Two large cardiovascular drug programs from two of the world's biggest drugmakers came apart within weeks of each other. Novartis said on September 4 that pelacarsen missed its primary goal in a Phase 3 trial that ran for about seven years. Three days later, trade press reported that Novo Nordisk had halted two more late-stage trials of ziltivekimab after an independent data monitoring committee concluded they were unlikely to reach a different result than an earlier study that had already failed.
The two drugs tested different ideas about what drives heart attacks and strokes. That is why the pair of failures landed harder together than either would have alone.
For patients, nothing changes at the pharmacy counter. Neither drug was approved, and standard treatment for high cholesterol and cardiovascular risk is unaffected. What changes is the medium-term outlook for people whose risk is not addressed by existing drugs.
Two Separate Theories, Both Tested and Both Negative
Pelacarsen, developed by Novartis with Ionis Pharmaceuticals, is an antisense drug designed to cut production of lipoprotein(a), an inherited particle that both builds arterial plaque and promotes clotting. Novartis reported topline results showing the Lp(a)HORIZON trial, which enrolled 8,323 patients with elevated Lp(a) and established cardiovascular disease, did not reduce a composite of cardiovascular death, non-fatal heart attack, non-fatal stroke and urgent coronary revascularization requiring hospitalization. Lp(a) levels did fall.
Shreeram Aradhye, Novartis president of development and chief medical officer, said the findings did not show that lower Lp(a) "translated into reduced cardiovascular risk in the overall study population." He added that the results were not what the company hoped for but advanced scientific understanding.
Ziltivekimab tested the inflammation hypothesis instead, blocking the interleukin-6 pathway with a monthly injection. The Phase 3 ZEUS trial enrolled more than 6,300 people with atherosclerotic cardiovascular disease, chronic kidney disease and elevated inflammation. Reported on July 31, it showed no reduction in cardiovascular events, with a hazard ratio of 0.99 and a confidence interval of 0.88 to 1.11, despite confirmed reductions in inflammatory markers. Serious infections were more common on the drug, a known risk of blocking this pathway, while overall adverse events and all-cause mortality were similar between groups.
Novo then halted the HERMES and ATHENA trials in heart failure. The company notified investigators on September 4 after a monitoring committee reviewed the totality of the data and found little likelihood of a different outcome. One late-stage cardiovascular readout remains: ARTEMIS, in patients following an acute heart attack, expected in the first half of 2027.
Why These Trials Cost So Much and Take So Long
Cardiovascular outcome trials are among the largest and slowest studies in medicine, which is what makes a failure expensive beyond the individual program.
These studies cannot measure a lab value and stop. They have to wait for heart attacks, strokes, and deaths to accumulate, which means enrolling thousands of patients and following them for years. Lp(a)HORIZON ran for about seven years. ZEUS randomized more than 6,300 people, and ARTEMIS is enrolling roughly 10,000 across two dozen countries.
Improving background care compounds the difficulty. Both programs added a drug on top of care that was already good. All Lp(a)HORIZON participants were receiving guideline-directed treatment, including lipid-lowering and blood pressure drugs, and reporting on the trial noted that background risk was unusually well controlled, with mean LDL cholesterol around 66 mg/dL. When event rates are already low, a new drug has less room to show added benefit, and the trial needed to detect it must be larger and longer.
Analysts had estimated peak annual sales of roughly $4 billion to $6 billion for pelacarsen. STAT reported on September 11 that the paired failures could have a chilling effect across the industry, citing industry sources rather than any regulator or company. That is a forecast, not a fact. Novartis absorbed a second late-stage setback days later when del-desiran failed in myotonic dystrophy.
The Patients Still Waiting on an Lp(a) Drug
Novartis describes elevated Lp(a) as an inherited cardiovascular risk factor affecting about one in five people worldwide with no approved targeted treatment. Levels are set largely by genetics rather than diet or exercise. Those patients were the intended beneficiaries of this class.
The failure carries over to competitors without settling the question. Eli Lilly's lepodisiran and Amgen's olpasiran are in late-stage outcome trials and lower Lp(a) more deeply than pelacarsen did. Reporting on the Novartis result described it as raising questions about the whole approach rather than ruling it out, and the open possibilities include deeper Lp(a) reduction and enrollment focused on patients with higher baseline levels. Neither of those has been tested to completion.
The inflammation side is more contested. Some analysts read the ziltivekimab results as a problem for the interleukin-6 target itself, not just for one molecule. Others note that ZEUS enrolled a specific population, people with cardiovascular disease plus chronic kidney disease plus elevated inflammation, which limits how far the result generalizes. ARTEMIS tests a different population, patients shortly after a heart attack, where the inflammatory picture is not the same.
What People with High Lp(a) Should Do Now
No one should change a prescribed cardiovascular medication because of these results. Statins, other lipid-lowering drugs, and blood pressure treatment retain their evidence base, and none of it was tested here.
People whose Lp(a) test shows an elevated level should understand that no targeted treatment is approved, and that management still focuses on controlling every other modifiable risk factor, which is where the proven benefit sits. That means blood pressure, LDL cholesterol, blood sugar, smoking, and weight. Anyone interested in the remaining studies can ask a cardiologist whether a trial is enrolling nearby, since that is currently the only route to these agents.
Full Lp(a)HORIZON results are expected at an upcoming medical meeting, and full ZEUS results at a scientific meeting later this year. Those presentations will show the subgroup and safety detail that topline figures cannot.
Key Questions Answered
What happened? Novartis said pelacarsen failed to reduce cardiovascular events in the 8,323-patient Lp(a)HORIZON trial, and Novo Nordisk halted the HERMES and ATHENA trials of ziltivekimab after its earlier ZEUS trial showed no benefit.
Is the chilling-effect claim a fact? No. It is an assessment attributed to industry analysts and reporting, not a finding by any regulator or company. The measurable facts are the trial results.
Does this change my current heart medication? No. Neither drug is approved, and nothing in these results affects statins, other lipid-lowering drugs or blood pressure treatment.
What is Lp(a) and who has high levels? Lipoprotein(a) is an inherited particle that contributes to arterial plaque and clotting. Novartis puts elevated levels at about one in five people worldwide, set largely by genetics.
Are the Lp(a) and inflammation approaches dead? Not necessarily. Lilly's lepodisiran and Amgen's olpasiran remain in late-stage trials and lower Lp(a) more deeply, and ziltivekimab's ARTEMIS trial tests a different patient group.
When will more data arrive? Full Lp(a)HORIZON results are expected at an upcoming medical meeting, full ZEUS results later this year, and the ARTEMIS readout in the first half of 2027.
