Novartis Abandons Heart Drug After Surprising Failure in Key Study

Novartis AG is largely abandoning an experimental drug analysts once considered a potential blockbuster after a study found it had little promise for preventing heart attacks and cardiovascular deaths.

The company will discontinue development of the drug known as pelacarsen for atherosclerotic cardiovascular disease, an umbrella term for heart disease and stroke that are leading causes of death worldwide. One trial will continue in a patients with a heart valve disease called calcific aortic valve stenosis, Novartis said in a statement.

The move came as details of a key Novartis study were being presented Saturday at the American Heart Association meeting in Chicago. The results, a setback for the approach being pursued by several drugmakers, found no suggestion of benefit among numerous groups analyzed. The monthly injection dramatically lowered levels of an inherited form cholesterol that’s been repeatedly tied to cardiovascular complications, but that didn’t translate into fewer heart attacks or strokes.

The trial “is completely neutral,” said Cleveland Clinic cardiologist Steven Nissen, senior author of the paper that was simultaneously published in the New England Journal of Medicine. “It is is not harmful. It is not helpful. It is just stone cold neutral.”

The results are the first definitive look at what had been a promising and widely heralded new approach to combating cardiovascular disease, which kills millions of people each year. Novartis’ seven-year study of pelacarsen involving 8,322 patients was the first to the finish line for the approach that targets Lp(a), a cholesterol-carrying particle that contributes to the accumulation of plaque in the arteries and promotes clotting.

Cardiologists had assumed that it would be a powerful medicine and usher in a new class of drugs. They were stunned in September when Novartis announced the trial had failed, and gave few details.

“I was devastated,” Novartis CEO Vas Narasimhan told journalists in October about his initial reaction to the results. “I’ve been working on the candidate since 2015 and had high hopes that it could work.”

Donald Lloyd-Jones, a professor of preventive medicine and epidemiology at Boston University, said Lp(a) shouldn’t be abandoned as a potential drug target until there’s more data from other medicines and in a broader range of patients.

“This does temper some of our enthusiasm, but I don’t think it tempers our desire to really understand more about this molecule and whether it’s something we can use as a target,” Lloyd-Jones told reporters at the Heart Association meeting.

Numerous other companies including Amgen Inc. and Eli Lilly & Co. are working on Lp(a)-lowering drugs, including some that appear more potent and may be better tolerated than the Novartis compound. In the study, about 21% of patients taking pelacarsen stopped treatment because of adverse events, compared with 7.5% on placebo

Novartis has another experimental drug, DII235, designed to lower Lp(a). The treatment, which uses a newer technology known as siRNA, is being tested in a midstage study. The company hasn’t yet committed to continuing its development and will provide an update in the future, a spokesperson said.

Moving Forward

Researchers had hoped that when the detailed results from the failed pelacarsen trial were presented there would be some hints about who might benefit. That could have provided a way forward for other scientists working in the field. But no matter which way the data was sliced, there weren’t any, the investigators said.

That leaves a mystery: Why didn’t the drug work when high levels of Lp(a) have been strongly linked to cardiovascular events in genetic and epidemiological studies?

One possibility lies in the nature of Lp(a). Unlike bad LDL cholesterol, which tends to start low early in life and rise during adulthood, Lp(a) levels are genetically determined. People with high levels have them their entire lives.

“It just may be that five years of treatment for a disease that is present for life when you start at age 60 isn’t going to get it done,” Nissen said in an interview.

Another possibility is that modern medicine already blunts some of the harm from Lp(a), he said. Patients in the Novartis trial also received intensive treatment for other cardiovascular risks, including cholesterol and blood pressure.

Nissen says Novartis’ failed trial shouldn’t close the door on Lp(a) as a target. It may be more beneficial to lower Lp(a) levels in healthier people who are at risk of a heart attack but haven’t had one yet. Some ongoing trials, including one on Lilly’s experimental injectable drug lepodisiran, include such patients, he added. Nissen led an earlier study on the Lilly drug and said he’s on a mission to ensure that drugmakers don’t pull the plug on future trials.

“The horse threw us,” he said. “We’re going to get back on the horse and keep going with the lepodisiran trial.”