One dose of experimental therapy reduced lipoprotein(a) more than 94% for nearly a year

Research Highlights:

• In this first trial in people, a single dose of a new therapeutic called lepodisiran reduced the harmful risk factor lipoprotein(a), or Lp(a), by up to 94%, with reductions lasting nearly a year.
• Lepodisiran is a small interfering RNA that lowers Lp(a) by blocking the production in the liver of a key protein component of the Lp(a) particle.
• Levels of Lp(a) are determined predominantly by genetics rather than lifestyle, and Lp(a) is not frequently measured because there are no treatments currently available.
• Lepodisiran is one of several therapeutics currently in development targeting Lp(a) and seems to have the longest-lasting effect, researchers said.

Embargoed until 3:45 p.m. ET, Sunday, Nov. 12, 2023

PHILADELPHIA, Nov. 12, 2023 — In the first human trial of a new therapeutic, a single injection of lepodisiran reduced levels of lipoprotein(a), or Lp(a), to undetectable levels for nearly one year, according to late-breaking science presented today at the American Heart Association’s Scientific Sessions 2023. The meeting, Nov. 11-13, in Philadelphia, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science. The full results and manuscript are simultaneously published today in the Journal of the American Medical Association (JAMA).

Lp(a) is a form of cholesterol that has some characteristics in common with LDL cholesterol (low-density lipoprotein cholesterol, also known as “bad cholesterol”), including causing plaque to build up in arteries and reduce blood flow to the heart, brain, kidneys, legs and other parts of the body. According to the American Heart Association, high Lp(a) levels are inherited from your family, and a high level of Lp(a) is a common independent risk factor for cardiovascular disease.

“If further trials show that this medication – lepodisiran – is safe and can reduce heart attacks and strokes, it would be good news for patients because it eliminates a risk factor we’ve been unable to treat,” said lead study author Steve Nissen, M.D., chief academic officer at the Heart, Vascular & Thoracic Institute at the Cleveland Clinic in Ohio. “This medication could be a once-a-year injection similar to a vaccine for people with high Lp(a) levels.”

Lifestyle changes, such as exercise and improved diet, have little impact on Lp(a) levels, and neither do medications that reduce “bad” cholesterol such as statins. Some people with elevated levels of Lp(a) plus other serious conditions, such as genetic disorders that raise bad cholesterol, are sometimes treated with apheresis — a dialysis-like treatment to remove harmful cholesterol from their blood. However, there is no FDA-approved medication targeted at Lp(a).

The medication, lepodisiran, is a small interfering RNA that reduces the production of Lp(a) in the liver by disabling messenger RNA that is involved in producing apolipoprotein(a), a key component in the Lp(a) particle. The medication is attached to a special sugar known as GalNAc, allowing the medication to be carried into liver cells because they have receptors for the sugar. It is also constructed to be chemically resistant to degradation so its effects last longer.

“How do you beat a risk factor that’s largely genetic? One highly effective approach is to interfere with the gene, and that’s what lepodisiran and other new therapies are designed to do,” Nissen said.

In the current study, 48 volunteers with abnormal levels of Lp(a), averaging 110 nmol/L, were given a single subcutaneous injection. Twelve participants were randomly assigned to receive a placebo and 36 participants received lepodisiran. In the lepodisiran group, six participants randomly received different doses of lepodisiran — 4, 12, 32, 96, 304 or 608 mg. The participants were discharged three days after receiving the injection, and follow-up blood tests were done for 48 weeks, just 4 weeks shy of one year.

The study found:

• Blood levels of the medication rose quickly and returned to baseline within 48 hours, likely because it was transported quickly out of the bloodstream and into the liver.
• With the highest (608 mg) dose of lepodisiran, blood levels of Lp(a) declined rapidly and were undetectable by day 29, remaining unmeasurable from days 29 to 281 and then rising slightly, with a median reduction of Lp(a) levels at 94% below baseline at 48 weeks.
• With smaller doses of lepodisiran, the reduced levels of Lp(a) didn’t last as long, although it remained down 75% at 48 weeks in those who received the 304 mg dose.
• Some people developed reactions at the injection site such as pain that resolved during the three-day in-patient monitoring period. Three participants had brief elevations in the enzyme creatine kinase, which was not considered a concern. Other adverse effects were mild and transient, such as a stuffy nose or headache.

“In our view, this therapeutic is very promising. These data indicate lepodisiran is safe, and its effectiveness at lowering Lp(a) was profound, with near-total elimination of Lp(a) that lasted for a long time. We’ll know more after the Phase 2 study, which is underway,” Nissen said.

Background:

• An Lp(a) level ≥75 nmol/dL constitutes a risk-enhancing factor for CVD, especially at higher levels of Lp(a).
• The Centers for Disease Control and Prevention estimated 64 million people in the U.S. and 1.4 billion globally are thought to have abnormal Lp(a) levels.
• According to Nissen, people from sub-Saharan Africa and their descendants are more likely to have high Lp(a) and the higher heart disease risk that accompanies it.
• The current study was conducted in the United States and Singapore from November 2020 to November 2022. The majority of the 48 adult participants were between the ages of 40 and 50, and half were men. Some volunteers also had elevated bad cholesterol, but none had existing heart disease.
• Participants self-identified their race and ethnicity, and included white, Black and Asian adults. However, in this small study, the participants were not evenly distributed among the different racial or ethnic groups (10 Hispanic 6 non-Hispanic white; 23 Asian; 7 Black; and 2 multi-racial/multiple ethnicity adults).

The ongoing Phase 2 trial is testing the medication in people with both high levels of Lp(a) and a high risk of early heart attack or stroke.

“For now, if you have a strong family history of early heart disease, you should insist on having your Lp(a) measured,” Nissen said. “As these therapies become available, you can seek treatment. In the meantime, you can take steps to lower your blood pressure, treat high LDL cholesterol if you have it, eat well and do other things to protect yourself.”

“There are several other treatments in development. Our priority should be finding effective treatment options for people with high Lp(a), so their risk of cardiovascular disease can be reduced,” Nissen said.

Disclosures are listed in the abstract, and coauthors are listed in the manuscript. The study was funded by Eli Lilly and Company.

Statements and conclusions of studies that are presented at the American Heart Association’s scientific meetings are solely those of the study authors and do not necessarily reflect the Association’s policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association’s scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

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