Novartis pelacarsen misses primary endpoint in Phase 3 Lp(a)HORIZON trial

What Novartis reported

Lp(a)HORIZON enrolled patients who already had cardiovascular disease and elevated Lp(a). Pelacarsen was given as a once-monthly subcutaneous injection on top of guideline-directed lipid and antihypertensive treatment. The composite primary endpoint covered cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and urgent coronary revascularization requiring hospitalization. Lower Lp(a) levels were achieved in the study, but Novartis did not disclose the magnitude, saying full data will be presented at a medical congress. The clinical benefit did not follow.

Shreeram Aradhye, Novartis' president of development and chief medical officer, said the results were not what the company hoped for, and that the data may inform future approaches to cardiovascular risk management.

The study enrolled 8,323 patients across 42 countries; Novartis' statement referred to more than 8,000 participants. DongA Science reported that the trial ran for seven years, with participants receiving monthly injections of pelacarsen or placebo. 36kr noted that before the readout, peak sales forecasts for pelacarsen had reached $3 billion to $6 billion.

Why the Lp(a) hypothesis is under scrutiny

Lp(a) levels are about 90% genetically determined and largely unaffected by diet or lifestyle. About 20% of people worldwide have elevated Lp(a), and nearly one-third of those with premature cardiovascular disease do. No approved targeted treatment exists. Pelacarsen cut Lp(a) by 72% to 80% in Phase 2, which is why the outcome trial carried so much weight. US and European guidelines recommend testing once in a lifetime for all adults.

BMO Capital Markets called it a meaningful setback for dedicated Lp(a)-lowering therapies. The firm said study design differences prevent the complete invalidation of Lp(a) as a therapeutic target.

"The Lp(a) hypothesis is weakened, but not disproven," Citi analysts said. They said more data are needed to show whether the shortfall comes from pelacarsen's mechanism of action, the trial design or the target itself. William Blair said it sees meaningful risk to future Lp(a)-driven cardiovascular trials. David Maron, president of the American Society for Preventive Cardiology, called the outcome "tremendously shocking." Harlan Krumholz, a cardiologist at Yale School of Medicine, said the failure was "enormously disappointing" and that a factor that appears to cause heart disease may be only a marker.

What the failure means for Amgen and Eli Lilly

Amgen's olpasiran showed Lp(a) reductions of more than 97% in late 2022, and Eli Lilly's lepodisiran showed a nearly 94% reduction in March last year. Both are siRNA therapies. Olpasiran's OCEAN(a) trial is slated for a topline readout in 2028, and lepodisiran's Phase 3 ACCLAIM-Lp(a) study has initial data expected in 2029. Merck last year agreed to pay nearly $2 billion in biobucks to partner with China's Jiangsu Hengrui on an Lp(a) inhibitor called HRS-5346.

Truist Securities is not writing olpasiran off. It said the gamble shifts to higher-risk, higher-reward rather than becoming outright impaired, citing the deeper Lp(a) reduction and OCEAN(a)'s higher-risk population.

Amgen shares fell about 5% in extended trading after the announcement. Ionis, which discovered pelacarsen, lost 10% of its value.

Market and pipeline pressure

Novartis shares fell about 3% on 7 September, with Reuters putting the early Swiss decline at 3.3%. The move built on a drop of more than 4% in after-hours trading following the late-Friday announcement, before the Monday session.

On Tuesday the stock plunged 12% in premarket trading, a fall BioSpace tied to the pelacarsen miss, the failure of del-desiran in a Phase 3 trial of myotonic dystrophy type 1 and the suspension of certain CAR T studies.

Novartis licensed pelacarsen from Ionis in 2019 for $150 million upfront and up to $650 million in milestones, pharmaphorum reported. BioSpace described the collaboration under which Novartis is advancing the drug as an August 2023 agreement, and 36kr put Novartis' cumulative cost at more than $400 million. The miss lands while the company works through a patent cliff. Entresto peaked at almost $8 billion in 2024 and came in under $2.5 billion in the first half of this year. Novartis expects around $4 billion in lost revenue this year from expiries. Jefferies kept a neutral rating and a 110 CHF price target, while Citi reiterated Buy with 142 CHF, according to analyst notes.

What happens next

Novartis said full Lp(a)HORIZON data will be presented at an upcoming medical congress. DongA Science reported that the detailed results are scheduled for the American Heart Association's annual scientific meeting in November. BMO said the failure raises the burden of proof for Lilly's lepodisiran and Amgen's olpasiran, both in late-stage outcome trials.