A single dose of Lilly’s VERVE-102, reduced PCSK9 by up to 88% and LDL-C by up to 62%, with durable effects supporting its potential as a one-time treatment for hypercholesterolemia

In the Phase 1b Heart-2 trial, a single intravenous infusion of VERVE-102 produced dose dependent lowering of PCSK9 and LDL-C, with both reductions sustained over follow up of up to 18 months in participants at high risk for cardiovascular disease. VERVE-102 is designed to mimic the protective effect of naturally occurring loss of function variants in PCSK9, which are associated with markedly lower lifetime risk of coronary heart disease. Lilly plans to begin enrolling the Phase 2 clinical study of VERVE-102 by the end of this year.

Eli Lilly and Company has announced positive Phase 1b Heart-2 study results for VERVE-102, an investigational in vivo base editing medicine designed to durably switch off the PCSK9 gene in the liver and lower blood low density lipoprotein cholesterol (LDL-C) following a single infusion. The Heart-2 trial is evaluating VERVE-102 in adults with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD). The data were presented as a late breaking oral presentation at the European Atherosclerosis Society (EAS) Congress and simultaneously published in The New England Journal of Medicine.

In the Heart-2 study, a single intravenous infusion of VERVE-102 produced meaningful lowering of circulating PCSK9 protein and corresponding reductions in LDL-C across all evaluated dose levels. In this interim analysis of 35 participants, a single dose of VERVE-102 produced dose dependent mean reductions in PCSK9 ranging from 51% at the lowest 0.3 mg/kg dose to 88% at the highest 1.0 mg/kg dose. Corresponding mean reductions in LDL-C were 9% (0.3 mg/kg), 44% (0.45 mg/kg), 45% (0.6 mg/kg), 33% (0.7 mg/kg), 51% (0.8 mg/kg), and 62% (1.0 mg/kg). These reductions were sustained over time, with durability observed for up to 18 months following 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, M.D., 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.”

VERVE-102 was well tolerated across all dose levels, with no treatment related serious adverse events and no dose limiting toxicities reported. Adverse events related to VERVE-102 included low grade infusion related reactions and fatigue. All participants received the full planned dose, and no participant withdrew from the study.

“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, M.D., 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 US Food and Drug Administration has granted Fast Track designation for VERVE-102 to reduce LDL-C in participants with hyperlipidemia and high lifetime cardiovascular risk. HeFH affects approximately 1 in 200 to 250 people and is characterised by lifelong elevations in LDL-C, leading to premature cardiovascular disease, including CAD. Worldwide, CAD remains a leading cause of death, affecting more than 300 million people.

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