Major Setback for Novartis as Experimental Cholesterol Drug Fails

Doctors say the upcoming release of trial details will shed light on whether drugs that target the blood particle, commonly referred to as Lp(a), or "LP little a," might be the next big breakthrough in heart disease prevention, or whether the fatty particle is merely an indicator of risk, rather than a cause.

The drug, pelacarsen, developed by Novartis and Ionis Pharmaceuticals, has been shown to lower blood levels of Lp(a) by 80%, but that failed to translate into a lower heart attack and stroke risk in the trial.

Around 20% of people have genes that instruct their liver to produce the extra-sticky cholesterol particle, although resulting blood levels vary. Incidence is higher for people of African or South Asian ancestry.

Unlike standard "bad" LDL cholesterol that deposits fat and plaque in the arteries, Lp(a) levels are not affected by diet, exercise, or lifestyle changes.

Heart disease is the leading cause of death in the United States, killing nearly a million people annually, according to the American Heart Association.

Full detailed results of the pelacarsen trial will be presented on Saturday in Chicago at the AHA's annual scientific meeting. 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, or even worse, had a negative effect.

Around 20% of people have genes that instruct their liver to produce the extra-sticky cholesterol particle, although resulting blood levels vary. Incidence is higher for people of African or South Asian ancestry.

Unlike standard "bad" LDL cholesterol that deposits fat and plaque in the arteries, Lp(a) levels are not affected by diet, exercise, or lifestyle changes.

Heart disease is the leading cause of death in the United States, killing nearly a million people annually, according to the American Heart Association.

Full detailed results of the pelacarsen trial will be presented on Saturday in Chicago at the AHA's annual scientific meeting. 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, or even worse, had a negative effect.

"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.

Other drugmakers are targeting Lp(a) with experimental drugs that rely on different mechanisms. Amgen's olpasiran and Eli Lilly's lepodisiran have been shown to lower Lp(a) levels by around 95%. Amgen's Phase 3 results are expected in early 2028, while Lilly's are expected in 2029.

Those studies are designed differently than 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 AHA meeting, but "we believe we have a differentiated molecule."

DOCTORS' QUESTIONS

Cardiologists already use Lp(a) blood tests to assess an individual's inherited risk for heart disease. The AHA and the American College of Cardiology earlier this year 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.

Novartis had said that the Phase 3 pelacarsen trial did not meet its main goal of significantly reducing the risk of a composite of death, heart attack, stroke and need for revascularization procedures to restore blood flow in blocked blood vessels. The news contributed to a 16% share price drop.

The Swiss drugmaker declined to comment further. The trial's lead investigator, Dr. Steven Nissen of the Cleveland Clinic, said he was unable to comment until after the trial presentation.

Doctors pointed to a handful of factors that could have influenced the study results, including the inclusion of stroke as part of the composite endpoint even though studies have shown an unclear relationship between Lp(a) and stroke.

UT Southwestern's Joshi said he is most interested to see the data for rates of heart attack and revascularization.

The Novartis trial tested a monthly dose of 80 milligrams for the first time. A previous midstage trial tested a highest monthly dose of 60mg as well as a weekly 20mg 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 patient tolerance of the drug.

In addition to pelacarsen or a placebo, patients in the trial were treated with LDL-lowering statins and more potent PCSK9 cholesterol drugs like 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 PCSK9s, Rosenson said.

"Did that offset the risk or not? That is one of the really big questions that I have," he said.