Verve’s Gene Editor Cuts Cholesterol in First-in-Human HeFH Trial

LDL-C_iStock, Md Saiful Islam Khan

Pictured: Gloved hand holding a specimen vial for an LDL-C test/iStock, Md Saiful Islam Khan 

Verve Therapeutics on Sunday unveiled early data from the Phase Ib heart-1 trial of its next-generation gene editing therapy VERVE-101, demonstrating strong cholesterol reductions in patients with heterozygous familial hypercholesterolemia (HeFH).

The results, presented at the 2023 Scientific Sessions of the American Heart Association, demonstrated a dose-dependent decrease in low-density lipoprotein cholesterol (LDL-C) following a single infusion of VERVE-101. The two patients who received the potentially therapeutic 0.45 mg/kg dose of the gene editor saw a time-averaged LDL-C drop of 39% and 48%.

Meanwhile, the one patient who was given the maximum dose of 0.6 mg/kg showed a 55% time-averaged reduction in LDL-C levels.

These promising early data from heart-1 indicate that the gene editor VERVE-101 “has the potential to induce meaningful and durable reductions in LDL-C when administered at therapeutic doses,” Verve chief scientific officer Andrew Bellinger said in a statement.

The company will now enroll more patients in the potentially therapeutic dose cohorts of the trial and will work toward expanding heart-1 into the U.S., following the recent FDA clearance of VERVE-101’s Investigational New Drug application.

“Our goal is to fundamentally disrupt the chronic care model for cardiovascular disease and provide a new single-course treatment option for patients,” Bellinger said.

HeFH is a heritable genetic disorder characterized by dangerously high levels of cholesterol that can lead to heart attack, stroke or heart disease. The disease is caused by pathogenic mutations in relevant genes, including PCSK9, which encodes a protein that affects the concentration of cholesterol in the blood.

VERVE-101 works by chemically modifying a single base in the PCSK9 gene to turn it off, thereby reducing overall LDL-C levels. Unlike other gene editors, Verve’s candidate does not make double-stranded cuts on the DNA in order to change a base, thereby avoiding many of the side effects and off-target edits associated with CRISPR/Cas9 systems.

Verve tested this mechanism of action out in heart-1 and found that aside from reducing LDL-C levels, VERVE-101 was also able to significantly decrease PCSK9 protein expression. The two patients who were given the 0.45 mg/kg dose saw a time-averaged reduction in blood protein levels of 59% and 84%, while PCSK9 protein concentrations fell by 47% in the patient who received the maximum dose of 0.6 mg/kg.

With these data, Verve has announced plans to select a single dose for VERVE-101 and initiate and complete an expansion cohort at this dose level in 2024. The company also expects to launch a Phase I study of VERVE-102 next year, likewise targeting PCSK9.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at or

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