An experimental Novartis drug designed to treat a genetic cause of heart disease has failed to prevent heart attacks and strokes in a major trial, despite sharply cutting levels of the blood particle it was designed to target.
Pelacarsen reduced levels of lipoprotein(a), known as Lp(a), by 78% in patients given a monthly dose over nearly five years. But the drug had no effect on deaths, second heart attacks, strokes or emergency procedures to unblock clogged arteries, according to detailed results presented on Saturday at the American Heart Association meeting in Chicago and published in the New England Journal of Medicine.
The trial enrolled more than 8,300 patients who had already suffered a major cardiovascular event, such as a heart attack. They were randomly assigned to a monthly 70-milligram dose of pelacarsen or a placebo and followed for a median of 4.7 years, with other risk factors including LDL cholesterol and blood pressure carefully controlled.
“Everybody in the world, me included, thought that this was going to work,” said Dr Steven Nissen of the Cleveland Clinic, who presented the results. “It didn’t do anything. It was completely neutral.”
Novartis and co-developer Ionis Pharmaceuticals had announced in September that the drug failed to meet the trial’s main goal, but experts had awaited the detailed figures to see whether it offered any benefit. A separate statistical analysis, published in NEJM Evidence, looked at patients with larger-than-average Lp(a) reductions and at those who stayed in the trial, and still found no benefit.
High Lp(a) is a genetic risk factor estimated to affect about a fifth of the world’s population, and there are currently no approved treatments for it. Researchers had hoped lowering it would bring benefits similar to statins, which cut heart attack and stroke risk by lowering LDL cholesterol.
The drug was also harder to tolerate than a placebo: 20.6% of patients on pelacarsen stopped taking it because of side effects, compared with 7.5% of those on placebo.
A second trial presented at the same meeting delivered a similar disappointment. Novo Nordisk’s ziltivekimab, an anti-inflammatory drug designed to neutralise interleukin-6, lowered inflammation as intended in 6,300 patients with heart disease, advanced kidney disease and systemic inflammation, but did not reduce deaths, heart attacks or strokes.
Taken together, the two failures question some long-held ideas about what drives heart disease. But experts cautioned against abandoning either target. Dr Donald Lloyd-Jones, a cardiology professor at Boston University, said he would not recommend giving up on Lp(a) until there was far more data in different patient groups. Nissen, who is leading a trial of Eli Lilly’s rival Lp(a) drug lepodisiran, noted that the rival drugs lower Lp(a) by about 95% and are tested in patients who have never had a heart attack or stroke, with results expected in 2028 and 2029.
Note: The featured image is a file photo of CT coronary artery imaging, not from the trial.
Sources: Reuters, “Trial failures of Novartis, Novo Nordisk heart drugs leave experts guessing”
