Longevity
Ziltivekimab cut inflammation but not heart events in a 6,376-patient trial
By John Hyland, . Life and Health Today.
A large clinical trial of ziltivekimab, a monoclonal antibody (a laboratory-made protein designed to block a specific target in the body) that suppresses the inflammatory signaling molecule interleukin-6, failed to reduce heart attacks, strokes or cardiovascular deaths in high-risk patients, even though it sharply lowered the inflammation markers it was designed to move. The findings were presented at the American Heart Association's annual meeting in Chicago and published simultaneously in the New England Journal of Medicine.
What the trial found
The ZEUS trial enrolled 6,376 patients, all of whom had atherosclerotic cardiovascular disease (a buildup of plaque in the arteries), chronic kidney disease and measurable cardiovascular inflammation. Half received ziltivekimab and half received a placebo. Over a median follow-up of 33 months, the primary endpoint, a composite of death from cardiovascular causes, nonfatal heart attack or nonfatal stroke, occurred in 561 patients (17.6%) in the ziltivekimab group and 565 patients (17.7%) in the placebo group. The hazard ratio was 0.99 with a 95% confidence interval of 0.88 to 1.11 and a p-value of 0.84, meaning the result was statistically indistinguishable from chance, according to MedPage Today and the New England Journal of Medicine.
The drug did work on its biological targets. Paul M. Ridker, of Harvard Medical School and Mass General Brigham Hospital in Boston, who presented the results, reported a 76% placebo-adjusted reduction in free interleukin-6 and a 64% placebo-adjusted reduction in high-sensitivity C-reactive protein, a standard marker of inflammation. Moving those markers did not translate into fewer events.
Why the result is surprising
Previous trials had shown that anti-inflammatory treatment can protect the heart. Ridker noted that the CANTOS trial, using a different drug called canakinumab, and two trials using colchicine, LoDoCo2 and COLCOT, all demonstrated that reducing inflammation lowered event rates in patients with stable coronary disease. ZEUS used a different drug in a different population, and the outcome was different.
Ridker offered one explanation: the ZEUS population was sicker. Compared with CANTOS participants, ZEUS patients had significant chronic kidney disease, more diabetes and more heart failure, and their all-cause mortality rate over the trial was roughly twice as high. He described this as suggesting "late-stage, non-modifiable disease," according to MedPage Today, and added: "The horse may already have been out of the barn."
He also drew a distinction between genetic evidence and therapeutic evidence. Mendelian randomization studies, which use inherited genetic variants to infer whether a biological pathway causes a disease, had pointed to interleukin-6 as causally involved in cardiovascular risk. But as Ridker put it, "genetic causality is not therapeutic reversibility," according to MedPage Today. The genetic signal and the trial result can both be correct: interleukin-6 may matter in the long arc of disease development without being a useful lever once disease is advanced.
The trial did confirm that inflammation predicts risk. Higher levels of C-reactive protein and interleukin-6 at baseline were associated with greater likelihood of reaching the primary endpoint and of dying from any cause, which Ridker and colleagues reported as consistent with inflammation remaining a meaningful treatment target, even if this particular drug in this particular population did not benefit from targeting it.
What happens to the drug program
According to STAT News, after top-line ZEUS results were disclosed, Novo Nordisk halted two other ziltivekimab trials, called HERMES and ATHENA, after a data monitoring committee found in September that those trials were unlikely to succeed.
Ridker framed the central question going forward as: "what drug, in which patient group?" The MedPage Today report covers only the first portion of a longer article and does not include the full discussion of secondary endpoints, subgroup analyses or the trial authors' complete conclusions; those appear in the New England Journal of Medicine publication.
The ZEUS result does not close the question of whether inflammation is a useful cardiovascular target. It narrows it: the approach that worked in earlier, less severely ill populations did not work here. Whether a different drug, an earlier intervention or a less compromised patient group would produce a different answer is not something this trial can answer.
Source: https://www.medpagetoday.com/meetingcoverage/aha/123773
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