Novo, Novartis drugs cut heart-risk markers but not cardiovascular events

Why it matters: Both trials tested ways to prevent heart attacks and strokes beyond lowering LDL cholesterol, one by suppressing inflammation and the other by reducing lipoprotein(a) (Lp(a)) a largely inherited cardiovascular risk factor elevated in approximately one in five people. Their failures challenge two closely watched drug-development strategies but do not establish conclusively that either biological target is ineffective.

By the numbers: Both trials, whose initial failures were announced in July and September, produced nearly identical cardiovascular event rates between treatment and placebo groups.

In ZEUS, 6,376 adults with atherosclerotic cardiovascular disease, chronic kidney disease and elevated high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, received monthly ziltivekimab or placebo. The antibody, which blocks interleukin-6 (IL-6), produced a 64-percentage-point greater median decline in hsCRP than placebo at two years. Yet cardiovascular death, heart attack or stroke occurred in 17.6% of treated patients versus 17.7% on placebo over a median 33 months. Serious infections were more frequent with ziltivekimab, occurring in 20.4% versus 17.9%.

In Lp(a)HORIZON, 8,350 patients were randomized to monthly pelacarsen, an antisense drug that suppresses Lp(a) production in the liver, or placebo. After one year, Lp(a) had fallen by 78.4% from baseline with pelacarsen, compared with 3.2% on placebo. Yet a major cardiovascular event occurred in 12.3% of treated patients versus 12.1% on placebo over a median 4.7 years. This trial’s broader primary endpoint also included urgent coronary revascularization.

Tolerability was a concern. According to the Cleveland Clinic, adverse events led 20.6% of pelacarsen recipients to discontinue treatment, compared with 7.5% on placebo. Overall, 35.1% versus 18.3% stopped treatment prematurely for any reason. The trial also recorded 19 cases of anaphylaxis among pelacarsen recipients, compared with none on placebo.

What may have happened: For ziltivekimab, Matthew Budoff, a professor of medicine at the University of California, Los Angeles, and endowed chair of preventive cardiology at Harbor-UCLA Medical Center, suggested that the patients’ underlying conditions may have made it particularly difficult to demonstrate a benefit.

“I think at least for IL6, there is a target population problem,” he told European Biotechnology. “Chronic kidney disease is hard to treat, even statins don’t work in advanced kidney disease patients, so I think it may be the right drug in the wrong population.”

For pelacarsen, Joshua Knowles, an associate professor of cardiovascular medicine at Stanford University, emphasized the strength of the evidence linking Lp(a) to heart disease. Observational studies, experiments and genetic research, he said, provide “very deep and very strong” evidence that Lp(a) is a causal risk factor for atherosclerotic cardiovascular disease.

“So I think the target is very solid,” Knowles said. He attributed the failure to “starting too late in the disease process or the drug not being effective enough to see a signal.” Mendelian randomization studies support a causal link between lifelong exposure to elevated Lp(a) and cardiovascular disease, suggesting that treatment may need to begin before atherosclerosis becomes too advanced, he added.

Budoff also questioned the drug rather than the biological target. “I think better drugs with lower side effect profiles may achieve greater LpA reduction and show event reduction,” he said.

Reality check: The additional Lp(a)HORIZON analyses found no cardiovascular benefit even among patients receiving uninterrupted treatment or achieving particularly large reductions in Lp(a).

The setbacks have already prompted corporate decisions. Novartis told TCTMD it is discontinuing pelacarsen’s development for atherosclerotic cardiovascular disease, including ongoing studies. Following a data monitoring committee recommendation to terminate both heart-failure trials, Novo Nordisk discontinued HERMES and ATHENA (ATHENA had already completed treatment). The company also recorded a DKK 4.6 billion (€615 million) non-cash impairment related to ziltivekimab in the third quarter.

What’s next: Novo Nordisk expects results from ARTEMIS, its Phase 3 ziltivekimab trial in patients recovering from an acute coronary event, in the first half of 2027. Budoff called it “the arbiter” of whether IL-6 inhibition reduces major cardiovascular events.

For Lp(a), attention is shifting to Amgen’s olpasiran, a different type of RNA-targeting therapy whose Phase 3 OCEAN(a)-Outcomes trial is expected to report in 2028. The company is also enrolling patients at high risk of their first major cardiovascular event in its Phase 3 OCEAN(a)-PreEvent trial. Knowles said he remains hopeful that such primary prevention studies will succeed, given the genetic evidence for the harmful effects of lifelong elevated Lp(a).

“I wouldn’t count either drug class out based on one study only,” Budoff added.

Editor’s note: Budoff has disclosed speaker fees from Novo Nordisk and Amgen and research funding from Novartis. Knowles has disclosed enrolling patients in Amgen-sponsored Lp(a)-lowering trials.