No more statins? One-time treatment for high cholesterol could lower heart attack risk for life

STANFORD, Calif. - It could transform how millions of Americans dealing with the number one leading cause of death, coronary artery disease, receive treatment — a one-time-only injection that could lower heart attack risk for the rest of a person's life. 

Gene-editing drug

A promising investigational gene-editing therapy called VERVE-102 has shown to mimic a natural genetic mutation that turns off the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein. 

Produced primarily in the liver, the protein is known to destroy liver receptors that are responsible for clearing so-called bad cholesterol or LDL-C (low-density lipoprotein cholesterol).

By the numbers:

Drugmaker Eli Lilly said that findings from its small, early-stage clinical study showed a single dose of VERVE-102 reduced PCSK9 by up to 88% and LDL-C by up to 62%.

"Results from the Heart-2 trial signal the potential for VERVE-102 to be the first-ever in vivo base editing medicine for broad patient populations, which could transform cardiovascular care from chronic management to a one-time treatment," a Lilly spokesperson told KTVU.

The company said the reductions in LDL-C were sustained over a follow-up of 18 months.

The drugmaker also said VERVE‑102 was "well tolerated across all dose levels." None of the trial participants reported serious adverse events, the company said. Some experienced mild side effects including low-grade infusion-related reactions and fatigue. 

PCSK9 inhibitors

Stanford Medicine cardiologist Dr. Joshua Knowles said there is precedent for this type of treatment.

While statins have long been the most commonly prescribed medication class to reduce LDL and prevent heart attacks, more innovative approaches have been adopted in recent years.

"This is another way of inhibiting the pathway called the PCSK9,"  Dr. Knowles said. "They knew that targeting this pathway, this enzyme, was safe, because there's other drugs that already did it."

Knowles said injectable drugs known as PCSK9 inhibitors were approved about a decade ago. But none of those options offer a one-and-done treatment. The frequency of use is either every two weeks or every six months. 

"The idea," he said, "is that you would mimic the effect of a PCSK9 inhibitor, but instead of having to give the drug every two weeks or every six months, you would just have to give this treatment once, and it would alter the gene, essentially in the liver, and knock out this enzyme basically permanently."

Natural PCSK9 mutations

The backstory:

The PCSK9 inhibitor approach stems from a groundbreaking finding about 20 years ago, a discovery that there are people born with a genetic mutation that naturally silences the PCSK9 enzyme, serving as a cardiovascular protectant that leads to low LDL-C for life that can shield against heart attack.

"There's actually human beings that are born with naturally occurring mutations in this same gene that lead to lifelong, low cholesterol levels, and they have no side effects. They have no problems," Knowles said.

He said the drugmaker capitalized on this concept, saying, "Look, we know that there's actually human superheroes out there that have a protective mutation. Can we mimic that through this kind of CRISPR editing approach?’" 

Those born with high levels of LDL

There are also people who are genetically inclined to have high levels of bad cholesterol.

"Familial hypercholesterolemia is a genetic condition caused by mutations in genes that are responsible for recycling LDL cholesterol," Dr. Knowles explained. 

He described LDL cholesterol in the bloodstream as a kind of waste product that needs to be recycled. 

"Some people with FH, familial hypercholesterolemia, they are born with an inability to recycle LDL cholesterol, which leads to extremely high cholesterol levels, essentially from birth, leading to a very, very high risk of early onset coronary artery disease, which is the leading cause of death in the world," Knowles said.

These patients are potentially target candidates for the experimental drug.

Knowles noted that the therapy could also be effective for those who have cardiovascular disease unrelated to familial hypercholesterolemia, patients with very high cholesterol, particularly those who can’t tolerate or take high enough doses of other types of medications designed to prevent plaque buildup in the arteries.

Dig deeper:

The doctor said Stanford was originally going to be considered as a potential site for testing the experimental drug, but when Lilly successfully completed its acquisition of Verve Therapuetics last year, the company changed its strategy for implementation in the U.S.

As part of the experimental process, the drugmaker has had to make adjustments to how the gene-editing apparatus is delivered to the liver, according to the cardiologist.

"They use a lipid nanoparticle to deliver this. It's like an envelope that packages it and says, ‘Take this to the liver, deliver this package to the liver.’ And that envelope itself, that packaging system seemed to have some toxicity in some patients that they initially enrolled," Knowles explained. "So then they stopped, and they got a new packaging formula, a new envelope that has been tested in more people and seems to work well, and that's this new trial."

Access to care 

If the next phase trials are successful, it could result in greater access to this type of drug to help treat the more than 18 million adults in the U.S. with coronary artery disease. 

Socioeconomic and geographic barriers often lead to a lack of intervention and can result in increased risk of death. 

For example, Knowles pointed to patients who have reported issues with getting treated with a competing drug, Inclisiran, which is taken every six months. 

"Access has been hard for some patients," Knowles explained. "You have to get it at a hospital every six months. Sometimes insurance companies deny it. And so my impression is that some of the initial patients that have been recruited for the study, and in the United States, have said, 'Look, I can't get the therapies that I need outside of this clinical trial.'"

Game-changer?

So a treatment that requires only one dose could be a game-changer in cardiovascular care. 

"The idea that, you know, Verve and Lilly were initially excited about was that this would be kind of a one-and-done approach. You know, maybe the expense would be high up front, but the downstream savings would be high later," the doctor said.

What's next:

As for the next phase in testing, Lilly said it has been granted fast-track designation by the U.S. Food and Drug Administration "to reduce LDL-C in participants with hyperlipidemia and high lifetime cardiovascular risk."

The company said it planned to begin rolling out its phase 2 clinical study by the end of the year, telling KTVU, beyond that, at this early phase, it could not comment on any regulatory timelines.

Knowles said there could be additional scrutiny on this type of therapy, as he's seen the FDA previously placing special regulations and requirements for therapeutic trials involving gene editing.  

"It's kind of a paradigm-shifting idea to do this kind of gene editing, gene therapy. So, I think to finish the trial will probably be a few years, and report the results, but it's not a huge number of patients, and so they want to be done as fast as possible."

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Phase 2 studies typically involve up to several hundred people with the condition that the medication is targeting, according to the FDA.

With coronary artery disease affecting so many people, there has been extremely high interest in VERVE-102. Though Knowles acknowledged that there will be hesitation among those who are apprehensive about the emerging medical field of genetic engineering therapies.

"Certainly, the patients are anxious, you know, some patients are anxious for it. The real question is going to be how willing are people going to be to take a therapy that alters your genome?" the Stanford expert asked. "There's going to be some people that are super excited about it and other people that are less."