August 11, 2025
6 min learn
Key takeaways:
- Investigational therapies to decrease Lp(a) embody antisense oligonucleotide therapies and small interfering RNA molecules.
- A number of part 3 trials are underway.
BOSTON — There are a selection of rising therapies in growth for reducing lipoprotein(a), and later-stage trials are underway.
Curiosity continues to develop in lipoprotein(a), generally referred to as Lp(a), each as a threat issue for CVD, in addition to therapies to decrease ranges of Lp(a).
Investigational therapies to decrease Lp(a) embody antisense oligonucleotide therapies and small interfering RNA molecules. Picture: Adobe Inventory
“There are issues that we are able to do in the present day to assist to mitigate threat in folks with elevated lipoprotein(a). We must always completely be measuring lipoprotein(a) in everybody in the present day, at the least as soon as,” Harpreet S. Bhatia, MD, MAS, FACC, FAHA, FASPC, assistant professor of medication at College of California, San Diego, stated throughout a presentation on the American Society for Preventive Cardiology Congress on CVD Prevention. “However we all know that even with these approaches, together with aggressive administration of conventional threat components [and] aggressive reducing of LDL ldl cholesterol, that residual threat persists and lipoprotein(a) continues to be a goal. It is a crucial reason behind residual threat and one thing that we want particular reducing therapies to have the ability to tackle.”
Bhatia’s speak centered on “peering into the longer term, with a whole lot of pleasure” about rising focused therapies for Lp(a) reducing.
Whereas there aren’t any pharmacological Lp(a)-lowering therapies presently authorised in the US, a number of therapies are in growth, in keeping with Bhatia.
“A variety of the rising therapies heart on RNA therapeutics,” Bhatia stated.
Novel therapies to decrease Lp(a) embody antisense oligonucleotide therapies and small interfering RNA molecules.
Pelacarsen
Pelacarsen (Novartis/Ionis) is an investigational antisense oligonucleotide remedy designed to decrease Lp(a) ranges. Pelacarsen is being studied as a month-to-month remedy, in keeping with Bhatia.
In a part 2 trial taking a look at completely different doses of pelacarsen, revealed in The New England Journal of Medication in 2020, researchers reported potential reducing of Lp(a) with a peak impact round 16 to 17 weeks with a weekly dose of 20 mg reaching an 80% reducing of Lp(a).
“Virtually everybody within the trial achieved an Lp(a) lower than 50 mg/dL and many individuals achieved Lp(a) ranges lower than 30 mg/dL, generally thought-about the low threat or regular vary for Lp(a),” Bhatia stated. “As well as, oxidized phospholipids … which contribute to the danger of each atherosclerotic heart problems and calcific aortic valve illness, have been considerably lowered by pelacarsen. So, some proof that these therapies won’t solely goal the Lp(a) however goal the oxidized phospholipids and probably tackle threat mediated by Lp(a) via a number of mechanisms.”
Pelacarsen is the topic of the continuing Lp(a)HORIZON part 3 trial, which is anticipated to finish in 2026, in keeping with Bhatia. This trial recruited greater than 8,000 people with established CVD, historical past of MI, stroke and/or peripheral arterial illness and elevated Lp(a).
The Lp(a)FRONTIERS CAVS trial can also be underway to evaluate the impression of Lp(a) reducing with pelacarsen on development of calcified aortic valve stenosis. The trial is recruiting people with equally elevated Lp(a) together with gentle or average calcified aortic valve stenosis.
“That is actually thrilling as a result of we’d have one remedy that’s addressing each ASCVD threat related to Lp(a) in addition to probably the primary medical remedy for aortic stenosis,” Bhatia stated.
Small interfering RNA therapies
Olpasiran
Olpasiran (Amgen) is an investigational small interfering RNA remedy.
Within the part 2 OCEAN(a)-DOSE examine, revealed in NEJM in 2022, olpasiran yielded substantial and sustained reductions in Lp(a) amongst sufferers with established ASCVD. Olpasiran 75 mg or greater each 12 weeks decreased Lp(a) concentrations by greater than 95%, in keeping with the outcomes.
Additional analyses of olpasiran confirmed that with the high-dose remedy, nearly a yr after the final dose, there was nonetheless about 50% to 60% discount in Lp(a), in keeping with Bhatia. “So, getting extra potential remedy with extra sustained efficacy coming down the road,” he stated.
Olpasiran additionally considerably decreased oxidized phospholipids.
Olpasiran is presently being investigated in an ongoing part 3 trial that’s estimated to complete in 2027 or 2028. The trial recruited people with elevated Lp(a) and historical past of ASCVD. Sufferers will likely be adopted for roughly 4 years to evaluate the impression of olpasiran on main CV occasions.
Like pelacarsen, olpasiran seems to be very properly tolerated and protected, Bhatia stated. Within the part 2 trial, there was a light enhance in hyperglycemia and new-onset diabetes, “in order that will likely be one thing that will likely be very fascinating to concentrate to within the part 3 trials,” Bhatia stated.
Lepodisiran
Lepodisiran (Eli Lilly) is an investigational long-acting small interfering RNA remedy.
Within the part 2 ALPACA trial, lepodisiran lowered Lp(a) ranges at 180 days, with a discount of greater than 90 share factors with a single 400 mg dose in contrast with placebo. When the outcomes have been introduced on the American School of Cardiology Scientific Session in March, Steven E. Nissen, MD, MACC, chief tutorial officer of the Sydell and Arnold Miller Household Coronary heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medication at Cleveland Clinic, instructed Healio that lepodisiran is “designed in another way from different small interfering RNAs or DNA-based therapies for lipoprotein(a). It’s a double-stranded RNA with a tetraloop of 4 nucleotides that be part of the 2 strands together with different options that give the drug a protracted period of motion.”
Lepodisiran is the topic of the ACCLAIM-Lp(a) part 3 trial, which is recruiting now and anticipated to finish in 2029, in keeping with Bhatia. This trial will consider the impact of lepodisiran on the discount of main opposed CV occasions in adults in adults with established ASCVD or those that are in danger for a primary CV occasion.
“This could possibly be the primary trial to point out efficacy of Lp(a) reducing in a major prevention inhabitants,” Bhatia stated.
Zerlasiran
Zerlasiran (Silence Therapeutics) is an investigational small interfering RNA molecule.
Within the part 2 ALPACAR trial, zerlasiran lowered Lp(a) by greater than 80% in contrast with placebo at 36 weeks.
The trial checked out three regimens of zerlasiran: 450 mg each 24 weeks, 300 mg each 16 weeks or 300 mg each 24 weeks.
“One of many fascinating issues that they famous on this examine was that there was some rebound in Lp(a), form of between doses, however with subsequent doses the efficacy of the medicine appears to extend,” Bhatia stated. “This may, I believe, result in some dialogue once they plan for a part 3 trial [about] how frequent the dosing will likely be, along with what dose. However that is one other potential remedy coming down the road with part 3 plans to be introduced.”
Oral small molecule inhibitors
Shifting away from RNA therapeutics, muvalaplin (Eli Lilly) is a novel oral small molecule Lp(a) inhibitor.
Presenting part 2 information on muvalaplin on the American Coronary heart Affiliation 2024 Scientific Periods, Stephen J. Nicholls, MD, stated throughout a press convention: “All therapies below investigation up to now are injectable and basically goal apolipoprotein A manufacturing within the liver. Muvalaplin is the primary oral agent to be developed to decrease Lp(a) ranges and it really works by disrupting bonding of apolipoprotein A and apolipoprotein B.”
Within the part 2 trial, adults with elevated Lp(a) at excessive threat for a CV occasion had substantial reductions over 12 weeks with muvalaplin.
As well as, Merck introduced in March that it entered into an unique license settlement with Jiangsu Hengrui Prescribed drugs Co., Ltd. for HRS-5346, an investigational oral small molecule Lp(a) inhibitor presently being evaluated in a part 2 medical trial in China, in keeping with an organization press launch.
Obicetrapib
Whereas not an Lp(a) remedy, Bhatia additionally mentioned obicetrapib (NewAmsterdam Pharma), an investigational CETP inhibitor.
Latest information confirmed Lp(a) reducing with the drug as much as at the least 30%.
“This could possibly be one thing that’s fascinating to concentrate to sooner or later, particularly for people with uncontrolled LDL ldl cholesterol,” Bhatia stated. “There should still be a niche in look after some time, however we await these therapies, and one thing like obicetrapib or different medicine which have … off-target Lp(a)-lowering results are nonetheless engaging.”
Future instructions, questions
Many questions on Lp(a) and coverings stay, Bhatia stated.
A few of these questions embody: Does reducing Lp(a) cut back CV threat? Are there any downsides to reducing Lp(a)? Is there such a factor as “too low?” Is there a physiologic position for Lp(a)? Will the completely different courses of medicines yield equal reductions in CV threat and CV outcomes?
“Total, there are a variety of novel therapies which are in growth. We’re hoping that we’re going to be seeing the info for pelacarsen within the subsequent yr. So, numerous questions will likely be addressed, or at the least begin to be addressed,” Bhatia stated.
References:
- Bhatia HS, et al. J Clin Lipidol. 2025;doi:10.1016/j.jacl.2025.06.004.
- Cho L, et al. Am Coronary heart J. 2025;doi:10.1016/j.ahj.2025.03.019.
- Merck enters unique license settlement for HRS-5346, an investigational oral lipoprotein(a) inhibitor, for heart problems from Jiangsu Hengrui Prescribed drugs Co., Ltd. Printed March 25, 2025. Accessed Aug. 8, 2025.
- Nicholls SJ, et al. JAMA. 2025;doi:10.1001/jama.2024.24017.
- Nicholls SJ, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2415820.
- Nissen SE, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2415818.
- Nissen SE, et al. JAMA. 2025;doi:10.1001/jama.2024.21957.
- O’Donoghue ML, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2211023.
- Tsimikas S, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1905239.
Sources/Disclosures
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Bhatia HS. Rising therapies for reducing lipoprotein(a): Scientific trial updates. Offered at: American Society for Preventive Cardiology Congress on CVD Prevention; Aug. 1-3, 2025; Boston.
Disclosures:
Bhatia stories consulting and/or advising for Abbott, Arrowhead, Kaneka, NewAmsterdam and Novartis.
