Novartis pelacarsen cuts lipoprotein(a) by 78 percent without preventing a single heart attack or stroke

An experimental Novartis injection called pelacarsen lowered lipoprotein(a) — a form of cholesterol set at birth — by 78 percent in a trial of 8,322 patients with a prior heart attack, stroke or other heart problem. It prevented no heart attacks, no strokes, no cardiovascular deaths and no procedures to open blocked arteries. The results were presented Saturday at a meeting of the American Heart Association and published the same day in the New England Journal of Medicine.

The trial, called Horizon, ran at nearly 800 sites under Steven Nissen, chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic. "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." Amanda Doran of Vanderbilt University Medical Center, one of the sites involved, said she had thought the trial "was going to be a slam dunk" and that the investigators were "pretty invested, so it obviously hurts."

Lp(a) attracted drugmakers precisely because it resists everything else. Unlike LDL cholesterol, it is fixed at conception; diet and exercise move it not at all. About one in five Americans carries high levels, most without knowing it, and the protein both builds arterial plaque and promotes blood clots. Pelacarsen did exactly what it was engineered to do — a 78 percent reduction against 13 percent on placebo — and the clinical endpoints did not move.

The leading explanation is timing. The average participant was 60 years old and was followed for roughly five years. "Remember that Lp(a) is a genetic disorder, so from the time a baby's conceived, their Lp(a) is high. If we just swooped in in the last five years, maybe that's too late," said Karol Watson, co-director of the Program in Preventive Cardiology at UCLA, who was not involved in the research. Participants were also treated aggressively for LDL cholesterol and blood pressure, and many may have been taking aspirin after their earlier events, which could have absorbed much of the clotting risk Lp(a) carries. "How much of the Lp(a)-associated risk was remaining? We just don't know," Watson said, adding that she had "not seen a more shockingly neutral trial in a while."

Earlier this year, the American College of Cardiology and the American Heart Association issued guidelines recommending that every adult have their Lp(a) checked. The first drug built to lower the reading has now been tested, and lowering it prevented nothing.