strategic commitment to cardiovascular disease.”

The result is a setback for a drug that had potential. For example, analysts had projected ziltivekimab as a potential multibillion-dollar addition to Novo Nordisk's portfolio, beyond its diabetes and obesity franchises. Guggenheim Securities analysts had estimated the drug's peak sales potential at about $3 billion. They called ZEUS a chance to unlock a large opportunity in treating CKD, according to Fierce Biotech.

BMO Capital Markets analysts had put the odds of a clinically meaningful benefit at 55% heading into the results. After the miss, the analysts said they now consider it unlikely that either of Novo Nordisk's two remaining ziltivekimab trials will succeed.

Novo Nordisk said the ZEUS result will not affect its 2026 adjusted operating profit outlook. It will, however, lead to a noncash impairment charge in the third quarter of 2026. The company is still awaiting results from two other phase 3 trials of ziltivekimab. One, called HERMES, is testing the drug in people with heart failure. The other, ARTEMIS, is testing it in folks recovering from a heart attack. Both trials are expected to read out in the first half of 2027.