New Heart Drugs Pelacarsen and Ziltivekimab Fail in Major Clinical Trials

For months, the cardiovascular community anticipated the details surrounding large clinical trials for the two experimental therapies. Novartis developed pelacarsen to plunge levels of the Lp(a) blood protein, which is widely believed to cause heart attacks and strokes. Novo Nordisk developed ziltivekimab to stop inflammation, a mechanism thought to drive plaque buildup in arteries. Instead of demonstrating a protective benefit, the full data presented on Saturday morning at the annual meeting of the American Heart Association showed neutral outcomes across the board.

Dr. Karol Watson, a director of UCLA’s preventive cardiology program, described the sentiment among physicians after reviewing the findings. The whole cardiovascular community was gobsmacked, Dr. Watson said, adding that the results are about as neutral as they can be. Simultaneous publications in The New England Journal of Medicine confirmed that neither drug made a dent in heart disease outcomes, leaving no evidence that any patient subgroup benefited from the treatments.

The Inflammation Hypothesis Under Scrutiny

Dr. Paul Ridker of Mass General Brigham served as the principal investigator for the inflammation trial, known as the Zeus study. A true believer in the therapeutic approach, Dr. Ridker had pointed to earlier encouraging data involving an experimental anti-inflammatory drug made by Novartis, alongside studies indicating that the gout medication colchicine offered protection. Until reviewing the trial data, he considered the trial a brilliant idea bound to prove the effectiveness of ziltivekimab, which blocks an inflammatory protein called il-6.

The 6,376 trial participants all suffered from severe heart disease, advanced kidney disease, and elevated inflammatory blood markers. Yet every subgroup fared identically, showing no advantage over patients taking placebos despite clear reductions in systemic inflammation. Did we pick the wrong target, the wrong patient population? Dr. Ridker asked during his presentation. He suggested that patients may have had heart disease so advanced that it could not be helped, noting that perhaps the horse was out of the barn. Other specialists questioned whether the underlying hypothesis was fundamentally flawed, wondering if arterial inflammation functions merely as a sign of disease, not a cause, as white hair is a sign of aging.

Novo Nordisk announced in September that it was stopping two separate studies of ziltivekimab involving patients with heart failure after an independent committee found no efficacy. However, the company continues to test the drug in patients who have survived a heart attack, with that specific study scheduled to conclude next year. Dr. Ridker remains convinced that targeting the broader inflammation pathway holds future clinical potential, though the immediate challenge involves identifying precise patient populations.

Evaluating Lp(a) Reduction and Advanced Disease Stages

Dr. Steven Nissen of the Cleveland Clinic directed the Horizon trial testing Novartis’s pelacarsen. He voiced concern that the disappointing results might discourage patient enrollment in two other ongoing studies testing separate therapies designed to lower Lp(a) levels. A single trial doesn’t necessarily give us all the answers, Dr. Nissen noted, emphasizing that elevated Lp(a) remains a powerful risk factor.

Researchers weighed multiple hypotheses to explain the trial outcome. Dr. Roger Blumenthal, director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, noted that participants already had exceptionally well-controlled blood pressure and L.D.L. cholesterol, meaning their baseline risk was already minimized. Dr. Ridker offered an alternative possibility, suggesting that because all Horizon participants took anti-clotting medications to counteract Lp(a)-related clotting, those standard therapies might have diluted the experimental drug’s effects. When asked if any signal pointed toward a benefit, Dr. Nissen was direct. Was there anything that we could point a finger to that said, ‘Yeah, there’s a benefit’? he asked. No, there was nothing.