Pelacarsen fails to improve patient outcomes in clinical trial

An experimental injectable drug designed to lower heart attack and stroke risk by targeting a sticky blood fat called lipoprotein(a) failed to improve patient outcomes in a major clinical trial, stunning cardiologists.

The stark failure of the drug, known as pelacarsen, challenges decades of medical assumptions regarding lipoprotein(a)—commonly referred to as Lp(a)—and its direct role in cardiovascular disease. Researchers unveiled the results on a Saturday at the American Heart Association’s annual conference in Chicago, with simultaneous data published in the New England Journal of Medicine and NEJM Evidence.

Investigators tested the therapy on 8,350 adults who had previously experienced a cardiovascular event such as a heart attack or stroke. Half the participants received pelacarsen while the rest received a placebo. Though the drug successfully suppressed Lp(a) levels by roughly 78%, it had no discernible impact on major adverse cardiovascular events after five years of follow-up.

High Hopes Meet Flat Results in the Horizon Trial

Anticipation for the trial had run exceptionally high across the cardiology community. Novartis moved the drug into final-stage clinical testing back in 2019. Medical professionals widely expected the therapy to be the first in a new wave of treatments for the disorder.

Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic and lead investigator for the trial, admitted he expected a gasp from the audience during his presentation.

Other specialists expressed equal disbelief. Dr. Amanda Doran, an assistant professor of medicine at Vanderbilt University Medical Center—one of nearly 800 trial sites—said she thought the treatment would be a slam dunk.

Searching for Answers After a Negative Trial

Despite the trial's failure, medical authorities emphasize that Lp(a) remains a strong marker of cardiovascular disease risk. New testing guidelines for Lp(a) were recently launched. However, the lack of an effective targeted treatment has fueled debate over the utility of universal testing.

Some specialists, such as Dr. Karol Watson, a professor at the David Geffen School of Medicine at UCLA, questioned the value of widespread screening when physicians have nothing specific to offer patients who test positive. Other researchers maintain that knowing one’s risk profile remains essential for optimizing standard preventive care.

Researchers Study Why Pelacarsen Failed to Protect Patients

Researchers are now analyzing why pelacarsen failed to protect patients despite successfully lowering the targeted blood fat. Hypotheses range from administering the therapy too late in life to patients whose heart disease was already advanced, to needing even deeper reductions in Lp(a) levels—potentially up to 95%—to achieve measurable clinical benefit.

Despite the setback, development efforts continue across the pharmaceutical sector. Eli Lilly is studying an oral drug called muvalaplin, and early-stage research is exploring CRISPR gene-editing technology designed to permanently switch off the gene responsible for producing Lp(a). Nissen confirmed he plans to finish two other ongoing trials for newer Lp(a)-lowering medications.