ZEUS trial: IL-6 suppressed, cardiovascular events unchanged
The ZEUS trial reduced IL-6 and hsCRP but not cardiovascular events (HR 0.99); Georgakis argues early drug development needs direct plaque measurements, not just blood biomarkers.
In the clinical trial ZEUS, 6,385 people with atherosclerotic cardiovascular disease and chronic kidney disease received ziltivekimab or placebo once a month. The primary endpoint was the first of three events: cardiovascular death, nonfatal heart attack, or stroke. The antibody lowered free IL-6 (an inflammatory signaling protein) and hsCRP (a blood marker of inflammation). The hazard ratio for that endpoint was 0.99, with a 95% confidence interval from 0.88 to 1.11.
A null result. The interval contains 1.0: these data cannot establish that the drug reduces cardiovascular risk.
The drop in hsCRP (a protein produced in response to IL-6 signaling) confirms only one thing: the antibody does suppress the IL-6 pathway. Geneticist Marios Georgakis writes in his analysis of the trial: "A reduction in CRP alone shows only that an IL-6 inhibitor is suppressing IL-6. It does not show whether the drug affects the blood vessels."
This does not refute the genetic evidence; those studies answered a different question. A 2025 study calculated a composite genetic score from 12 DNA variants near the IL6 gene. The biomarker profile of these variants resembles the action of ziltivekimab, and carrying them is associated with lower lifetime risk of coronary artery disease, peripheral artery disease, and atherosclerotic stroke. But these variants reduce IL-6 signaling slightly from birth, whereas ZEUS treated people whose atherosclerosis had already formed. These are different settings, and the genetic associations do not directly predict how effective late treatment will be.
If a blood biomarker does not reflect the state of the plaque, the plaque itself needs to be measured: volume, inflammation, stability. Georgakis argues that early drug development should include direct measurements of the atherosclerotic plaque. An early-phase trial by Cyclarity tests the removal of 7KC (an oxidized form of cholesterol) and plans to use computed tomography to measure atherosclerotic plaque volume separately. That intermediate endpoint can show whether an intervention modifies vascular disease before a phase III trial starts counting heart attacks, strokes, and deaths.
Open the related Eternal Search page
Sources
[1] clinicaltrials.gov
[2] novonordisk.com
[3] doi.org
[4] thecodon.substack.com
[5] t.me
The ZEUS result gives a concrete, numbers-backed lesson on surrogate marker failure in a large cardiovascular trial. The Clarity company page on Eternal Search is directly relevant because its early trial plans to use CT to measure atherosclerotic plaque volume, the kind of direct disease endpoint the ZEUS design lacked, making it a useful contrasting example for readers evaluating cardiovascular biotech.