A highly anticipated experimental drug designed to lower an inherited and dangerous form of cholesterol failed to prevent heart attacks or strokes, according to clinical trial findings unveiled Saturday at an American Heart Association meeting in Chicago.
The injectable medication, pelacarsen, developed by Novartis, successfully slashed blood levels of lipoprotein(a), commonly known as Lp(a), by an average of 77 percent to 78 percent. Yet the five-year trial of more than 8,300 patients showed that dramatic reduction translated into zero cardiovascular protection compared with a placebo, researchers reported.
The outcome stunned cardiologists who had viewed the drug as a potential breakthrough for a genetic disorder that affects about 20 percent of people globally and roughly one in five Americans.
A jarring clinical trial result
Lp(a) is an inherited particle that contributes to arterial plaque buildup and blood clot formation. Unlike low-density lipoprotein, or LDL cholesterol, Lp(a) levels cannot be lowered through diet, weight loss or exercise, leaving physicians with no approved targeted treatment.
In the Horizon study, led by Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, volunteers who already had cardiovascular disease received either pelacarsen or a placebo. The findings were published Saturday in the New England Journal of Medicine.
Researchers tracked major adverse cardiovascular events, including deaths, heart attacks, strokes and emergency procedures such as bypass surgery or stents. Roughly 12 percent of patients in each group suffered a serious cardiovascular event during the study, CNN reported.
“Everybody, me included, believed that lowering levels of lipoprotein(a) substantially would reduce the risk of major cardiovascular events,” Nissen told NBC News. “There is simply no evidence here that people that got more reduction did better.”
Following the disappointing outcome, Novartis decided to abandon pelacarsen, CNN reported. In a statement cited by NPR, the drugmaker said the study provides meaningful evidence that may help inform future approaches, noting that scientific progress requires testing challenging questions even when results disappoint.
Theories on why the drug fell short
Researchers are now trying to determine why such a steep drop in Lp(a) failed to improve health outcomes. Several cardiologists suggested the treatment may have arrived too late in life for the trial participants, who had an average age of 60 and established heart disease.
Trial participants were also receiving aggressive care to manage other risk factors, including statin therapy to control LDL cholesterol, blood pressure medication and aspirin. Those interventions may have already mitigated much of the threat posed by Lp(a), NBC News reported.
Other specialists noted the possibility that Lp(a) may be an indicator rather than a direct cause of cardiovascular disease, or that levels might need to drop by 90 percent to 95 percent to produce measurable improvements.
What the failure means for patients
Earlier this year, the American Heart Association and the American College of Cardiology issued guidelines recommending that all adults undergo a one-time blood test to check their Lp(a) levels. Physicians emphasized that those screening recommendations remain vital despite the trial results.
Doctors said patients with elevated Lp(a) should still be identified so they can aggressively address other modifiable risks, including blood pressure, weight and standard cholesterol.
Meanwhile, the search for treatments continues. Other pharmaceutical companies, including Amgen and Eli Lilly, are conducting trials on alternative Lp(a)-lowering medications that use small interfering RNA technology rather than antisense oligonucleotides. An oral drug and early-stage gene-editing strategies are also in development, with results from additional trials expected in the coming years.
