CHICAGO — A large trial of an experimental Novartis heart drug has failed to reduce the risk of heart attacks and strokes, even though the drug cut blood levels of a genetically determined cholesterol particle by 80%, raising fresh questions among cardiologists about one of the most closely watched targets in preventive cardiology.
The drug, pelacarsen, developed by Novartis and Ionis Pharmaceuticals, did not meet its main goal in a Phase 3 trial, Novartis has said. The result was reported by Reuters on Monday, 2 November 2026, ahead of the full presentation of the trial data, which is due on Saturday in Chicago at the American Heart Association's annual scientific meeting.
The stakes are high because heart disease is the leading cause of death in the United States, killing nearly a million people a year, according to the American Heart Association. For years, researchers have hoped that lowering lipoprotein(a) — commonly called Lp(a) or "LP little a" — could become the next major advance in prevention, alongside the established strategy of lowering LDL, or "bad", cholesterol.
Illustration: Researchers in a cardiology laboratory reviewing heart health data and blood test results. This is an illustration, not a photograph of a real event.
What Happened
Pelacarsen was designed to lower Lp(a), a sticky cholesterol-carrying particle whose levels are set largely by a person's genes. Around 20% of people carry genes that instruct the liver to produce the extra-sticky particle, although resulting blood levels vary, Reuters reported. Incidence is higher among people of African or South Asian ancestry.
Unlike standard LDL cholesterol, Lp(a) levels are not affected by diet, exercise or lifestyle changes, which is one reason the particle has attracted so much research attention: if it could be lowered with a drug, it might offer protection to people whose risk cannot be addressed by lifestyle measures alone.
In the Phase 3 trial, however, that 80% reduction in Lp(a) blood levels did not translate into a lower risk of the trial's composite outcome: death, heart attack, stroke, and the need for revascularisation procedures to restore blood flow in blocked blood vessels. Novartis said the trial did not meet its main goal of significantly reducing that composite risk. News of the failure contributed to a 16% fall in Novartis shares, according to Reuters.
The Swiss drugmaker declined to comment further, Reuters reported. The trial's lead investigator, Dr. Steven Nissen of the Cleveland Clinic, said he was unable to comment until after the trial presentation in Chicago.
Background
Doctors say the detailed results, when they are presented, will determine whether Lp(a) remains a promising drug target or whether enthusiasm for the field fades. Much will hinge on whether the trial narrowly missed being statistically significant — meaning the drug had a positive impact, but not enough to meet the study's goal — had no impact at all, or even had a negative effect, Reuters reported.
"If there are no signals at all, then that will really dampen any further enthusiasm for the space," said Dr. Parag Joshi, a cardiologist at UT Southwestern Medical Center in Dallas and an investigator on the study.
Cardiologists already use Lp(a) blood tests to assess a person's inherited risk for heart disease. Earlier this year, the American Heart Association and the American College of Cardiology issued new guidelines for all adults to have their Lp(a) measured at least once in their lifetime.
"When I see someone with a family history of premature heart disease, there is a 95% chance it's going to be from LP little a," said Dr. Nathaniel Lebowitz, a cardiologist at Hackensack University Medical Center, who helped draw up the guidelines.
Several factors could have influenced the pelacarsen result, doctors told Reuters. One is the inclusion of stroke in the composite endpoint, even though studies have shown an unclear relationship between Lp(a) and stroke. Joshi said he is most interested to see the data for rates of heart attack and revascularisation specifically.
Illustration: A medical illustration of a heart and arteries with cholesterol particles in the bloodstream. This is an illustration, not a photograph of a real event.
Dosage is another open question. The Novartis trial tested a monthly dose of 80 milligrams for the first time, whereas a previous midstage trial tested a highest monthly dose of 60 milligrams as well as a weekly 20-milligram dose. "One possibility is that maybe there were (patient) dropouts. They never studied that dose all at once," said Dr. Robert Rosenson, director of metabolism and lipids at Mount Sinai Fuster Heart Hospital in New York City, noting that dosage is linked to how well patients tolerate a drug.
Background treatment may also matter. In addition to pelacarsen or a placebo, patients in the trial were treated with LDL-lowering statins and more potent PCSK9 cholesterol drugs such as Amgen's Repatha, which has been shown to lower Lp(a) by a more modest 25% or so. Doctors said use of PCSK9 drugs has grown significantly following studies showing the benefit of dramatic LDL lowering.
"In the absence of being able to get rid of LP little a, we've been driving down LDL much more aggressively," Lebowitz said. "What if that strategy works in terms of risk reduction?" Participants whose condition worsened during the trial, which was launched in 2019, were likely put on PCSK9 drugs, Rosenson said. "Did that offset the risk or not? That is one of the really big questions that I have," he said.
Why It Matters
The pelacarsen result does not, by itself, settle whether Lp(a) causes heart disease or is merely a marker of risk. That distinction is central to the debate now facing cardiology: a risk marker can identify people who need closer monitoring and more aggressive treatment of other factors, while a causal factor can itself be a drug target. The Chicago presentation will be read closely for any sign of benefit in subgroups, in particular outcomes, or at particular levels of Lp(a) reduction.
The result also matters for patients who have already had their Lp(a) measured under the new guidelines. A failed trial does not make the test useless — clinicians say it still helps assess inherited risk — but it does leave patients and doctors without a drug specifically approved to lower Lp(a), and reliant for now on driving LDL down as far as possible.
For the pharmaceutical industry, the outcome is a cautionary tale about surrogate endpoints: a drug can move a blood measurement dramatically — in this case, by 80% — without improving the clinical outcomes that matter to patients. Investors and rival drugmakers will be watching whether that lesson applies to Lp(a) in general, or only to pelacarsen's particular molecule, dose and trial design.
What Happens Next
- Full detailed results of the pelacarsen trial will be presented on Saturday in Chicago at the American Heart Association's annual scientific meeting, where cardiologists will examine whether the trial narrowly missed significance, showed no signal, or showed harm.
- Attention will focus on the breakdown by outcome — heart attack and revascularisation rates in particular — and on whether stroke, whose relationship with Lp(a) is unclear, diluted the composite result.
- Rival Lp(a) programmes continue: Amgen's olpasiran and Eli Lilly's lepodisiran have each been shown to lower Lp(a) levels by around 95%, using different mechanisms, with Amgen's Phase 3 results expected in early 2028 and Lilly's in 2029.
- Those rival studies are designed differently from the Novartis trial, including enrolling only patients with higher Lp(a) levels than many who took part in the Novartis trial. Paul Burton, Amgen's chief medical officer, said he will be monitoring the data at the Chicago meeting, but "we believe we have a differentiated molecule."
- Guidance on Lp(a) testing is unchanged for now: the American Heart Association and the American College of Cardiology recommend that all adults have Lp(a) measured at least once in their lifetime, so clinicians can assess inherited risk even while no Lp(a)-specific drug is available.
Illustration: Doctors gathered in a large cardiology conference hall listening to a presentation. This is an illustration, not a photograph of a real event.
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FAQ
What is pelacarsen, and what did its trial find?
Pelacarsen is an experimental Novartis drug, developed with Ionis Pharmaceuticals, designed to lower lipoprotein(a). In its Phase 3 trial it cut Lp(a) blood levels by 80%, but did not significantly reduce the composite risk of death, heart attack, stroke and need for revascularisation, Novartis has said.
What is Lp(a), and why does it matter?
Lp(a), or "LP little a", is a sticky cholesterol-carrying particle whose levels are largely set by genes, not by diet, exercise or lifestyle. Around 20% of people carry genes that prompt the liver to produce it, with higher incidence among people of African or South Asian ancestry. It is used to assess inherited heart disease risk.
Does the trial failure mean Lp(a) is not a cause of heart disease?
Not necessarily. Cardiologists say the full Chicago data will show whether the trial narrowly missed significance, showed no signal, or showed harm, and whether factors such as the stroke endpoint, the 80-milligram monthly dose, or background PCSK9 treatment affected the result. The key question is whether Lp(a) is a cause of disease or merely a marker of risk.
Should adults still have their Lp(a) measured?
Yes, under current guidance. The American Heart Association and the American College of Cardiology earlier this year recommended that all adults have Lp(a) measured at least once in their lifetime, because the test helps assess inherited risk even though no drug specifically lowering Lp(a) is currently available.
What other Lp(a) drugs are still in development?
Amgen's olpasiran and Eli Lilly's lepodisiran have each lowered Lp(a) by around 95% in testing, using different mechanisms from pelacarsen. Amgen's Phase 3 results are expected in early 2028 and Lilly's in 2029, and their trials enrol patients with higher Lp(a) levels than many in the Novartis trial.
Sources
Reuters, "Novartis heart drug failure leaves doctors seeking evidence for genetic cholesterol target," 2 November 2026 (pelacarsen Phase 3 result, 80% Lp(a) reduction, composite endpoint, 16% share fall, Chicago AHA presentation, doctors' comments from Joshi, Lebowitz, Rosenson and Burton, Amgen and Lilly programmes); American Heart Association, heart disease mortality figures as cited by Reuters.
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