Novartis has reported that pelacarsen, an antisense oligonucleotide (ASO) licensed from Ionis Pharmaceuticals targeting apolipoprotein(a) to lower lipoprotein(a), failed the primary MACE-4 endpoint in the Phase III Lp(a)HORIZON study (n=8,323) in patients with established cardiovascular disease (CVD) and Lp(a) at or above 70 mg/dL, with a high-risk subgroup defined at or above 90 mg/dL.

The trial tested pelacarsen 80 mg subcutaneously every four weeks against placebo on top of guideline-directed lipid-lowering and antihypertensive therapy, measuring cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularisation; despite deep Lp(a) reduction, the study did not demonstrate a statistically significant drop in major adverse cardiovascular events.

The readout is pivotal for the whole Lp(a) field because it is the first Phase III disclosure for any targeted Lp(a) lowerer, and it tempers the assumption that cutting a genetically determined, causality-linked risk factor will convert quickly into hard-event benefit. Roughly 20% of the global population carry elevated Lp(a), US and European guidelines now recommend one-time adult screening, and no targeted therapy is yet approved, so the result pressures peers such as Eli Lilly's lepodisiran, Amgen's olpasiran, and Silence/Blackstone's zerlasiran to show cleaner event curves, longer follow-up, or higher Lp(a) suppression.