Dive Brief:

• An RNA drug from Novartis and Ionis Pharmaceuticals failed to reduce the risk of heart attacks, strokes and death in a clinical trial, an outcome that could fuel doubt about an emerging way to protect cardiovascular health.
• Called pelacarsen, the drug is designed to sharply lower levels of a protein particle — known as lipoprotein(a), or “Lp(a)” — that scientific research has linked to heart disease. But in a multiyear Phase 3 study of more than 8,000 participants, a combination of pelacarsen and standard medications didn’t lower the risk of major cardiovascular events when compared to those typical therapies and a placebo.
• Novartis didn’t provide specific details in a Friday statement. They’ll be presented at an upcoming medical meeting. The company did, however, note that the negative results occurred even though pelacarsen dropped levels of Lp(a) in treated participants. “These are not the results we hoped for,” but could “help inform future approaches to cardiovascular management,” said Chief Medical Officer Shreeram Aradhye, in the statement.

Dive Insight:

High cholesterol and fat levels have long been linked to a higher risk of heart problems, making treatments that can reduce them mainstays of cardiovascular care.

Genetic and epidemiological studies have shown a similar tie between Lp(a) — a fatty, cholesterol-carrying protein particle — and heart disease. According to the American Heart Association, about 20% of people have high levels of Lp(a) and, as a result, are more likely to have harmful plaques accumulate in their arteries. But they can’t lean on diet or exercise to alter their Lp(a) counts, and physicians don’t often test for the protein because there aren’t medications that can help.

Several large pharmaceutical companies have been racing to address that problem by bringing forth a new crop of therapies able to plunge Lp(a) levels in one way or another. Pelacarsen was the most advanced among these, making Novartis and Ionis’ trial one of the most eagerly anticipated in cardiovascular medicine.

Novartis had a lot riding on the outcome, too, as pelacarsen is one of a handful of prospects it hopes might offset a wave of patent expirations for key products. Analysts at William Blair estimated $6 billion in peak annual U.S. sales alone if the drug were to succeed in clinical testing.

The negative results revealed Friday, then, raise questions about this approach's impact on cardiovascular health, and suggest there's “meaningful risk” in other ongoing trials, wrote William Blair’s Myles Minter, in a Friday research note.

In an earlier trial, pelacarsen decreased Lp(a) levels in study participants by as much as 80% after 24 weeks, Minter noted. While the companies didn’t provide specifics, the reductions observed with the latest study were “in the range previously observed,” Minter’s team wrote after speaking with Ionis management.

There might be an opportunity for approaches with “deeper Lp(a) inhibition,” he added. Companies such as Eli Lilly, Amgen and Silence Therapeutics are advancing drugs that use different methods to stop genes from making Lp(a) particles, or block their formation. Amgen’s drug plummeted Lp(a) by more than 95% in mid-stage testing.

The study details will be crucial in gauging the potential for other medicines to perform better. In a separate note, Jefferies analyst Dennis Ding wrote that his team will be paying close attention to “any correlation” between Lp(a) levels at the start of the study, the magnitude of Lp(a) reduction and the associated clinical benefit. They’ll also keep a close eye on how close pelacarsen came to succeeding, as well as the statistical impact from patients who didn’t complete the trial.

“This will be an important dataset to dig into,” Ding wrote.