Eli Lilly and Company has reported positive Phase 1b results from the Heart-2 study of VERVE-102, an experimental in vivo base editing therapy designed to permanently switch off the PCSK9 gene in the liver and reduce LDL cholesterol after a single infusion. 

 

The trial tested VERVE-102 in 35 adults with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD). A single intravenous dose produced clear, dose-dependent reductions in circulating PCSK9 protein and LDL-C levels across all dose groups.

 

PCSK9 reductions ranged from 51% to 88% across doses from 0.3 mg/kg to 1.0 mg/kg. LDL cholesterol reductions followed a similar pattern: 9%, 44%, 45%, 33%, 51%, and 62%. Effects were sustained, with durability reported for up to 18 months after treatment.

 

"These early data give us encouraging evidence that in vivo base editing of PCSK9 may offer a novel approach to achieving substantial and durable LDL-C reduction with a one-time treatment," said Riyaz S. Patel, cardiologist at Barts Health NHS Trust and professor of cardiology at University College London. 

 

"Many patients with elevated LDL-C struggle to achieve sustained control despite ongoing efforts with the medicines available today, putting them at significant risk for cardiovascular events. With coronary artery disease still one of the leading causes of death worldwide, the need for new approaches is real."

 

The company reported the therapy was generally well tolerated. There were no treatment-related serious adverse events, no dose-limiting toxicities, and all participants completed dosing. Reported side effects were mostly low-grade infusion reactions and fatigue.

 

"Twenty years ago, genetics showed us that people born with PCSK9 naturally turned off have low LDL-C for life and are remarkably protected from heart attack, yet today's chronic therapies struggle to deliver this lifelong lowering," said Sekar Kathiresan, Lilly senior vice president, and co-founder of Verve Therapeutics. 

 

"The Heart-2 results provide early clinical evidence that a single dose of VERVE-102 may mimic the LDL-C lowering effects of PCSK9 cardioprotective variants, potentially transforming cardiovascular care from chronic management to a one-time treatment."

 

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for VERVE-102 for LDL-C reduction in patients with high lifetime cardiovascular risk. 

 

HeFH affects roughly 1 in 200 to 250 people and is linked to early-onset cardiovascular disease, while coronary artery disease remains a leading global killer affecting more than 300 million people.

 

Lilly plans to launch a Phase 2 study of VERVE-102 by the end of the year.

 

VERVE-102 uses lipid nanoparticle delivery of mRNA encoding an adenine base editor plus guide RNA to target and disable the PCSK9 gene in liver cells. The approach is designed as a single-course therapy using proprietary delivery technology to reach hepatocytes.