Promising Gene Therapy for High Cholesterol Shows Progress

A new experimental gene therapy targeting high cholesterol is gaining traction in clinical trials and is approaching potential approval.

Named VERVE-102, this treatment is currently being evaluated in individuals with familial hypercholesterolemia (FH), a genetic disorder that leads to increased levels of low-density lipoprotein (LDL) cholesterol—the detrimental type—in the bloodstream. Additionally, it’s being tested on patients with premature coronary artery disease (CAD), characterized by narrowing arteries that fail to supply sufficient oxygen-rich blood to the heart muscle. The definition of “premature” CAD typically refers to onset before 65 in women and 55 in men.

According to Verve Therapeutics, the developer of the therapy, both patient categories require significant, lasting reductions of LDL cholesterol levels. In an ongoing clinical trial involving 14 participants with FH and/or premature CAD, the administration of a single dose resulted in an average 53% decrease in LDL.

These preliminary findings come from three separate groups who received varying dosages of the treatment. Interestingly, those in the highest dosage group experienced the most substantial benefits, with a maximum LDL reduction of 69%.

Across all groups, VERVE-102 was well-received, with the company reporting no serious adverse events linked to the treatment and no significant lab abnormalities.

This innovative therapy employs a modified version of CRISPR, the renowned gene-editing tool. The traditional CRISPR approach creates a “break” in both strands of DNA, inviting the cell’s repair mechanisms to step in. Yet, this method can also lead to unintended mutations.

In contrast, the new cholesterol-lowering method utilizes “base editing,” which only changes a single letter in DNA’s genetic code—thus minimizing the risks associated with double-stranded breaks. Similar to standard CRISPR, base editing utilizes a guiding molecule to target specific genes, allowing an enzyme to modify just one section of the DNA.

VERVE-102 focuses on a gene known as PCSK9, which regulates the number of LDL receptors present on cells. The count of these receptors dictates how efficiently LDL is removed from the bloodstream. In cases of FH, PCSK9 is overly active and reduces the availability of LDL receptors on cell surfaces, leading to increased LDL levels in the blood.

This therapy, administered through a single IV infusion lasting two to four hours, is designed to inhibit PCSK9 function, particularly in the liver, where LDL receptors are plentiful. Data gathered across the three dosing groups showed decreases in PCSK9 activity and LDL levels within 28 days post-treatment, with greater dosage correlating with more significant decreases.

Currently, the company is enrolling a fourth cohort of patients who will undergo treatment at even higher doses, with recruitment taking place in the UK, Canada, Israel, Australia, and New Zealand. As of April, two individuals from this group have already received treatment.

Verve anticipates releasing results from this trial segment later this year and plans to commence another clinical trial that will include more participants, likely expanding to U.S. patients, especially since the FDA granted the therapy “Fast Track Designation” to speed its development and approval.

Notably, in June, Verve was acquired by Lilly, a pharmaceutical firm that plans to continue advancing this treatment.

Ruth Gimeno, Lilly’s group vice president for diabetes and metabolic research and development, stated, “VERVE-102 has the potential to be the first in vivo gene editing therapy for a wide patient base, potentially transforming cardiovascular disease treatment from ongoing management to a one-time intervention.”

To gain approval and broaden its patient access, larger and more prolonged clinical trials will be necessary for VERVE-102.