Pelacarsen's Phase 3 Failure Puts $2.3 Billion Lp(a) Bets at Risk

Ionis Pharmaceuticals' stock plunged 28.1% on Monday after detailed Phase 3 data confirmed that its once-monthly heart injection pelacarsen delivered no cardiovascular benefit — despite cutting Lp(a) levels by the measure scientists hoped would matter.

The data landed over the weekend in a medical journal. It showed pelacarsen didn't lower the risk of major adverse cardiovascular events such as heart attacks or strokes after roughly five years of follow-up in the closely watched trial. Novartis, Ionis' partner on the drug since their 2019 collaboration, had already disclosed in September that pelacarsen failed the late-stage study. The full results now raise hard questions for every drugmaker chasing the same target.

What does the failure mean for Novartis and Ionis?

Novartis has stopped work on pelacarsen for patients with atherosclerotic cardiovascular disease, a company spokesperson said. The Swiss drugmaker will keep studying the drug as a treatment for calcific aortic valve stenosis.

Ionis took the heavier market hit. Its shares fell 28.1% Monday morning, hit by both the trial data and third-quarter results that included lowered sales guidance for Tryngolza, another heart drug in its portfolio. The stock now trades at its lowest price this year. It closed at $38.80 on Thursday, down from its year-to-date high of $86.50 on Feb. 6. Swiss-listed shares of Novartis, by contrast, edged up 0.3%.

Why did the market expect this drug to work?

Pelacarsen is an antisense oligonucleotide — a drug class that blocks production of certain proteins that can damage the heart. In the "Horizon" trial, it did its biochemical job: it reduced lipoprotein(a), or Lp(a), a particle similar to "bad" cholesterol except that it's inherited. Diet changes and statins don't lower Lp(a).

That's why the hypothesis carried so much weight. Scientists believed that reducing Lp(a) would translate into fewer serious heart events. In 2025, one doctor went as far as calling targeting Lp(a) "the next frontier in cardiovascular disease." Pelacarsen cut the marker. It just didn't cut the events.

How much trouble are Eli Lilly and Amgen in?

The readout now shadows two of the biggest programs in the field: Eli Lilly's lepodisiran and Amgen's olpasiran, both currently in Phase 3 studies. Analysts have projected olpasiran will generate $2.3 billion in peak sales by 2036 — a figure now under direct threat from the Horizon data.

BMO Capital Markets analyst Evan David Seigerman didn't mince words in a Sunday note to investors. "The data from the HORIZON [trial] call the trial designs of other LP(a) focused programs like Amgen's olpasiran and Lilly's lepodisiran into question," he wrote. "Given what we saw today, we think the probability of either of their programs demonstrating a clear benefit in secondary prevention in patient populations with well-controlled LDL-C is extremely low."

That judgment cuts to the core of the Lp(a) thesis: if lowering the marker alone doesn't reduce cardiovascular events in patients whose LDL cholesterol is already controlled, the mechanism behind a multibillion-dollar pipeline segment may need rethinking. Both Lilly's and Amgen's Phase 3 readouts will now serve as the sector's next decisive test of whether the target survives contact with outcomes data.