Lp(a)-lowering therapies (olpasiran / pelacarsen / lepodisiran / zerlasiran / muvalaplin)

What the evidence says

Until 2025 Lp(a) was a non-modifiable risk factor — the entire class is a major shift. Network meta-analyses (Wu Pharmacol Res 2026; Hu Front Cardiovasc Med 2026) confirm olpasiran most potent. Muvalaplin is uniquely oral and would be the first non-injectable in the class. Concomitant PCSK9i further enhances LDL reduction (synergy). For patients with elevated Lp(a) (>50 mg/dL or >125 nmol/L) — roughly 20% of the population — these will likely become standard of care once outcomes are confirmed. Biohacker-relevant: heritable Lp(a) is one of the most undertreated CV risks. **Status change, 29 Aug 2026: Lp(a)HORIZON has finished.** The registry record (NCT04023552) was updated on 28 Aug to mark the trial COMPLETED with an *actual* primary completion date of 16 July 2026 — it had previously carried an estimated 30 June date and had been sitting past it with no update, which is why this row was flagged overdue for weeks. No results are posted and neither Novartis nor Ionis has issued a topline, so nothing is yet known about whether lowering Lp(a) actually prevents events. What has changed is that the answer now exists and is being analysed rather than still being collected. This is the first trial ever to test whether lowering Lp(a) reduces cardiovascular events, in 8,323 people with established cardiovascular disease and elevated Lp(a); the primary endpoint is a composite of heart attack, stroke, cardiovascular death and urgent revascularisation. A 5,700-participant open-label extension (NCT07517263) is recruiting people rolling off it, which is consistent with a finished parent trial. Expect topline by press release first and full data at a cardiology meeting. **Either result matters:** a positive trial makes Lp(a) the first newly-modifiable major cardiovascular risk factor in a generation; a null would undercut the rationale for the whole class, including the four other programmes in this row.

Mechanism

Class targeting LPA gene/apolipoprotein(a) production: siRNAs (olpasiran [Amgen], lepodisiran [Lilly], zerlasiran [Silence]) silence LPA mRNA in hepatocytes via N-acetylgalactosamine conjugation; antisense oligonucleotide pelacarsen (Novartis) blocks LPA mRNA translation; muvalaplin (Lilly) is the first oral small-molecule disrupter of apo(a)-apoB100 covalent bond formation

Studied, labeled, or reported dose & route

Olpasiran 75-225 mg SC every 12 weeks; pelacarsen 80 mg SC monthly; lepodisiran SC every 6 months; zerlasiran SC every 6 months; muvalaplin 60-240 mg PO daily

This records doses and routes described in studies, approved labeling, clinical practice, or documented use. It is not individualized guidance and does not establish safety; context changes with indication, formulation, health history, monitoring, and other medicines.

Citations

• DOI · 10.1016/j.phrs.2026.108178 ↗
• DOI · 10.3389/fcvm.2026.1758366 ↗
• DOI · 10.4070/kcj.2025.0380 ↗
• ClinicalTrials.gov · NCT04023552 ↗
• ClinicalTrials.gov · NCT07517263 ↗

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