Pelacarsen and Ziltivekimab Hit Their Targets but Not Cardiovascular Events. Six Outcome Trials Are Still Running.

Two of the most closely watched cardiovascular outcome trials in years, presented Nov. 7 at the American Heart Association's Scientific Sessions in Chicago, lowered the biomarkers their drugs were designed to lower and did not reduce major cardiovascular events.

Lp(a)HORIZON tested pelacarsen, Novartis's antisense drug against lipoprotein(a), in 8,323 patients with prior cardiovascular events. ZEUS tested ziltivekimab, Novo Nordisk's monoclonal antibody against interleukin-6, in more than 6,300 patients with atherosclerotic disease, chronic kidney disease and elevated high-sensitivity C-reactive protein. Both were published the same day in the New England Journal of Medicine (pelacarsen, ziltivekimab), with extended pelacarsen analyses in NEJM Evidence.

Neither result was a surprise by Saturday. Novo Nordisk disclosed the ZEUS miss in a July 31 filing with the Securities and Exchange Commission, and Novartis said on Sept. 4 that Lp(a)HORIZON "did not meet its primary endpoint." What the full presentations added is the size of the gap between the biomarker effect and the clinical one, and that is the part worth putting side by side.

What did each trial show?

Each drug produced a large, durable change in its target and a hazard ratio of about 1.0 on the primary endpoint. The figures below come from the published results as summarized by the American College of Cardiology, Cleveland Clinic, home of Lp(a)HORIZON's study chair and first author, and TCTMD's report of the ZEUS presentation.

Our side-by-side, target versus outcome:

Lp(a)HORIZON (pelacarsen 80 mg subcutaneously, monthly): about 78 percent lower Lp(a) than placebo at 12 months. Primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke or urgent coronary revascularization) in 511 patients (12.3 percent) on pelacarsen and 503 (12.1 percent) on placebo over a median 4.7 years. Hazard ratio 1.02 (95% CI, 0.90 to 1.15).

ZEUS (ziltivekimab 15 mg, monthly): high-sensitivity CRP 64 percentage points lower and free IL-6 76 points lower than placebo at 24 months. Primary endpoint (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in 17.6 percent on ziltivekimab and 17.7 percent on placebo over a median 33 months. Hazard ratio 0.99 (95% CI, 0.88 to 1.11).

The pelacarsen result did not change in the patients with the highest Lp(a). Among the 78.6 percent of participants with baseline Lp(a) of 90 mg/dL or more, the event rate was 12.3 percent in both arms, a hazard ratio of 1.00 (95% CI, 0.87 to 1.15). Steven Nissen, the study chair and chief academic officer of Cleveland Clinic's Heart, Vascular and Thoracic Institute, put it plainly in Cleveland Clinic's account: "These results were disappointing and unexpected," and "they don't represent a near miss."

Paul Ridker of Brigham and Women's Hospital, who presented ZEUS, called the outcome comparison "about as neutral as one can get," TCTMD reported.

Both drugs moved their biomarkers by more than half. Neither moved the event curves. For now, Lp(a) and IL-6 remain risk markers, not treatment targets with outcome evidence.

What did the safety data show?

Pelacarsen was harder to stay on than placebo, and ziltivekimab carried more infections. In Lp(a)HORIZON, drug-related adverse events occurred in 56.8 percent of the pelacarsen group and 18.0 percent of the placebo group; investigator-reported hypersensitivity in 17.1 and 5.4 percent; and adverse events leading to discontinuation in 20.6 and 7.5 percent. Overall, 35.1 percent of patients on pelacarsen stopped the study drug early, against 18.3 percent on placebo, according to Cleveland Clinic's summary. Nissen and colleagues reported that on-treatment and uninterrupted-treatment analyses were also neutral, which argues against discontinuation alone explaining the result.

In ZEUS, serious adverse events were balanced at 54.6 and 54.8 percent, but serious infections occurred in 20.4 percent on ziltivekimab and 17.9 percent on placebo, and cellulitis in 2.9 and 1.0 percent, TCTMD reported.

Who was in these trials?

Both populations were already well treated for LDL cholesterol, which matters for interpreting the null results. Lp(a)HORIZON patients had a median LDL cholesterol of about 65 mg/dL and a median hs-CRP of 0.8 mg/L, and 77 to 78 percent were on high-intensity statins. ZEUS patients had a median LDL of 71 mg/dL, a median hs-CRP of 4.5 mg/L, a mean eGFR of 44.5 and diabetes in 65.8 percent. Leslie Cho, the trial's first author and co-section head of preventive cardiology at Cleveland Clinic, said in the Cleveland Clinic account that "Lp(a)HORIZON shows how crucial lowering LDL cholesterol remains."

ZEUS also lowered Lp(a) by 29 percent, by TCTMD's account of the presentation, without an outcome benefit. That is a second, unplanned data point in the same direction as Lp(a)HORIZON, though a 29 percent reduction is far smaller than pelacarsen's. Both results are a reminder that a biomarker change is a prediction, not an outcome. The trials that change practice are the ones where the hard endpoint moves, as heart failure events did with conduction-system pacing in LEAP-Block, or where a clean null, like VASSPR's earlier vasopressin start, settles a question.

What is still coming?

We searched ClinicalTrials.gov on Nov. 9 for phase 3 trials of the Lp(a)-lowering agents olpasiran (Amgen), lepodisiran and muvalaplin (both Eli Lilly) and the IL-6 antibodies ziltivekimab and clazakizumab (CSL Behring) that have a cardiovascular-events primary endpoint and are still running. We found six. Together they list 59,157 participants. Dates are the sponsors' estimated primary completion dates in the registry; day counts are ours, from Nov. 9, 2026.

Our count of pending outcome trials:

ARTEMIS (ziltivekimab, acute myocardial infarction, 10,000 participants): Jan. 29, 2027, 81 days away. Novo Nordisk's July filing said it expects a readout in the first half of 2027.

OCEAN(a)-Outcomes (olpasiran, prior MI or PCI with Lp(a) of 200 nmol/L or more, 7,297): March 31, 2028, 508 days.

ACCLAIM-Lp(a) (lepodisiran, established ASCVD or high risk of a first event, Lp(a) of 175 nmol/L or more, 17,300): March 2029, about 843 days.

POSIBIL6ESKD (clazakizumab, patients on dialysis with hs-CRP of 2 mg/L or more, 3,110 across its phase 2b and phase 3 parts): May 22, 2029, 925 days.

MOVE-Lp(a) (muvalaplin, oral, prior event or high risk, Lp(a) of 175 nmol/L or more, 10,450): March 2031, about 1,573 days.

OCEAN(a)-PreEvent (olpasiran, no prior event, Lp(a) of 200 nmol/L or more, 11,000): Oct. 20, 2031, 1,806 days.

Two patterns stand out in the registry entries. First, three of the four remaining Lp(a) trials enroll patients without a prior event, which Lp(a)HORIZON did not test; Nissen noted that limitation in his presentation, per the ACC summary. Second, the newer trials set higher Lp(a) entry thresholds, 175 or 200 nmol/L, than Lp(a)HORIZON's 70 mg/dL. That may not rescue the hypothesis: pelacarsen's 90 mg/dL subgroup, which Cleveland Clinic equates to about 192 nmol/L, was as null as the full cohort. The registry also shows Novo Nordisk's heart failure trial of ziltivekimab, HERMES, as terminated, with an actual end date of Sept. 3, 2026, about five weeks after the company's July filing said it would continue.

The timelines themselves are part of the story. By our count, Lp(a)HORIZON ran 2,522 days from its first enrollment on Dec. 12, 2019, to Saturday's presentation, and ZEUS 1,895 days from Aug. 30, 2021. The next Lp(a) outcome result on the registry's current dates is about 17 months out.

What it means in clinic

Nothing about current lipid management changes. No Lp(a)-lowering drug is approved, and the 2018 AHA/ACC cholesterol guideline already treats Lp(a) of 50 mg/dL or 125 nmol/L and above as a risk-enhancing factor, which supports intensifying LDL lowering, not treating Lp(a) directly. Both trials reinforce that point: they were run on top of low LDL, and that background therapy is what patients should be on.

Patients with a known high Lp(a) may ask about these headlines this week. The accurate answer is that one drug that lowered Lp(a) by about three-quarters did not prevent events in people who had already had one, that more potent drugs are still being tested, and that the first of those results is not expected before 2028. For patients with elevated hs-CRP and kidney disease, ZEUS adds a reason for caution about expecting benefit from IL-6 blockade outside a trial. The next date to watch is ARTEMIS, which Novo Nordisk expects to read out in the first half of 2027.

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This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.