The failure of an experimental heart drug from Novartis (NVS) in a large trial has raised questions among cardiologists and investors about the widely held view that lowering levels of lipoprotein(a), a genetically determined cholesterol carrier, can improve heart health.
Doctors say the upcoming release of detailed trial data will show whether drugs targeting the particle, known as Lp(a), could be the next big breakthrough in heart disease prevention, or whether it is merely a marker of risk rather than a cause.
The drug, pelacarsen, developed by Novartis and Ionis Pharmaceuticals (IONS), lowered blood levels of Lp(a) by 80 per cent but did not translate into a lower risk of heart attack and stroke in the trial.
About 20 per cent of people carry genes that instruct the liver to produce the extra-sticky particle, although blood levels vary. Incidence is higher among people of African or South Asian ancestry. Unlike standard “bad” LDL cholesterol, which 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 US, killing nearly a million people a year, according to the American Heart Association.
Full results will be presented at the AHA’s annual scientific meeting in Chicago. Much will hinge on whether the trial narrowly missed statistical significance, meaning the drug had a positive effect that fell short of the study’s goal, had no effect, or, worse, had a negative one.
“If there are no signals at all, then that will really dampen any further enthusiasm for the space,” said Parag Joshi, a cardiologist at UT Southwestern Medical Center in Dallas and an investigator on the study.
Other drugmakers are pursuing Lp(a) with experimental drugs that work through different mechanisms. Amgen’s (AMGN) olpasiran and Eli Lilly’s (LLY) lepodisiran have lowered Lp(a) levels by about 95 per cent. Phase 3 results for Amgen’s drug are expected in early 2028, with Lilly’s due in 2029. Those trials differ in design from the Novartis study, 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 would be monitoring the data at the AHA meeting but added: “We believe we have a differentiated molecule.”
Cardiologists already use Lp(a) blood tests to assess inherited heart disease risk, and the AHA and the American College of Cardiology issued guidelines this year recommending that all adults have their levels measured at least once. Nathaniel Lebowitz, a cardiologist at Hackensack University Medical Center who helped draw up the guidelines, said that when he sees a patient with a family history of premature heart disease, there is a 95 per cent chance Lp(a) is the cause.
Novartis said the Phase 3 trial did not meet its primary goal of significantly reducing a composite of death, heart attack, stroke and the need for procedures to restore blood flow in blocked vessels. The news contributed to a 16 per cent fall in its shares. The Swiss drugmaker declined to comment further, and the trial’s lead investigator, Steven Nissen of the Cleveland Clinic, said he could not comment until after the presentation.
Doctors pointed to several factors that may have influenced the outcome, including the inclusion of stroke in the composite endpoint, even though studies have shown an unclear relationship between Lp(a) and stroke. Joshi said he was most interested in the data on heart attack and revascularization rates.
The trial also tested a monthly 80mg dose for the first time. An earlier midstage study tested a highest monthly dose of 60mg as well as a weekly 20mg dose. Robert Rosenson, director of metabolism and lipids at Mount Sinai Fuster Heart Hospital in New York, said patient dropouts were one possibility, noting that dosage is linked to how well patients tolerate the drug.
Patients in the trial received pelacarsen or a placebo alongside statins and more potent PCSK9 drugs such as Amgen’s Repatha, which lowers Lp(a) by a more modest 25 per cent or so. Use of PCSK9 drugs has grown significantly following studies showing the benefits of sharply reducing LDL. Rosenson said participants whose condition worsened during the trial, which began in 2019, were likely moved onto PCSK9 drugs. “Did that offset the risk or not? That is one of the really big questions that I have,” he said.
Lebowitz said that in the absence of a way to remove Lp(a), doctors had been driving down LDL far more aggressively. “What if that strategy works in terms of risk reduction?” he asked.