New experimental drugs designed to lower dangerous levels of cholesterol were shown to be safe and effective in two groundbreaking research presented Sunday during an annual meeting of the American Heart Association.
Both drugs are for people who are born with a genetic predisposition to high cholesterol. And while medications such as statins, as well as diet and exercise, can help these people control cholesterol, they cannot change the underlying genetic cause.
The two new approaches work in different ways, but with a singular mission: They work with the genes responsible for raising cholesterol to change the trajectory of a person’s risk for heart attack and stroke.
None of the treatments had been tested before in humans. And both will need years of additional research before the Food and Drug Administration will consider approval. Still, experts said they were impressed with the results.
“The only way to describe this is as revolutionary,” said Dr. Hugh Cassiere, director of critical care services at South Shore University Hospital, Northwell Cardiovascular Institute in New York. Cassiere was not involved in any of the studies.
A small change in a gene
One of the treatments, from Boston-based Verve Therapeutics, uses a gene editing approach called base editing. This is an intravenous infusion of a drug that targets the PCSK9 gene, which plays a critical role in the production of LDL, often called “bad” cholesterol.
When the drug targets PCSK9, it makes a small change to the gene. The effect is similar to that of a permanent eraser, which eliminates its ability to raise cholesterol, explained Dr. Sekar Kathiresan, co-founder and CEO of Verve.
In theory, The treatment, with a single application, should last a lifetime. But so far the patients have only been followed for six months.
Verve’s preliminary study, which was presented Sunday, aimed to test the drug’s safety. Ten patients participated. Most received doses that made no measurable difference in their levels of LDL, or bad cholesterol, but were found to be safe.
However, three patients were given higher doses and their LDL cholesterol levels were reduced by more than half. Additional studies will be needed to ensure that the treatment remains safe, free of 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 affected people suffer heart attacks at an early age, between 30 and 40 years old.
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 don’t. .
The doctor has a strong family history of high cholesterol. In 2012, his brother died of a heart attack at age 40. It was then that Kathiresan decided to “try to develop a therapy that could prevent tragedies like what happened in my family.”
It is not clear whether the approach will a measurable impact on the risk of heart attack and stroke; that remains to be seen in future studies. However, experts remain optimistic about the technology.
“While larger, longer-term studies are needed to evaluate both efficacy, durability and safety, this should be the beginning of a new era of gene therapy to address cardiovascular disease,” said Dr. Sahil Parikh, Ph.D. director of endovascular services at Columbia University Irving Medical Center in New York. Parikh was not involved in the Verve investigation.
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Attacking the messenger
The results of a second novel therapy were also presented on Sunday.
The results, although 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) have an extremely high risk of fat and cholesterol building up in the arteries. This is because Lp(a) attaches to LDL cholesterol, making those LDL particles even stickier and more likely to cause plaque.
It’s like adding glue to duct tape. And it’s purely genetic, meaning 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, academic director of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic. “The only way to attack that genetic risk factor is to find a way to interfere with the gene product.”
Nissen and his colleagues used a novel approach to correct the way that gene acts. They used a drug called lepodisiran, which targets mRNA. If this sounds familiar, it should: most Covid vaccines use mRNA to prompt the body to produce an antibody against SARS-CoV-2.
In this case, the mRNA tells the body to make Lp(a). And the drug prevents this from happening, essentially attacking the messenger.
Nissen’s study was intended to test the safety of lepodisiran. It was small, including only 48 adults in the United States and Singapore. They all had very high levels of Lp(a). Overall, the drug was found to be safe and had no major side effects, Nissen said.
But it also dramatically reduced their Lp(a) levels. The study found that a single injection of lepodisiran reduced Lp(a) by more than 94% for almost a year.
The results of the study, sponsored by the pharmaceutical company 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 are working as quickly as we can because there are patients dying every day from this disorder. “We haven’t been able to treat it and we need to change that.”
Up to 64 million Americans have elevated Lp(a) levelsmost of them are of African and South Asian descent.
More research is essential. An important question going forward is whether lowering Lp(a) actually reduces cardiac risks.
