Inflammatory Hypothesis Proponents Undaunted by ZEUS Flop

When topline results emerged from the ZEUS trial that investigational interleukin (IL)-6 agent ziltivekimab failed to reduce major cardiovascular events in patients with high-risk heart plus kidney disease, some saw it as a blow to the inflammatory hypothesis. Targeting IL-6 was supposed to reduce inflammation in these patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and high C-reactive protein. The monoclonal antibody appeared to hit that mark, cutting both levels of the proinflammatory cytokine it targeted and high-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation. However, ziltivekimab had almost no impact on major adverse cardiovascular events compared with placebo (hazard ratio, 0.99; 95% CI, 0.88-1.11), as drug developer Novo Nordisk announced in a statement on July 31. Rather than generalizing the lesson of the neutral trial as a critical blow against the causal role of inflammation in ASCVD, proponents of that so-called inflammatory hypothesis say it’s just part of the process in building evidence for how to treat within that framework — another signal that broad is better than narrow when targeting inflammatory pathways. “A lot of people are interpreting ZEUS as the end of the journey of trials in inflammation, but that would be a terrible mistake,” said Mark Nidorf, MD, of Perth GenesisCare in Australia. Building Evidence Inflammation plays a central role not just as a marker but as a cause of atherosclerotic disease, with “rock solid” evidence from mechanistic, biomarker, genetic, and epidemiologic studies, said Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Center and research chair in atherosclerosis at the Université de Montréal, Montreal, Quebec, Canada. “There’s no doubt that inflammation is at the center of the initiation, the progression, and the deep destabilization of atherosclerosis,” he said. “That we know. Then the next question obviously was, what about if you reduce inflammation? And we have two lines of investigation that have shown that it actually works.” First was the success of targeting IL-1, which is upstream in the inflammatory pathway, with canakinumab, Tardif said. In the CANTOS trial among high-risk patients with a prior myocardial infarction (MI) and persistently elevated hs-CRP, that monoclonal antibody reduced risk for nonfatal MI, nonfatal stroke, and CV death by 15% compared with those receiving placebo. Second was the success of colchicine, which also acts upstream and on multiple inflammatory pathways, in Tardif’s COLCOT trial in a post-MI population and Nidorf’s LoDoCo2 in chronic coronary disease. It was not really much surprise that a solely anti-IL-6 agent didn’t work, Tardif said because that inflammatory cytokine is downstream in the vascular inflammatory pathway amid redundant innate and acquired pathways. “This tells us it’s complex, and you’ve just got to keep on hammering away, just like you had to do with lipid lowering in the past,” Nidorf said. “If you go back to the lipid-lowering trials in the early ’80s, people were skeptical that any drug could modify the natural history of atherosclerosis by lowering cholesterol, and it was because they didn’t have the right drugs,” Nidorf said. Despite failures with agents such as colestyamine and niacin, statins and PCSK9 inhibitors proved worth the search. On a similar journey for the inflammatory hypothesis, Nidorf said, “ZEUS should be seen as a logical next step of the CANTOS trial of precision medicine,” triangulating where in the cascade can be effectively targeted. “The single, highly targeted IL-6 was just too far down the inflammatory pathway,” he said. Implications for CRP Like the CANTOS trial, the ZEUS trial enrolled over 6300 people with elevated inflammation as measured by hs-CRP levels of at least 2 mg/L. While hs-CRP is tied to inflammation, it’s not specific to the cardiovascular system. Elevations can also come from infection, tissue injury, obesity, pregnancy, and even normal daily variation. “It’s not a bad marker of risk, but it’s not telling you the whole story,” Tardif said. “ZEUS tells you that ziltivekimab reduced CRP by a large extent and had no effect on cardiovascular events.” Nidorf pointed also to studies like the EKSTROM trial of low-dose colchicine in stable coronary artery disease. While a neutral trial overall, subanalysis showed that there was imaging evidence of slowing of the atherosclerotic process in patients with hs-CRP less than 1 mg/L. “It’s not a very good marker of the presence of atherosclerosis or the success or failure of a drug or the inability of a drug to provide more benefit,” he said. But it is a good prognostic marker. “CRP doesn’t always equal inflammation. CRP equals risk,” Nidorf said. Thus, it can be used as an entry risk criterion to enrich the population to ensure a high event rate. On an individual level, though, “CRP is not necessarily fit for purpose when we come to decide who should be treated and whether treatment is effective,” he cautioned. No other inflammatory biomarker waits in the wings to serve that purpose either, Tardif acknowledged, noting need for further study. “If I had to predict, it’s probably going to be a proteomic-based marker or a panel of proteomic-based biomarkers.” The ZEUS trial results are yet to be published or presented at a medical meeting in greater detail. When they are, Nidorf said he looks forward to seeing if, similar to the CANTOS trial, the effect of the monoclonal antibody was greater in patients whose CRP dropped < 2 mg/L on treatment. That would suggest CRP will have a role in monitoring the progress of patients, Nidorf said: “Not is treatment working, but who is still at risk, which is a different question, a different way of using the CRP marker.” Future Directions Ziltivekimab remains under study, with ongoing cardiovascular outcomes trials in people with heart failure (HERMES) and in people following an acute heart attack (ARTEMIS). Results of both are expected in 2027. “Obviously, the odds of a positive finding for ziltivekimab have gone down tremendously,” Tardif cautioned. Nidorf agreed. “No anti-inflammatory has ever been shown to be useful in heart failure so I doubt that’ll be helpful,” he said. Both agreed on the need for new broad-targeted drugs. “We need to actually develop new anti-inflammatory drugs which are as good as, and more, capable of being a multiple set of drones, if you like, as opposed to just a missile which is going to hit one silo,” Nidorf said. “It just doesn’t work. The inflammatory process is too sophisticated for that.” And the complexities of chronic kidney disease likely should be left out of the equation initially, Nidorf suggested. Even statins have been very difficult to prove beneficial in patients with renal disease, he said. But the ZEUS trial probably would have been negative even if that hadn’t been an entry criterion, he added. “And the reason is that the inflammatory process has redundancies, and you need to be turning it off at a much higher level.” Other orally administered anti-inflammatory drugs are being tested in CVD, and the COLCOT T2D trial is underway testing colchicine in some 10,000 patients with type 2 diabetes in hopes of prompting greater uptake. “Hopefully, when we report that trial, there’ll be a sea change, but we’re not there yet,” Tardif said. The ZEUS trial was supported by Novo Nordisk. Nidorf and Tardif disclosed having no relevant conflicts of interest. Crystal Phend is an award-winning medical journalist with decades of experience reporting on clinical research and healthcare developments across specialties. When not walking the halls at a medical conference, she can be found at a keyboard in upstate New York.