Pelacarsen, olpasiran, lepodisiran, and oral muvalaplin can each cut Lp(a) by 80–95%+. None has yet proven that lowering Lp(a) prevents a heart attack or stroke — and the trial expected to answer that question first is already overdue.
For decades, elevated lipoprotein(a) — Lp(a) — has been a risk factor you could measure but not treat. It's genetically determined, causally linked to atherosclerosis and aortic valve stenosis, and largely unmoved by diet, exercise, or most existing lipid-lowering drugs. Four investigational therapies are now trying to change that: two injectables already deep into Phase 3 outcomes trials (pelacarsen, olpasiran), and two newer entrants following behind them (lepodisiran, and the first oral candidate, muvalaplin).
| Drug | Sponsor | Trial | Status |
|---|---|---|---|
| Pelacarsen | Novartis / Ionis | Lp(a)HORIZON | Readout overdue — guided to H1 2026, that window closed June 30 with no results reported |
| Olpasiran | Amgen | OCEAN(a)-Outcomes | Results expected December 2026 |
| Lepodisiran | Eli Lilly | ACCLAIM-Lp(a) | Phase 3 enrolling/ongoing; event-driven, expected completion ~2029 |
| Muvalaplin | Eli Lilly | MOVE-Lp(a) | Phase 3 ongoing; first oral Lp(a)-lowering candidate |
All four remain investigational. No Lp(a)-lowering drug has reported a positive cardiovascular outcomes result at the time of writing.
New to Lp(a)? Start with the complete guide to lipoprotein(a) — what it is, what counts as high, and why it's measured once.
Two mechanisms are being tested: antisense/siRNA approaches that silence Lp(a) production at the genetic source (pelacarsen, olpasiran, lepodisiran), and a small molecule that blocks apo(a) from assembling with ApoB into a finished Lp(a) particle (muvalaplin, the only oral option). All four cut Lp(a) by roughly 80–95%+ in earlier-phase trials. The open question for every one of them is the same: does lowering Lp(a) actually reduce heart attacks and strokes? Lp(a)HORIZON (pelacarsen) is furthest along and was expected to answer that first — its readout is now overdue.
Lp(a) is a genetically determined, independent, causal risk factor for atherosclerotic cardiovascular disease, myocardial infarction, stroke, peripheral artery disease, and aortic valve stenosis.
Until now, the only available levers have been aggressive lowering of other risk factors (LDL-C, ApoB, blood pressure), lipoprotein apheresis for extreme cases, or niacin, which lowers Lp(a) modestly but has never shown an outcomes benefit. The unmet need has always been a safe, effective therapy that directly targets Lp(a) production. These four drugs are the current attempts.
Pelacarsen is an antisense oligonucleotide (ASO) that binds apo(a) mRNA inside liver cells, blocking production of apolipoprotein(a) and reducing Lp(a) particle assembly and secretion. It's GalNAc-conjugated for hepatocyte-specific delivery, dosed as an 80 mg subcutaneous injection once monthly. Phase 2 trials showed Lp(a) reductions of roughly 70–92%.
| Sponsor | Novartis / Ionis |
|---|---|
| Design | Phase 3, randomized, double-blind, placebo-controlled |
| Population | 8,323 patients with established cardiovascular disease |
| Inclusion | Lp(a) ≥70 mg/dL (~149 nmol/L) |
| Primary endpoint | Major adverse cardiovascular events (MACE) |
| Enrollment completed | 2022 |
| Guided readout | H1 2026 — window closed June 30 with no results disclosed |
Why the delay matters: Lp(a)HORIZON is the first cardiovascular outcomes trial for any Lp(a)-lowering therapy, and its result — whenever it lands — will effectively serve as a proof-of-concept readout for the entire drug class, injectable and oral alike. An overdue event-driven trial isn't itself a signal of good or bad news; these trials read out when a pre-specified number of cardiovascular events has accrued, not on a fixed calendar date. But it does mean the field's most-anticipated answer is still pending as of this writing.
Olpasiran silences the LPA gene directly inside hepatocytes, preventing translation of apo(a) mRNA. Also GalNAc-conjugated, it's dosed by subcutaneous injection every 12 weeks — a meaningful convenience advantage over pelacarsen's monthly schedule. In the Phase 2 OCEAN(a)-DOSE trial, the highest dose achieved greater than 95% Lp(a) reduction, with suppression persisting for months after dosing stopped.
| Sponsor | Amgen |
|---|---|
| Population | ~7,000 patients with established ASCVD |
| Inclusion | Lp(a) ≥200 nmol/L |
| Started | December 2022 |
| Estimated completion | December 2026 |
Lepodisiran is Eli Lilly's siRNA entrant, distinguished by dosing durability rather than a different mechanism: Phase 2 (ALPACA) data showed reductions of roughly 94% that stayed suppressed for a year or more after a single dose, suggesting an eventual once- or twice-yearly injection schedule — the least frequent of any Lp(a)-lowering agent in development.
| Sponsor | Eli Lilly |
|---|---|
| Design | Phase 3, randomized, double-blind, placebo-controlled |
| Population | ~12,500 participants, secondary and primary prevention |
| Inclusion | Adults ≥55 with high cardiovascular risk (established ASCVD, or risk equivalents such as carotid/peripheral artery disease or FH) |
| Dosing | Subcutaneous; first three doses 6 months apart, then every 12 months |
| Estimated completion | ~2029 |
ACCLAIM-Lp(a) is the first Lp(a) outcomes trial to include primary-prevention patients (people who haven't yet had a cardiovascular event) alongside secondary prevention — a broader population than either Lp(a)HORIZON or OCEAN(a)-Outcomes, and part of why its timeline runs longer.
Muvalaplin, also from Eli Lilly, works differently from the three siRNA/ASO agents above: it's a small molecule taken by mouth that blocks the non-covalent bond between apo(a) and ApoB, preventing the Lp(a) particle from assembling in the first place rather than silencing its production upstream. Because it doesn't require an injection, muvalaplin is the candidate most likely to broaden access if the class is eventually proven and approved — particularly for primary prevention, where uptake of injectable therapies tends to be lower.
| Sponsor | Eli Lilly |
|---|---|
| Modality | Oral, small molecule, once-daily |
| Status | Phase 3 outcomes trial ongoing |
Muvalaplin's Phase 2 data showed strong Lp(a) reduction, though earlier readouts of the oral mechanism were generally more modest than the siRNA agents' near-complete suppression. Its outcomes trial is behind pelacarsen and olpasiran in the queue, so its cardiovascular-events data will likely follow theirs.
| Drug | Modality | Sponsor | Dosing | Lp(a) reduction (earlier-phase) | Outcomes trial | Expected data |
|---|---|---|---|---|---|---|
| Pelacarsen | ASO | Novartis/Ionis | Monthly SC | ~70–92% | Lp(a)HORIZON | Overdue (guided H1 2026) |
| Olpasiran | siRNA | Amgen | Every 12 weeks SC | >95% | OCEAN(a)-Outcomes | December 2026 |
| Lepodisiran | siRNA | Eli Lilly | Every 6–12 months SC | ~94% | ACCLAIM-Lp(a) | ~2029 |
| Muvalaplin | Oral small molecule | Eli Lilly | Once daily, oral | Strong, generally less than the siRNA agents | MOVE-Lp(a) | Behind pelacarsen/olpasiran |
Key pattern: the injectable RNA-based agents achieve the deepest, most durable Lp(a) suppression with infrequent dosing; muvalaplin trades some efficacy ceiling for the convenience of a daily pill. Which trade-off matters more in practice depends entirely on whether the outcomes trials — starting with Lp(a)HORIZON — show that lowering Lp(a) changes cardiovascular events at all.
Established ASCVD with elevated Lp(a) despite optimal LDL-C/ApoB control; familial hypercholesterolaemia, where elevated Lp(a) is common and adds meaningfully to residual risk; progressive disease despite maximal therapy (statins, ezetimibe, PCSK9 inhibitors); and, pending outcomes data, very-high-risk primary prevention with a strong family history.
The likely sequence, if any of these drugs is approved: measure Lp(a) once in all high-risk patients, as guidelines already recommend. Optimize standard therapy first — high-intensity statin, ezetimibe if needed, and a PCSK9 inhibitor, which also lowers Lp(a) modestly as a secondary effect. If Lp(a) remains elevated with residual risk, an Lp(a)-targeted agent would be added on top of — not instead of — that foundation.
Does Lp(a) lowering reduce cardiovascular events at all — the central question, still unanswered by outcomes data. What magnitude of reduction is required for benefit? What baseline threshold justifies treatment? What does long-term safety look like across modalities? And can these agents eventually be combined with PCSK9 inhibitors? Lp(a)HORIZON's overdue readout is the first domino; until it falls, every other trial in this class is still, in a sense, a bet on the same open hypothesis.
No. All four remain investigational, available only within their respective clinical trials. None has completed a Phase 3 outcomes trial or received regulatory approval. Pelacarsen is furthest along; its Lp(a)HORIZON readout was guided to the first half of 2026, but that window has closed without results.
Get it measured at least once — most people never have been (see how to read an Lp(a) result). Then focus on aggressively controlling the risk factors that are modifiable today: LDL-C and ApoB through statins, ezetimibe, and PCSK9 inhibitors if indicated, along with blood pressure and other cardiovascular risk factors. This doesn't eliminate Lp(a)-driven risk, but it reduces the overall atherogenic burden while the field waits on these trials.
Lp(a) is an independent, causal risk factor — its risk isn't captured by LDL-C alone, and only partially reflected in total ApoB (since Lp(a) particles carry their own ApoB). Someone with excellent LDL-C and ApoB control can still carry meaningful residual cardiovascular risk if Lp(a) is elevated, because diet, exercise, and most standard lipid-lowering drugs don't meaningfully change it.
Dosing frequency and route are the biggest near-term differences: pelacarsen is monthly, olpasiran quarterly, lepodisiran potentially twice-yearly — all by injection — while muvalaplin is a once-daily pill. Which one becomes preferred in practice will come down to each drug's outcomes-trial results and eventual approval status, starting with whichever reads out first.
None of these four drugs is approved yet — but a high Lp(a) is something you can act on today. The most effective move now is driving every other risk factor (ApoB, LDL-C, blood pressure, metabolic health) to optimal, so your Lp(a) has less to add to.
Prefer to see your own number read against optimal targets rather than population averages? See a CardioIQ report — Lp(a) is included in the Standard tier.
Related: Lp(a): The Complete Guide · Lp(a) vs LDL · High Lp(a) and ApoB Targets