In Two Studies, Experimental Drugs for Cholesterol Show ‘Revolutionary’ Promise

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New, experimental drugs designed to drive down dangerous levels of cholesterol were shown to be safe and effective in two groundbreaking bodies of research presented Sunday at an annual meeting of the American Heart Association.

Both medications target people born with a genetic predisposition to high cholesterol. While drugs like statins, as well as diet and exercise, can help these individuals manage cholesterol, they cannot change the underlying genetic cause.

The two new approaches work in different ways, but with a singular mission: go after genes responsible for raising cholesterol to change the trajectory of a person’s risk for heart attack and stroke.

Neither treatment had ever been tested in humans before. And both will need years of additional research before they'd be considered for approval by the Food and Drug Administration. Still, experts are impressed with the results.

"There is no way to categorize this other than revolutionary," said Dr. Hugh Cassiere, director for critical care services at South Shore University Hospital, Northwell Cardiovascular Institute in New York. Cassiere was not involved with either study.

A tiny change to a gene

One of the treatments, from Boston-based Verve Therapeutics, uses a gene-editing approach called base editing. It involves an IV infusion of a drug that targets the PCSK9 gene, which is instrumental in the production of LDL, often called "bad" cholesterol.

When the drug zeroes in on PCSK9, it makes a tiny change to the gene. The effect is akin to a permanent eraser, removing its ability to raise cholesterol, said Dr. Sekar Kathiresan, Verve's co-founder and chief executive officer.

In theory, the one-timetreatment should last a lifetime. Patients so far have only been followed for six months.

Verve's preliminary study, which was presented on Sunday, was meant to test the safety of the drug. Ten patients participated. Most received doses that didn't make a measurable difference in their LDL levels, but were found to be safe.

Three patients, however, were given higher doses — and their LDL cholesterol levels were reduced by more than half. Additional studies will be needed to ensure the treatment remains safe, without unexpected side effects, and effective.

Verve's research was limited to people with a genetic condition called heterozygous familial hypercholesterolemia, in which cholesterol levels are sky-high from birth. Many people affected suffer heart attacks at young ages, in their 30s or 40s.

Kathiresan, a cardiologist who previously worked at Massachusetts General Hospital and was a professor of medicine at Harvard Medical School, has long focused his research on understanding why some people have heart attacks at young ages, and why others do not. He has a strong family history of high cholesterol. In 2012, his brother died from a heart attack at age 40.

That's when Kathiresan decided "to try to develop a therapy that could avert tragedies like what's happened in my family."

It is unclear whether the approach will make a measurable impact on heart attack and stroke risk — that remains to be seen in future studies.

Experts were still optimistic about the technology.

"While larger and longer-term studies are required to assess both effectiveness, durability and safety, this should be the dawn of an era of therapeutic gene targeting for cardiovascular disease," said Dr. Sahil Parikh, director of endovascular services at Columbia University Irving Medical Center in New York. Parikh was not involved with Verve's research.

Shooting the messenger

Findings on a second novel therapy were also presented on Sunday.

The results, though early, offer a promising glimpse of what could be the first treatment for a particularly dangerous type of cholesterol called lipoprotein(a).

People with high levels of Lp(a) are at extremely high risk of having fats and cholesterol build up in their arteries.

That's because Lp(a) gloms onto LDL cholesterol, making those LDL particles even stickier and more likely to cause plaque.

It's like adding super glue to duct tape. And it's purely genetic, meaning that people are born with this elevated risk. Diet and exercise have no impact on Lp(a) levels.

"It is essentially untreatable," said study author Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic. "The only way to target such a genetic risk factor is to find a way to interfere with the product of the gene."

Nissen and colleagues used a novel approach to correcting how that gene acts.

They used a drug called lepodisiran, which targets mRNA. If that sounds familiar, it should: Most Covid vaccines use mRNA to prompt the body to make an antibody against SARS-CoV-2.

In this case, the mRNA in question tells the body to produce Lp(a). The drug stops this from happening, essentially shooting the messenger.

Nissen's study was meant to test the safety of lepodisiran. It was small, including just 48 adults in the U.S. and Singapore. All had very high levels of Lp(a). Overall, the drug was found to be safe, with no major side effects, Nissen said.

But it also dramatically lowered their Lp(a) levels. A single shot of lepodisiran drove down Lp(a) by more than 94% for nearly one year, the study found.

The results of the study, which was sponsored by drugmaker Eli Lilly, were published Sunday in the Journal of the American Medical Association.

"This really offers a lot of hope for patients with elevated lipoprotein(a)," Nissen said. "We're working as fast as we can because there are patients dying every day because of this disorder. We've not been able to treat it, and we need to change that."

As many as 64 million Americans have elevated Lp(a) levels, most commonly people of African and South Asian descent.

Additional research is critical. An important question moving forward is whether lowering Lp(a) actually cuts heart risks.

"We've had to wait until this generation of therapeutics where we can directly and specifically target Lp(a) and do it safely to see whether that will also result in fewer heart attacks and strokes," said Dr. Donald Lloyd-Jones, professor and chair of the department of preventive medicine Northwestern Feinberg School of Medicine in Chicago. Lloyd-Jones, also a past president of the American Heart Association, was not involved with the lepodisiran study.

Nissen predicts that the treatment could someday be used as an "annual vaccine-like treatment for this previously untreatable disorder."

While many heart problems may be avoided with lifestyle changes such as exercise and healthy diets, Lloyd-Jones said, the medical community needs therapies to help people whose genes put them at greater risk for heart attacks and stroke.

"We'll always need some medication for people who are at very high risk," he said.

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