Why it matters: The 8,323-patient Lp(a)HORIZON study was supposed to answer a question that genetic and epidemiological data could not: Does actively lowering Lp(a) prevent heart attacks, strokes and other cardiovascular events?
- For pelacarsen, the answer was no. But whether that means Lp(a) is the wrong therapeutic target — or that it needs to be lowered more aggressively — remains unresolved.
Zoom in: The Phase 3 trial enrolled patients with established cardiovascular disease and Lp(a) levels of at least 70 mg/dL. All were receiving guideline-directed treatments for other cardiovascular risk factors.
- Pelacarsen lowered Lp(a), but failed to significantly reduce a composite of cardiovascular death, non-fatal heart attack, non-fatal stroke and urgent coronary revascularization requiring hospitalization compared with placebo. Novartis has not yet disclosed the event rates, effect size or detailed subgroup results. Full data are due at an upcoming medical congress.
How it works: Originally developed by Ionis Pharmaceuticals, pelacarsen is a hepatocyte-directed antisense oligonucleotide (ASO) that binds LPA messenger RNA, reducing production of apolipoprotein(a) and therefore circulating Lp(a). Novartis licensed the programme in 2019 after starting a collaboration with Ionis in 2017. Ionis received a $150 million licensing payment and was eligible for up to $675 million in milestones plus royalties.
The catch: Pelacarsen may simply not lower Lp(a) enough.
- In Phase 2, monthly pelacarsen reduced Lp(a) by 72%, while the most intensive weekly regimen reached 80%. Rival siRNA drugs have produced reductions above 90%, raising the possibility that cardiovascular benefit only becomes visible beyond a certain degree of suppression.
What to watch: Two much larger siRNA programmes will now carry much of the burden of testing the Lp(a) hypothesis.
- Amgen’s olpasiran reduced Lp(a) by more than 95% at higher doses in Phase 2. Its 7,297-patient Phase 3 OCEAN(a)-Outcomes study is testing whether that translates into fewer cardiovascular events in patients with established disease. The current trial registry lists completion in March 2028.
- Eli Lilly’s lepodisiran achieved about 94% placebo-adjusted lowering at the highest dose in Phase 2. The Phase 3 ACCLAIM-Lp(a) outcomes study is expected to enroll about 17,300 patients and currently lists completion in March 2029.
Also notable: The result gives Ionis a second cardiovascular outcomes disappointment in two months. Its AstraZeneca-partnered ASO eplontersen failed in July to significantly reduce cardiovascular death and recurrent cardiovascular events in Phase 3 ATTR-CM testing. The drugs target different proteins and diseases, however, making the two failures poor evidence for a broader problem with ASOs themselves.
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