CHICAGO, IL—The topline results were already known—ziltivekimab, a monoclonal antibody targeting interleukin-6, failed to reduce the risk of cardiovascular outcomes when compared with placebo—but investigators say the inflammatory hypothesis is still worth investigating.
“Cardiovascular inflammation is highly prevalent,” said ZEUS lead Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), during a press conference at the American Heart Association (AHA) Scientific Session. “It remains a mechanistically compelling therapeutic target. CANTOS, LoDoCo2, and COLCOT have already proven that lowering inflammation lowers risk. Our challenge is what patient, and what drug for what patient group.”
The ZEUS trial, which was published simultaneously in the New England Journal of Medicine, may have included patients who were too unwell to benefit from anti-inflammatory therapy, said Ridker. In the randomized, double-blind trial, investigators randomized 6,376 patients (mean age 69.4 years; 27.5% female) with established cardiovascular disease, chronic kidney disease (CKD), and high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg/L) to monthly subcutaneous ziltivekimab 15 mg or placebo
“ZEUS evaluated a very unusual, selective population,” said Ridker. “Maybe the horse was already out of the barn.”
Back in 2017, Ridker published the findings from CANTOS, another large trial testing a monoclonal antibody targeting the inflammatory pathway. Canakinumab (Novartis), which targets interleukin-1β (IL- 1β), added to guideline-directed medical therapy in patients with a prior MI and elevated high-sensitivity C-reactive protein (hs-CRP) reduced the relative risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke by 15% compared with placebo.
Maybe the horse was already out of the barn.
Paul Ridker, MD
Novartis ultimately chose not to pursue a cardiovascular indication for canakinumab, although the therapy currently holds orphan drug designations for several rare, inflammatory conditions.
In 2024, the CLEAR SYNERGY (OASIS 9) study showed that colchicine, an anti-inflammatory therapy with a challenging side-effect profile, did not reduce the risk of major adverse cardiovascular events when used in patients who underwent PCI for acute MI. The results were a surprise given that two other studies, COLCOT and LoDoCo2, showed colchicine significantly cut the risk of cardiovascular events in acute MI and stable coronary disease patients, respectively.
Ridker said that colchicine is relatively contraindicated because it is metabolized by the kidney. Patients with chronic kidney disease are a high-risk population, he said, and investigators wanted to test a different agent, one downstream from colchicine’s mechanism of action, in ZEUS.
“Mendelian randomization studies in the past suggested the genetics of this should play out nicely,” said Ridker. “There’s abundant epidemiologic data, including from Framingham, showing that IL-6 predicts risk. We have lots of experimental data in humans and in mice…Our own CANTOS trial had a secondary hypothesis-generating observation that downstream IL-6 really mattered. So, we said let’s give it a shot.”
‘Seemed to Hit its Target’
In ZEUS, the median hs-CRP and IL-6 levels were 4.5 mg/L and 4.9 pg/mL, respectively. Patients were well treated with GDMT, with 92.6% treated with lipid-lowering therapy, 76.4% with a renin-angiotensin-aldosterone inhibitor, 37.1% with a sodium-glucose cotransporter 2 inhibitor, and 11.4% with a glucagon-like peptide 1 (GLP-1) receptor agonist. The median LDL cholesterol was 71 mg/dL, the mean eGFR was 44.5 ml/min/1.73m2, and the mean body mass index was 30.3.
In terms of good news, Ridker pointed out that increasing levels of both hs-CRP and IL-6 were associated with higher risks of cardiovascular death, MI, or stroke and all-cause mortality alone. Treatment with ziltivekimab also significantly reduced IL-6 and hs-CRP compared with placebo: there was a 76% placebo-adjusted reduction in free IL-6 and 64% placebo-adjusted reduction in hs-CRP at 24 months. Serum amyloid A and fibrinogen, which are also inflammatory biomarkers, were reduced with treatment. There was a 29% reduction in Lp(a).
“The drug seemed to hit its target,” said Ridker.
After a median follow-up of 33 months, there was no significant difference in the 3-point MACE endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke between treatment groups: 17.6% in the ziltivekimab arm vs 17.7% in the placebo group (HR 0.99; 95% CI 0.88-1.11).
The 4-point MACE endpoint, which included hospitalization for unstable angina necessitating coronary revascularization, was also not significantly different between the treatment groups: 18.4% in the ziltivekimab arm vs 18.5% in the placebo group (HR 0.99; 95% CI 0.88-1.10). There was no difference in a composite kidney endpoint between the treatment groups.
Serious adverse events occurred in 54.6% of the ziltivekimab-treated patients and 54.8% of those who received placebo. Serious infections occurred in 20.4% of those treated with ziltivekimab and 17.9% of patients treated with placebo.
Serious venous thromboembolism occurred in 1.6% of patients receiving ziltivekimab versus 0.6% receiving placebo; serious hemorrhage occurred in 5.1% versus 4.0%, respectively.
Wrong Target or Nonmodifiable Disease
To Cardiology Now News, Deepak Bhatt, MD (Icahn School of Medicine at Mount Sinai, New York, NY), said he was more surprised by the null results from Lp(a)HORIZON, the study testing Lp(a)-lowering therapy with pelacarsen, than by ZEUS.
“I wasn’t necessarily super excited about ZEUS being in chronic kidney disease,” he said. “Even when you look at CANTOS, the subgroup with CKD looked good, but CKD is a tough population because a lot of cardiovascular drugs that work in other populations don’t work as well in CKD.”
Compared with CANTOS, patients in ZEUS were roughly 10 years older and had more advanced kidney disease. Patients also had high rates of hypertension, diabetes, and heart failure. The incidence of all-cause mortality was twofold higher in ZEUS than it was in the CANTOS trial (6.2 vs 3.0 per 100 patient-years, respectively).
Ridker told Cardiology Now News that up until the trial was unblinded, he had figured they targeted an ideal population. “That’s what we do as investigators,” he said. “What’s my biggest unmet need? We design the study and sometimes we get disappointed.”
The take-home from this session should not be that
Priscilla Hsue, MD
inflammation doesn’t matter.
With hindsight, Ridker said they’d focus more on stable patients with chronic coronary artery disease. The CLEAR SYNERGY (OASIS 9) trial, on the other hand, included patients with acute MI treated with colchicine after PCI.
The NLRP3 inflammasome promotes activation of IL-1β and IL-18, while IL-1β signaling stimulates downstream IL-6 production.. Experts say it’s possible that ziltivekimab, which is a direct IL-6 ligand inhibitor, might be too far downstream to reduce clinical outcomes.
Priscilla Hsue, MD (University of California Los Angeles), the discussant following the late-breaking science session, questioned whether the IL-6 inhibitor was able to get to the root cause of inflammation.
“IL-6 receptor biology and treatment is incredibly complicated,” said Hsue. “Long story short, ziltivekimab impacts the IL-6 ligand while other agents like tocilizumab impact the IL-6 receptor antagonist. Clearly, [ziltivekimab] may not reach all pathways. You have to think, ‘was the inhibition of IL-6 somehow incomplete using this approach?'”
Upstream targets, including the NLRP3 inflammasome, might be more effective for not only reducing markers of inflammation, but also clinical events. “The take-home from this session should not be that inflammation doesn’t matter,” said Hsue. Instead, a better understanding of the biology of inflammation and atherosclerosis, and more mechanistic studies, are needed.
More data with ziltivekimab is expected in 2027. The ARTEMIS phase 3 trial is currently ongoing. In that trial, investigators are testing the therapy in patients with a recent MI. The HERMES trial, another testing ziltivekimab, was recently stopped for futility. In that study, investigators were evaluating the therapy in patients with heart failure with preserved ejection fraction.
Source:
Ridker PM, Lincoff AM, Marx N, et al. Interleukin-6 inhibition with ziltivekimab for atherosclerotic disease. N Engl J Med. Published online November 7, 2026.
Disclosures:
Ridker reports consulting for Agepha, Angiowave, Arrowhead, AstraZeneca, BioAge Labs, Boehringer Ingelheim, Cardiotherapeutics, CSL Behring, Eli Lilly and Company, GlaxoSmithKline, HeartFlow, IQVIA, Merck, Mirador, New Amsterdam, Nodthera, Novartis, Novo Nordisk, SOCAR, Tourmaline Bio, and Uppton. He reports grant/research support from Bristol Myers Squibb, Esperion Therapeutics, Kowa Pharmaceuticals, National Cancer Institute, National Heart, Lung, and Blood Institute, Novartis, and Pfizer.
Shah reports research funding from nference Inc, Novo Nordisk, Owkin, and AstraZeneca.
Hsue reports consulting for Genentech, Gilead, and Pfizer and serving on an advisory board for Marea Therapeutics. She reports research funding from Excision Biotherapeutics.