Following the world of clinical trials can feel like peering into a bright new future. On any given day, there could be a new study that could dramatically improve melanoma patient outcomes, for example, or an exciting new use for an existing drug. But what happens when promising trials fail?
On September 4, Novartis shared disappointing news: Pelacarsen, an RNA drug from Novartis and Ionis Pharmaceuticals, failed to meaningfully reduce the risk of heart attacks, strokes, and death when compared with a placebo, per the topline results of a Phase III trial. Read on for a summary of the announcement, which has sent shock waves through the cardiovascular research community.
Pelacarsen Trial Shocks the Cardiovascular Community
The September 4 Novartis announcement referred to the company’s pelacarsen Phase III Lp(a)HORIZON trial. The trial, which began enrolling patients in 2019, ultimately enrolled 8,323 patients. All enrolled patients exhibited two factors: elevated Lipoprotein(a), or Lp(a), an inherited risk factor that increases a patient’s chance of developing cardiovascular disease, and established atherosclerotic cardiovascular disease (ASCVD).
The trial sought to assess pelacarsen, described by the company as “an investigational antisense oligonucleotide designed to potently inhibit Lp(a) production at its source.” Researchers hoped that the drug would reduce the risk of cardiovascular events in the enrolled patient population.
The Hope: Pelacarsen Meaningfully Reduces Negative Cardiovascular Outcomes
Pelacarsen was designed to lower levels of Lp(a), a fatty protein particle that has been linked to heart disease. The American Heart Association notes that individuals with high levels of Lp(a) are more likely to see harmful arterial plaque accumulation, which can lead to heart attack and stroke. Unfortunately, no medication exists to reduce Lp(a), and it can’t be reduced through diet and exercise alone. Pharmaceutical companies have been racing to address this problem by developing new therapies meant to reduce Lp(a) levels. As reported by BioPharma Dive, pelacarsen was widely considered to be the most advanced among these new candidates. That anticipation makes the Phase III trial’s underwhelming results all the more disappointing.
The Reality: Pelacarsen Trial Fails to Meet Key Endpoints
Per the topline results, combining pelacarsen with standard medications failed to meet the study’s key endpoints. The Novartis release explains that these primary endpoints included “reducing the risk of cardiovascular events, a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, compared to placebo.”
On a positive note, the Novartis release does note that the study population did achieve “lower Lp(a) levels” with pelacarsen. This is consistent with results from the Phase 2 trial, during which pelacarsen decreased Lp(a) levels in study participants by as much as 80% after 24 weeks.
Dr. David Maron, president of the American Society for Preventive Cardiology, told The New York Times that the results were “a huge blow.” However, detailed results have not yet been released, making the scale of this setback somewhat difficult to determine. Per the Times, the complete data set will be presented in November at the American Heart Association annual meeting.
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Other companies, including Eli Lilly, Amgen, and Silence Therapeutics, are advancing drugs that use different methods to reduce Lp(a). However, at this point, researchers may question whether Lp(a)-targeting drugs are worth pursuing. The failed pelacarsen trial illuminates a harrowing possibility: that high Lp(a) may be associated with heart disease, but it is not necessarily a direct cause.
“These are not the results we hoped for,” said Novartis Chief Medical Officer Shreeram Aradhye in the company’s release. “But they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management.”
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