New Treatments to Lower Lipoprotein(a)

First discovered approximately 60 years ago, lipoprotein(a) is a variant of low-density lipoprotein. Elevated lipoprotein(a), which experts often refer to as “L-P-little-a,” has been associated with an increased risk of atherosclerotic cardiovascular disease leading to myocardial infarction, stroke, peripheral artery disease and cardiovascular death.

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Genetic factors primarily determine lipoprotein(a) levels, and lifestyle patterns that affect other cardiovascular risk factors, such as diet and exercise, have no effect on circulating lipoprotein(a). Traditional lipid-lowering agents, including statins and fibrates, have proven unsuccessful at lowering this lipid. Niacin and proprotein convertase subtilisin/kexin type 9 inhibitors, such as Praluent (alirocumab) and Repatha (evolocumab), have some effect, but it is minimal.

Lipoprotein(a) is made by the binding of apolipoprotein A to apolipoprotein B. This is mediated by the transcription of the LPA gene, which produces messenger RNA encoded for apolipoprotein A. Several companies are developing treatments that interfere with this transcription process to reduce the production of lipoprotein(a) in the liver.

Furthest ahead is pelacarsen, an antisense oligonucleotide discovered by California-based Ionis Pharmaceuticals and licensed to Novartis for worldwide development, manufacturing and marketing. The pivotal phase 3 Lp(a)HORIZON trial is evaluating the efficacy and safety of pelacarsen in lowering the risk of major cardiovascular events in adults with established cardiovascular disease (CVD) and elevated lipoprotein(a) levels.

The study has completed enrollment of 8,325 participants who arerandomly assigned to receive pelacarsen subcutaneously once per month or placebo. Top-line results are anticipated in May 2025.

Results from a previous study showed that pelacarsen significantly reduced lipoprotein(a) levels compared with placebo in a dose-
dependent manner in patients with established CVD and elevated levels of lipoprotein (a) levels.

Olpasiran is a small interfering RNA (siRNA) being developed by California-based Amgen. The investigational agent is in the phase 3 OCEAN(a) trial evaluating its effect on major cardiovascular events in patients with CVD and elevated lipoprotein(a). An estimated 6,000 participants will be randomly assigned to receive olpasiran subcutaneously once every 12 weeks or placebo.

Preliminary results are expected at the end of 2026. Results from the phase 2 OCEAN(a)-DOSE study were published in the New England Journal of Medicine and presented in August 2023 at the European Society of Cardiology’s annual meeting. At 36 weeks, participants receiving the highest olpasiran dose (225 milligrams every 12 weeks) had a mean decrease in lipoprotein(a) of 101% whereas those randomly assigned to take a placebo had a 3.6% increase in lipoprotein(a).

Candidates in phase 1 and 2 trials

Lepodisiran is another siRNA being developed by Eli Lilly to lower lipoprotein(a). In a phase 1 dose-ascending trial, lepodisiran significantly lowered lipoprotein(a) levels in a dose-dependent manner in adults with elevated lipoprotein(a) without CVD.

After one subcutaneous injection of 608 milligrams of lepodisiran (the highest study dose), participants had a mean decrease in lipoprotein(a) of 97% versus a 5% decrease in the placebo group. A 94% reduction was sustained nearly a year after the lepodisiran dose was given. Lepodisiran is in a phase 2 safety and efficacy study with an estimated completion date of October 2024.

London-based Silence Therapeutics is developing zerlasiran, a siRNA. In the phase 1 APOLLO trial, zerlasiran reduced lipoprotein(a) up to 99% from baseline levels at 90 days.

Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina.