By Julie Steenhuysen
CHICAGO, Nov 7 (Reuters) – An experimental Novartis drug designed to treat a genetic cause of heart disease failed to reduce deaths and non-fatal heart attacks, dashing hopes for the first of several such drugs in clinical trials.
Despite a 78% reduction of the blood particle commonly known as Lp(a), a monthly dose of the Novartis drug, pelacarsen, over nearly five years had no effect in preventing a second heart attack, or reducing the risk of stroke or need for emergency procedures to unblock clogged arteries in the trial of more than 8,300 patients, according to detailed results.
“Everybody in the world, me included, thought that this was going to work,” said Dr. Steven Nissen of the Cleveland Clinic, who presented the results on Saturday at the American Heart Association meeting in Chicago.
In September, Novartis and co-developer Ionis Pharmaceuticals announced that their drug had failed to meet the trial’s main goal, but experts and investors were eager for details to see if the treatment had some benefit.
“It didn’t do anything. It was completely neutral,” Nissen said in an interview.
A second failed study testing a Novo Nordisk drug aimed at reducing heart inflammation presented at the AHA meeting likewise hit the intended target of reducing inflammation, but failed to prevent major adverse cardiovascular events.
Taken together, the findings question some foundational theories about key factors underpinning heart disease.
Currently, there are no treatments for patients with high Lp(a), a genetic risk factor for heart disease estimated to affect roughly 20% of the global population, though few individuals know they have it.
Researchers were hoping lowering Lp(a) would yield similar benefits to drugs like statins that significantly reduce the risk of heart attacks and strokes by knocking down levels of LDL, the so-called bad cholesterol.
STUDY DETAILS AND ANALYSIS
Patients were randomized to a monthly 70-milligram dose of pelacarsen or a placebo and followed for a median of 4.7 years.
All patients had a previous major cardiovascular event, such as a heart attack. Other risk factors like high LDL cholesterol and blood pressure were carefully controlled.
Nevertheless, the drug failed to provide any meaningful benefits.
Some 20.6% of patients stopped taking pelacarsen due to adverse effects versus 7.5% among those who received a placebo.
In addition to the study presented on Saturday and published in the New England Journal of Medicine, the team did a separate statistical analysis published in NEJM Evidence. The analysis looked across several measures, including patients who had a higher-than-average reduction in Lp(a) after three months, and only looking at patients who remained in the trial, and it still showed no benefit.
Dr. Donald Lloyd-Jones, a professor of cardiology at Boston University, said in a media briefing that he would not recommend abandoning Lp(a) as a causal risk factor or as a therapeutic target until there is a lot more data in different patient populations.
Pelacarsen belongs to a class of drugs called antisense oligonucleotides, or ASOs, that reduce the production of proteins made by faulty genes.
Other experimental drugs targeting Lp(a), such as Amgen’s olpasiran and Eli Lilly’s lepodisiran, rely on small interfering RNA, or siRNA, and have been shown to lower Lp(a) levels by around 95%.
Nissen, who is also leading the lepodisiran trial, said there is still strong evidence that Lp(a) is a major cause of heart disease, and suggested differences between pelacarsen and other treatments that may sway the outcome of future trials.
He noted that pelacarsen was tested in people who had already had one major cardiovascular event, while the trials being run by Lilly and Amgen include more patients who have never had a heart attack or stroke.
He also said that siRNAs have been shown to be better tolerated and have higher efficacy. “Whether that will translate into better outcomes remains to be seen.”
Amgen’s Phase 3 results are expected in early 2028, while Lilly’s are expected in 2029.
TOO LATE TO TREAT?
Dr. Paul Ridker of Harvard’s Brigham and Women’s Hospital, a pioneer in explaining the link between inflammation and heart disease, on Saturday presented trial results for Novo Nordisk’s ziltivekimab, an anti-inflammatory drug designed to neutralize interleukin-6, a key source of inflammation in high-risk heart patients.
The Danish drugmaker, best known for its GLP-1 diabetes and obesity drugs, in July announced that the study, which involved 6,300 patients with heart disease, advanced kidney disease and systemic inflammation, failed to show a benefit.
Although the drug lowered inflammation as intended, it did not translate into reduced risk of death, heart attacks or strokes compared with a placebo.
The news shocked many experts and dimmed Novo’s hopes of expanding beyond its blockbuster GLP-1 franchises.
On September 7, Novo ended two other late-stage trials evaluating ziltivekimab in patients with heart failure and inflammation based on the recommendation of an independent data monitoring committee, which concluded the trials were unlikely to succeed.
Ridker raised the possibility that the drug was studied in a population whose disease was too advanced to respond to anti-inflammatory intervention, but said targeting inflammation remains compelling.
Dr. Priscilla Hsue of UCLA, who was not involved in the study, said at the briefing that the ziltivekimab trial involved an incredibly sick population and it was possible that inflammation had already done its harm.
Given similarly disappointing outcomes for these two drugs, Lloyd-Jones said, “It’s clear we need further trials using different compounds and different strategies.”
(Reporting by Julie Steenhuysen Editing by Bill Berkrot)
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