Trial of 8,000+ people finds cardiovascular drug fails to cut heart attacks and strokes, leaving a key longevity risk unresolved.
The drug pelacarsen did exactly what it was supposed to do, chemically speaking. It just didn’t translate into fewer patients having heart attacks or strokes, and that’s the part that stings.
Novartis said earlier this month that pelacarsen, the drug it’s been developing with Ionis Pharmaceuticals, missed the primary endpoint in its Phase III trial, Lp(a)HORIZON. The trial enrolled 8,323 patients who already had elevated Lp(a), a genetically inherited cholesterol-like particle, plus established heart disease [1]. Pelacarsen lowered their Lp(a) levels, which is what an antisense drug like this is built to do. However, fewer of them ended up avoiding cardiovascular death, heart attack, stroke or urgent artery procedures than researchers had hoped, compared with placebo, even with everyone also on standard heart medications.
A quick note on what Lp(a) is
If you’ve never heard of Lp(a), most people haven’t, and that’s part of the problem researchers have been trying to solve. Roughly one in five people carry elevated levels of it. It’s almost entirely inherited; diet and exercise barely touch it. Think of it as a particle that both carries cholesterol into artery walls and makes clotting a bit more likely once it’s there. Nearly a third of people who develop heart disease young turn out to have high Lp(a). And before pelacarsen came along, there wasn’t a single approved drug built to target it directly.
That’s what made this trial such a big deal in cardiology circles, since it was really testing a whole theory about this risk factor, not just one drug.
Novartis’ own executives didn’t try to soften it much.
“Lp(a)HORIZON was a pioneering cardiovascular outcomes trial designed to answer one of the most important unanswered questions in cardiovascular medicine by evaluating whether lowering Lp(a) can reduce residual cardiovascular risk beyond optimized, guideline-directed care, when other major cardiovascular risk factors are already being managed,” said Shreeram Aradhye, the company’s President of Development and Chief Medical Officer.
Aradhye explained that although lower Lp(a) levels were observed with pelacarsen, the findings failed to demonstrate that this reduction translated into lower cardiovascular risk across the overall study population.
While acknowledging that these were not the hoped-for results, Aradhye emphasized that the study provides critical evidence to advance scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes, which could help guide future strategies for managing cardiovascular risk.
Finally, Aradhye thanked the more than 8,000 trial participants and investigators who made the study possible, while reaffirming the company’s commitment to driving cardiovascular innovation.
Full data will be presented at an upcoming medical congress, so there’s likely more nuance coming; maybe some subgroup of patients with especially high Lp(a) will turn out to have benefited even if the overall group didn’t. That’s speculation on our part, worth watching for, not something Novartis has confirmed.
What it means beyond this one drug
A missed endpoint like this doesn’t just hurt one pipeline. It pokes at an assumption longevity researchers have leaned on for years: that moving a biomarker in the right direction is basically the same as reducing someone’s actual risk. Lp(a) seemed like a clean test case, since it’s genetic, measurable with a single lifetime blood test and now, with pelacarsen, actually drugable.
Except here, lowering the number didn’t lower the outcome, at least not in this particular group of patients.
Other drugmakers are still chasing Lp(a) through different molecular routes, and this won’t stop them. But it probably slows down how quickly anyone expects an approved Lp(a) therapy to reach patients, and it adds to a growing pile of evidence that reversing cardiovascular risk later in life may be a lot harder than preventing it from building up in the first place.
