Novartis Heart Drug Slashes Lp(a) by 78% — Yet Fails to Prevent Heart Attacks
An experimental Novartis drug that cut a genetically driven cholesterol particle by 78% failed to prevent a single extra heart attack or stroke, full results presented on Saturday showed — a result that stunned cardiologists.
Pelacarsen, an injectable drug designed to lower lipoprotein(a) — known as Lp(a) — was tested in more than 8,300 people with established heart disease at 797 sites in 42 countries. After nearly five years, major cardiovascular events occurred in 12.3% on the drug and 12.1% on placebo. Reuters reported the findings from the American Heart Association’s Scientific Sessions in Chicago, where Dr Steven Nissen of the Cleveland Clinic presented results published simultaneously in the New England Journal of Medicine.
A 78% cut that changed nothing
The trial, called Lp(a)HORIZON, enrolled 8,350 adults with Lp(a) of at least 70 milligrams per decilitre — roughly the top 15 to 20% of the population. Most had already survived a heart attack. Half received a monthly 70-milligram injection of pelacarsen; the rest received a placebo.
The drug did exactly what it was designed to do. Lp(a) levels fell by about 78% within a year, yet the primary measure — cardiovascular death, heart attack, stroke and urgent artery procedures — did not budge. The hazard ratio was 1.02, meaning risk was essentially identical in the two groups.
Extra analyses offered no rescue: even patients whose Lp(a) fell furthest showed no benefit. The drug was also harder to tolerate — 20.6% stopped pelacarsen because of side effects, against 7.5% on placebo.
Novartis had warned in September that the trial had missed its main goal but withheld the numbers until Chicago. The company, which developed pelacarsen with Ionis Pharmaceuticals, has now discontinued it for atherosclerotic cardiovascular disease, keeping only a smaller aortic-valve study.
Why doctors expected it to work
Lp(a) has long looked like the perfect target. Levels are largely set by a person’s genes and are barely touched by statins, the standard cholesterol drugs. Decades of studies have linked higher Lp(a) with greater risk of heart attacks and strokes.
That made pelacarsen one of cardiology’s most watched drugs. It is an antisense oligonucleotide, which switches off production of the protein that builds Lp(a). If lowering it prevented events, doctors believed, it would open a new front for the roughly one in five people with raised levels.
The failure does not settle the question for good, its authors stressed. The trial enrolled only people who had already had a cardiovascular event, so it cannot say whether lowering Lp(a) earlier might help. “A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a),” Nissen said.
A second failure on the same stage
Pelacarsen was not the only disappointment in Chicago. A second study of Novo Nordisk’s anti-inflammatory drug ziltivekimab also hit its biological target and missed its clinical one. The drug neutralises interleukin-6, a driver of inflammation, in 6,300 patients with heart disease, advanced kidney disease and systemic inflammation. It reduced inflammation as intended, but did not prevent major cardiovascular events, according to results presented by Dr Paul Ridker of Harvard’s Brigham and Women’s Hospital.
Together, the two results have left cardiologists rethinking two confident ideas: that cutting Lp(a) must cut risk, and that cooling inflammation must do the same. The American Heart Association said the findings were unexpected, and researchers will now examine why biology and outcomes parted ways.
What happens next for Lp(a) drugs
The failure is a setback, not necessarily the end of the road. Two rival drugs that attack Lp(a) through a different mechanism — small interfering RNA — are still in large trials. Amgen’s olpasiran is expected to report phase 3 results in early 2028, and Eli Lilly’s lepodisiran in 2029. Both lower Lp(a) by around 95%, and their backers argue a deeper or earlier cut might still succeed.
For now, doctors say the advice is unchanged: know your Lp(a) level and control the risks that can be changed — blood pressure, smoking, cholesterol and diabetes. The result is also a reminder that promising biology does not always translate into benefit, a lesson drugmakers have learned before, including in the long-running litigation over PFAS ‘forever chemicals’ that ended in a multi-billion-dollar settlement.
Novartis is meanwhile dealing with a separate FDA investigation into its gene therapy Zolgensma, which is being examined over a possible tumour risk in children. Regulators continue to weigh new therapies case by case — the FDA recently fast-tracked a sleep drug for children with insomnia, which speeds review but is not approval.
For patients who had pinned hopes on pelacarsen, the message from Chicago was blunt. “I cannot avoid the disappointing conclusion — it didn’t work,” Nissen said. “Pelacarsen improved Lp(a) measures significantly — 78% lower; however, cardiovascular outcomes were unchanged.”
