Novartis' Pelacarsen Fails to Cut Heart Attacks and Strokes in Pivotal Trial, Shares Fall

Novartis announced Friday, September 4, that its experimental heart drug pelacarsen failed the primary goal of its pivotal Lp(a)HORIZON trial: reducing cardiovascular death, non-fatal heart attack, non-fatal stroke, or urgent hospitalization for coronary procedures compared to placebo.

The drug lowered lipoprotein(a), or Lp(a), a cholesterol-carrying particle that is roughly 90% genetically determined and largely untouched by diet or exercise, according to both Novartis and its development partner Ionis Pharmaceuticals. The reduction did not result in fewer heart attacks or strokes for patients already on standard cardiovascular care.

"Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population," said Shreeram Aradhye, Novartis' President of Development and Chief Medical Officer. "These are not the results we hoped for."

Ionis CEO Brett Monia struck a similar tone. "We are disappointed that this did not translate to cardiovascular risk reduction," Monia said, adding that the trial "provide[s] clarity that will meaningfully inform future cardiovascular care."

A Six-Year Bet That Didn't Pay Off

Lp(a)HORIZON enrolled more than 8,000 adults with elevated Lp(a) and established cardiovascular disease, and ran for over six years, according to reporting from KSL News. It was the first dedicated outcomes trial to test whether lowering Lp(a) specifically, on top of already-optimized lipid and blood pressure treatment, actually prevents heart attacks and strokes.

No approved treatment currently targets Lp(a) directly. The particle affects roughly one in five people worldwide and nearly a third of people with premature cardiovascular disease, according to both Novartis and Ionis. U.S. and European guidelines already recommend a once-in-a-lifetime Lp(a) test for all adults, but until now doctors have had nothing specific to prescribe if the number comes back high.

Wall Street Reacts, With Some Disagreement on the Numbers

Investors punished the news, though outlets differ on the exact magnitude. KSL News reported Novartis' U.S.-listed shares declined 5% and Ionis fell 12% in aftermarket trading, with Amgen also down 5%. Briefs.co reported Novartis' U.S.-listed stock fell over 7% after hours and Amgen dropped almost 7%. Either way, all three companies took a hit.

Amgen's exposure is notable because it isn't Novartis' drug. Amgen and Eli Lilly are both developing their own Lp(a)-lowering medicines, olpasiran and lepodisiran respectively, and both remain in earlier stages of late-stage testing, according to KSL News. Investors are now viewing the entire drug class as riskier.

Citi analyst Geoff Meacham, quoted by KSL News, said the full trial data are needed to figure out whether the miss reflects pelacarsen's specific mechanism, insufficient Lp(a) reduction, trial design flaws, or a more fundamental problem: that lowering Lp(a) simply doesn't reduce heart disease risk the way lowering LDL cholesterol does. "The first dedicated outcomes failure lowers confidence across the class and places greater pressure on later studies to demonstrate that deeper lowering of Lp(a) can produce a clinically meaningful reduction of major cardiovascular events," Meacham said.

The Bigger Picture for Novartis

The timing stings for Novartis. The Basel-based drugmaker is navigating one of its steepest patent cliffs in years and losing revenue from its blockbuster heart drug Entresto, according to KSL News. Pelacarsen was one of three late-stage assets, alongside anti-inflammatory drug remibrutinib and gene therapy del-desiran, that investors were counting on to drive long-term growth, with the trio potentially generating more than $10 billion in combined peak annual sales if approved.

That pipeline had a genuinely good week before this. Remibrutinib succeeded in a separate late-stage trial for a form of multiple sclerosis earlier in the week, with analysts projecting up to $9 billion in peak annual sales for that drug alone, according to KSL News. Pelacarsen's failure doesn't erase that win, but it removes one of the three legs investors were standing on.

Skeptics of the Lp(a)-lowering approach have raised a fair question: modern statins and GLP-1 weight-loss drugs are already so effective at preventing heart attacks and strokes in trial populations that it may be getting harder for any add-on drug to show a statistically significant benefit, since fewer cardiovascular events occur during these studies to begin with, as KSL News noted.

Novartis said pelacarsen showed an acceptable safety profile despite the missed primary endpoint, and full Lp(a)HORIZON data will be presented at an upcoming medical congress, per both the company and Ionis. Until that data drops, doctors, patients with elevated Lp(a), and rival drugmakers Amgen and Eli Lilly are left waiting to find out whether their own Lp(a) programs are chasing the same dead end, or whether pelacarsen simply didn't lower the particle enough to matter.