Recently, a clinical trial conducted by Swiss pharmaceutical company Novartis aimed at treating hereditary heart disease has failed, failing to demonstrate a reduction in mortality and the incidence of non-fatal heart attacks.
This trial marks the first failure among several such drugs currently undergoing clinical evaluation.
Detailed results from the trial revealed that although Novartis’ medication, pelacarsen, successfully reduced the common lipoprotein Lp(a) levels in the blood by 78%, it did not yield any advantages in preventing subsequent heart attacks, lowering the risk of strokes, or reducing the necessity for urgent surgeries due to arterial blockages after nearly five years of monthly administration.
The study included over 8,300 patients, who were randomly assigned to receive either a 70 mg monthly dose of pelacarsen or a placebo, with an average follow-up duration of 4.7 years.
All participants had previously experienced significant cardiovascular events like heart attacks. Additionally, other risk factors such as high LDL cholesterol and hypertension were strictly controlled.
Despite these stringent conditions, the medication failed to provide any substantial benefits.
Approximately 20.6% of patients discontinued pelacarsen due to adverse reactions, compared to only 7.5% in the placebo group.
At a meeting of the American Heart Association in Chicago on November 7, Dr. Steven Nissen from the Cleveland Clinic announced the disappointing results of the trial, stating, “People all over the world, including myself, believed this would succeed.”
Earlier in September, Novartis and its collaborative developer, Ionis Pharmaceuticals, had already announced that their drug did not meet the primary objectives of the trial. However, experts and investors expressed a keen interest in understanding the specifics to determine if there were any remaining benefits from this treatment.
During an interview, Nissen remarked, “It did nothing. Not at all.”
Another disappointing trial result presented at the AHA conference involved ziltivekimab, a drug from the Danish company Novo Nordisk. Although ziltivekimab achieved its goal of reducing inflammation, it failed to prevent major adverse cardiovascular events.
Dr. Paul Ridker, a leading expert from Brigham and Women’s Hospital at Harvard University, explained the implications of this finding regarding the connection between inflammation and heart disease. He announced the trial results for Novo Nordisk’s anti-inflammatory medication during the AHA meeting.
This drug is designed to neutralize interleukin-6, a key inflammatory mediator in patients at high risk for heart conditions.
Novo Nordisk is well-known for its GLP-1 medications for diabetes and obesity. In July, the company announced that a study involving 6,300 patients suffering from heart issues, advanced kidney disease, and systemic inflammation had failed to show beneficial effects.
While the medication achieved expected reductions in inflammation, there was no corresponding decrease in the risks of death, heart attacks, or strokes compared to placebo.
The announcement shocked many experts and dimmed Novo Nordisk’s hope of expanding its impressive GLP-1 product line into other therapeutic areas.
On September 7, Novo Nordisk halted two additional late-stage trials evaluating the effectiveness of ziltivekimab in treating heart failure and inflammation, following recommendations from an independent data monitoring board that indicated low likelihood of success for these trials.
Ridker suggested that this drug might have been tested in patients whose conditions were already too severe to respond to anti-inflammatory interventions. Nonetheless, he maintained that targeting inflammation still presented an attractive therapeutic opportunity.
Dr. Priscilla Hsue from the University of California, Los Angeles, who was not involved in the research, remarked during the briefing that the patients enrolled in the ziltivekimab study were in very serious condition, where inflammation might have already caused irreversible damage.
In summary, these trial results raise serious questions regarding the foundational theories surrounding critical factors linked to heart disease.
Currently, there are no effective treatments available for patients with high levels of Lp(a), a hereditary risk factor for heart disease that affects approximately 20% of the global population. Unfortunately, very few individuals are aware of their condition. Researchers had hoped that lowering Lp(a) levels could yield benefits similar to those provided by statin medications, which significantly decrease heart attack and stroke risks by lowering low-density lipoprotein (LDL) cholesterol levels.
In addition to the study published on Saturday in the New England Journal of Medicine, Novartis conducted an independent statistical analysis published in NEJM Evidence. This analysis examined multiple indicators, including the reduction in Lp(a) levels after three months among patients who showed above-average declines and included only those who adhered to the trial. Unfortunately, the results still indicated no benefit.
Dr. Donald Lloyd-Jones, a cardiology professor at Boston University, emphasized during a media briefing that he would not advise abandoning Lp(a) as a pathogenic risk factor or treatment target until more data from diverse patient populations becomes available.
Pelacarsen belongs to a class of drugs known as antisense oligonucleotides (ASOs), which can reduce the production of proteins generated by faulty genes.
Other experimental drugs targeting Lp(a), such as Amgen’s olpasiran and Eli Lilly’s lepodisiran, utilize small interfering RNA (siRNA) technologies and have demonstrated the ability to lower Lp(a) levels by approximately 95%.
The results from Amgen’s Phase 3 clinical trials are expected to be released by early 2028, while Eli Lilly’s results are anticipated for 2029.
Dr. Nissen is also responsible for the lepodisiran trial and asserted that there is still strong evidence linking Lp(a) as a major cause of heart disease. He highlighted that the differences between pelacarsen and other therapies could influence outcomes in future studies.
Notably, pelacarsen was tested in patients who had already experienced a significant cardiovascular event, while the trials conducted by Eli Lilly and Amgen included more patients who had never suffered from heart disease or stroke.
He further noted that siRNA technology has been shown to offer better tolerance and increased efficacy, “but whether this can translate into better treatment outcomes remains to be seen.”