Lp(a)HORIZON: Top-line Results Dash Hopes for Pelacarsen

The much-anticipated Lp(a)HORIZON trial testing whether the novel drug pelacarsen can improve cardiovascular outcomes by decreasing lipoprotein(a) levels has failed to meet its primary endpoint.

Novartis announced the top-line results for pelacarsen, an investigational antisense oligonucleotide, via press release on September 4. Lp(a)HORIZON, which enrolled more than 8,300 patients with established CVD and elevated Lp(a), found no reduction in the combined risk of cardiovascular death, nonfatal MI, nonfatal stroke, and urgent coronary revascularization with pelacarsen versus placebo.

Largely genetically determined, Lp(a) has been shown to be an independent predictor of ASCVD risk and calcific aortic stenosis. Several genetic studies have shown a causal relationship between high levels of Lp(a) and cardiovascular disease.

Elevated Lp(a) has historically been an untreatable abnormality, but there are now several drugs in development to lower levels, including not only pelacarsen but also lepodisiran (Eli Lilly), olpasiran (Amgen), and zerlasiran (Silence Therapeutics). None have yet been approved by the US Food and Drug Administration.

Notably, the 2026 American College of Cardiology and American Heart Association dyslipidemia guidelines place greater emphasis on Lp(a) than did prior versions of the document. They advise measuring Lp(a) once in a person’s lifetime, an approach that aligns with current European and Canadian guidelines.

Yet with the Lp(a)HORIZON results in hand, many cardiologists are questioning Lp(a)’s role in prevention and management.

The medication did in fact decrease Lp(a) levels in this study population on the backdrop of guideline-directed lipid-lowering and antihypertensive therapies. However, this did not bear fruit in the form of fewer CV events.

“These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management,” Shreeram Aradhye, president of development and chief medical officer for Novartis, said in the company’s announcement. 

The news follows on the heels of another letdown in the cardiology space: doubt about the inflammatory hypothesis. Last month, Novo Nordisk announced negative top-line results from the ZEUS trial of ziltivekimab (Novo Nordisk), a human monoclonal antibody that targets the interleukin-6 (IL-6) pathway to reduce inflammation with the hope of improving CV outcomes. 

According to Novartis, the Lp(a)HORIZON trial data will be presented at an upcoming medical meeting.