Abstract
Background
Lipoprotein(a) (Lp(a)) is an low-density lipoprotein (LDL)-like particle whose elevation is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. Currently, there are no published clinical trials showing whether Lp(a) lowering in conjunction with optimal LDL cholesterol control reduces ASCVD risk.
Methods
Clinicaltrials.gov, an online database for clinical research studies, was used to identify ongoing clinical trials studying targeted Lp(a) lowering pharmacotherapy as of May 2025. Twelve clinical studies met the criteria and were included in this summary.
Results
The three large, multicenter phase 3 outcome trials evaluating clinical cardiovascular disease endpoints of major adverse cardiac event (MACE) are Lp(a)HORIZON (NCT04023552), OCEAN(a) (NCT05581303), and ACCLAIM-Lpa(a) (NCT06292013), which investigate pelacarsen, olpasiran, and lepodisiran, respectively. Other phase 2 and phase 3 trials are also under way.
Conclusion
Results from upcoming trials will inform us whether Lp(a) reductions translate to improved cardiovascular clinical outcomes.
Keywords: Cardiovascular disease prevention, lipoprotein (a)
Lipoprotein(a) (Lp(a)) is an low-density lipoprotein (LDL)-like particle containing apolipoprotein (a) and apolipoprotein B, whose elevation is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis.1 The plasma concentration of Lp(a) is predominantly dependent on genetic factors.2 Measuring Lp(a) could help identify higher-risk individuals who may need further ASCVD risk reduction. Universal Lp(a) screening for all adults is recommended by the European Atherosclerosis Society.3 Currently, there are no published clinical trials showing whether Lp(a) lowering in conjunction with optimal LDL-C control reduces ASCVD risk. Although pharmacotherapies, including proprotein convertase subtilisin/kexin (PCSK9) and niacin, have been shown to lower Lp(a) levels, no Food and Drug Administration–approved treatment presently exists for targeted Lp(a) lowering, as phase III cardiovascular outcomes trials specifically targeting Lp(a) have not been completed.1,4 Niacin has demonstrated an Lp(a) reduction of 23% but is not advised for use due to a lack of displayed cardiovascular disease mortality and morbidity benefit as well as its notable side effects.5
Recent developments in Lp(a) lowering pharmacotherapy have primarily focused on targeting the hepatic production of apo(a). Antisense oligonucleotides, such as pelacarsen, bind to hepatic apo(a) mRNA, with subsequent cleavage of the sense strand by ribonucleic H1(RNaseH1),6 and have displayed encouraging Lp(a) lowering effects of approximately 80%.7,8 Another promising approach is with small interfering RNA (siRNA) agents, such as lepodisiran, olpasiran, and zerlasiran, leading to apo(a) mRNA breakdown through RNA interference and effective Lp(a) lowering of >90%.2,9 Muvalaplin is an oral agent that disrupts Lp(a) particle assembly by interfering with the binding of apo(a) to apoB100, with demonstrated Lp(a) reductions of up to 85.8%.10 Ongoing clinical trials explore the benefits of novel treatment avenues for effective Lp(a) lowering, which we summarize in this article.
METHODS
Clinicaltrials.gov, an online database for clinical research studies, was used to identify ongoing clinical trials studying targeted Lp(a) lowering pharmacotherapy as of May 2025 with the advanced search terms “lipoprotein a” OR “lpa” OR “lipoprotein(a)” OR “lp(a).” Studies were included if they included participants >18 years of age and were “not yet recruiting,” “recruiting,” “active, not recruiting,” or “enrolling by invitation.” Only “interventional” study types were included and studies were excluded if Lp(a) lowering was not assessed. Twelve clinical studies met the criteria.
RESULTS
Ongoing trials meeting the inclusion criteria are summarized in Table 1 with some key trials summarized below.
Table 1.
Ongoing interventional clinical trials of Lp(a) management
| NCT number | Acronym | Intervention | Outcome measure(s) | Phase | Enrollment | Funder type | Completion year |
|---|---|---|---|---|---|---|---|
| NCT06292013 | ACCLAIM-Lp(a) | Lepodisiran, placebo | Time to first occurrence of any component of the MACE 4 composite endpoint; change in Lp(a) level | 3 | 12,500 | Industry | 2029 |
| NCT04023552 | Lp(a)HORIZON | Pelacarsen (TQJ230), placebo | Time to first MACE in patients with Lp(a)>70 mg/dL; time to the first MACE in patients with Lp(a) > 90 mg/dL; change in Lp(a) from baseline | 3 | 8323 | Industry | 2025 |
| NCT05581303 | OCEAN(a) | Olpasiran, placebo | Time to CHD death, MI, or urgent coronary revascularization; change in Lp(a) level | 3 | 7297 | Industry | 2026 |
| NCT06267560 | Pelacarsen (TQJ230), placebo | Change in log-transformed Lp(a) concentration | 3 | 400 | Industry | 2027 | |
| NCT06813911 | ADD-VANTAGE | Pelacarsen and inclisiran, placebo + inclisiran | Change in log-transformed Lp(a) concentration from baseline to 6 months | 3 | 340 | Industry | 2027 |
| NCT06816264 | HRS-5346, placebo | Percent change from baseline in Lp(a) after 12 weeks | 2 | 120 | Industry | 2025 | |
| NCT06496243 | VINCENT | Obicetrapib followed by obicetrapib + evolocumab combination | Lp(a) concentration 16 weeks from baseline and 8 weeks on combination therapy | 2 | 30 | Industry | 2025 |
| NCT05900141 | Pelacarsen | Incidence of adverse events or serious adverse events; duration of drug exposure | 3 | 41 | Industry | 2028 | |
| NCT05305664 | Pelacarsen (TQJ230), placebo | Rate of lipoprotein apheresis sessions performed | 3 | 51 | Industry | 2025 | |
| NCT05646381 | Lp(a) FRONTIERS CAVS |
Pelacarsen (TQJ230), placebo | Change in peak aortic jet velocity; change in aortic valve calcium score; change in Lp(a) level | 2 | 502 | Industry | 2029 |
| NCT05565742 | Lepodisiran (LY3819469), placebo | Change in time-averaged Lp(a) level | 2 | 216 | Industry | 2024 | |
| NCT06406140 | Niacin, standard therapy | Change in serum phosphorus level and Lp(a) concentration | 2/3 | 50 | Other | 2024 |
CHD indicates coronary heart disease; Lp(a), lipoprotein (a); MACE, major adverse cardiac event; MI, myocardial infarction.
Pelacarsen
Lp(a)HORIZON (NCT04023552) is a large randomized, double-blind, placebo-controlled phase 3 trial with 8323 estimated enrolled participants that explores the effect of monthly subcutaneous pelacarsen (TQJ230) on lowering major adverse cardiac events (MACE) comprising cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization requiring hospitalization over 4 years. The study population is participants with established ASCVD and elevated Lp(a) ≥ 70 mg/dL. The change in Lp(a) is a secondary outcome assessed in this study. It is estimated to be completed in 2025.
NCT06267560 is a phase 3, randomized, double-blind, placebo-controlled trial studying the effect of monthly subcutaneous pelacarsen (TQJ230) in an estimated 400 enrolled Black/African American and Hispanic participants with elevated Lp(a) ≥ 125 nmol/L (50 mg/dL) and established ASCVD. The primary outcome is the change in log-transformed Lp(a) level after 52 weeks. It is estimated to be completed in 2027.
NCT05305664 is a phase 3, randomized, double-blind, placebo-controlled trial investigating the effect of monthly subcutaneous pelacarsen (TQJ230) in 51 estimated enrolled participants with elevated Lp(a) > 60 mg/dL and established cardiovascular disease currently undergoing weekly lipoprotein apheresis. This study will assess if there is a reduction in the rate of apheresis sessions achieved with pelacarsen treatment compared to a placebo over 52 weeks. The estimated completion date is in 2025.
Lp(a)FRONTIERS CAVS (NCT05646381) is a phase 2, randomized, double-blind, placebo-controlled trial with 502 estimated enrolled participants that investigates the effect of monthly subcutaneous pelacarsen (TQJ230) on delaying the advancement of calcific aortic valve stenosis by lowering Lp(a) levels. Included participants are 50 to 80 years old with mild to moderate calcific aortic valve stenosis and Lp(a) ≥ 175 nmol/L (70 mg/dL). The primary outcomes are the change in peak aortic jet velocity and aortic valve calcium score. The secondary outcome is the change in Lp(a) levels, and the estimated completion date is in 2029.
ADD-VANTAGE (NCT06813911) is a phase 3, randomized, placebo-controlled, double-blind trial with an estimated 340 participants that is exploring the effect of monthly subcutaneous pelacarsen 80 mg versus placebo in addition to background inclisiran therapy for elevated LDL cholesterol. Included participants have established ASCVD and an Lp(a) ≥ 175 nmol/L (70 mg/dL) as well as LDL > 70 mg/dL. The primary outcome is the change in Lp(a) level from baseline after 6 months.
Olpasiran
OCEAN(a) Outcomes (NCT05581303) is a large phase 3, double-blind, randomized, placebo-controlled trial exploring the effect of subcutaneous olpasiran administered every 12 weeks in 7297 estimated enrolled participants with ASCVD and elevated Lp(a) ≥ 200 nmol/L (80 mg/dL). The primary outcome is the time to a composite MACE of coronary heart disease death, myocardial infarction, or urgent coronary revascularization over approximately 4 years. It is estimated to be completed in 2026.
Lepodisiran
ACCLAIM-Lp(a) (NCT06292013) is a large phase 3, randomized, double-blind, placebo-controlled trial with 12,500 estimated enrolled participants investigating the effect of subcutaneous lepodisiran in participants with elevated Lp(a) levels ≥ 175 nmol/L (70 mg/dL) and ASCVD or at high risk for ASCVD. The primary outcome is the reduction in MACE including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization over approximately 4.5 years. The change in Lp(a) level will also be assessed as a secondary outcome. It is estimated to be completed in 2029.
NCT05565742 is a phase 2, randomized, double-blind, placebo-controlled trial that studies lepodisiran (LY3819469) in participants with elevated Lp(a) ≥ 175 nmol/L (70 mg/dL). The primary outcome is the time-averaged change in Lp(a) from baseline.
Niacin
NCT06406140 is a phase 2/3 trial that studies the effect of 3 months of treatment with niacin compared to an active control on Lp(a) and phosphorus levels in end-stage renal disease participants undergoing hemodialysis.
DISCUSSION
Elevated Lp(a) is an important contributor to ASCVD and calcific aortic valve stenosis, as Lp(a) is a key transporter of oxidized phospholipids, which drive aortic valve inflammation and calcification as well as induce vascular disease.11,12 While preceding trials investigating Lp(a) therapies have demonstrated substantial Lp(a) lowering, results from upcoming trials will inform us if these Lp(a) reductions translate to improved cardiovascular clinical outcomes. Phase 2 and 3 studies comprise ongoing clinical trials regarding Lp(a) management, with four trials studying the antisense oligonucleotides pelacarsen and three trials examining the siRNA agents olpasiran and lepodisiran. The three large multicenter phase 3 outcome trials evaluating clinical cardiovascular disease endpoints of MACE are Lp(a)HORIZON (NCT04023552), OCEAN(a) (NCT05581303), and ACCLAIM-Lpa(a) (NCT06292013), which investigate pelacarsen, olpasiran, and lepodisiran, respectively.
Limitations of this summary include that it only comprises trials listed in clinicaltrials.gov and that ‘completed’ trials without released results were not included.
Several ongoing trials investigate Lp(a) lowering pharmacotherapy. Our summary summarizes these trials and provides insights into what can be expected in this arena in upcoming years.
Disclosure statement/Funding
The authors report no funding. Anurag Mehta, MD, has received grant funding from Novartis and Amgen. The other authors report no potential conflicts of interest.
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