A One-Time Experimental Treatment Might Control Cholesterol for Life

Heart disease kills more people worldwide than any other malady, and even though doctors use cholesterol-lowering medications and recommend lifestyle habits to control major risk factors. Making these changes, however, is not easy for people, and sticking with them is even harder.

The hope is that one day soon, people may not have to rely solely on these interventions. In a study conducted by Verve Therapeutics, which is owned by Eli Lilly Co., and published May 25 in the New England Journal of Medicine, researchers report some encouraging news about a one-time gene therapy that could control cholesterol, one of the prime contributors to heart disease. Among the 35 people who participated in the study, the gene therapy reduced LDL cholesterol by anywhere from 9% to 62%, depending on the dose they received.

The therapy targets a gene called PCSK9. About 20 years ago, researchers at UT Southwestern Medical Center found that people with mutations in their PCSK9 gene tended to have very low levels of LDL, and therefore low rates of heart events. PCSK9 works in the liver to regulate cholesterol, and it turns out that these people had an inactive form of the gene that led to lower levels of cholesterol in the blood, without any other apparent physiological effects. Scientists went to work developing drugs to inhibit the gene, and there are currently four such drugs approved for lowering cholesterol. But all of them are injectable medications; one requires a doctor to administer. The inconvenience of the injections means that about 30-50% of people stop using the drugs after about a year, and the drop-off rate is similar to that for daily statin pills.

The gene therapy, called VERVE-102, is meant to address that compliance problem with a one-time treatment to edit genes in liver cells so they continuously produce the changed version of PCSK9 that leads to low cholesterol. The alteration generated by the therapy doesn’t cause the exact change in the PCSK9 gene found in those born with the low-cholesterol version of the gene, but the end result is the same: the gene is inactivated, and LDL levels drop.

“[This study] is early clinical evidence that we can give protection to people who weren’t born with it,” says Dr. Sek Kathiresan, senior vice president at Eli Lilly Co. and CEO of Verve Therapeutics. “We still have a lot to learn. But if it holds up, we think it would mean an entirely new way to treat high cholesterol with one infusion for lifelong cholesterol-lowering.”

If it proves safe and effective in later clinical trials and eventually gets approved, the gene therapy could replace regular injections or daily pills because the liver cells that the therapy targets turn over every 200 to 300 days. Once the cells have been edited by VERVE-102, they produce more cells with the same genetic change, therefore sustaining the effect of the altered PCSK9—potentially over a lifetime. So far, the patients in the study have been followed for about 18 months and continue to show low LDL levels. Kathiresan says studies in animals show they continue to have low LDL levels after three years, which makes the scientists confident that the treatment is durable.

The only side effect of note is that the drug temporarily causes higher levels of a liver enzyme, says Kathiresan, reflecting the fact that the gene therapy targets liver cells and initially may disrupt levels of liver compounds.

The current trial included people either with a genetic predisposition to high cholesterol or who had early heart events, but Lilly plans to conduct a larger trial of about 200 people—including more people in the latter category who might be more representative of those who have heart disease. The company will also continue to follow the 35 people in this first trial for 15 years to monitor the safety of the gene therapy they received.

For safety reasons, people in the current study also continued taking cholesterol-lowering medications, including statins, during the trial. But future research will address whether at some point, a one-time gene therapy like VERVE-102 could replace statins altogether. “It’s too early to say right now, and a lot will depend on where people start in terms of their cholesterol and where their goal is,” says Kathiresan. “But ultimately, we would love to be in a position where this is the preferred therapy of choice.”