Eli Lilly and Company reported positive Phase 1b Heart-2 data for VERVE-102, an investigational in vivo base editing therapy designed to durably switch off the PCSK9 gene in the liver and lower low-density lipoprotein cholesterol (LDL-C) with a single intravenous infusion. The Heart-2 study is enrolling adults with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD), and the new results were presented as a late-breaking oral session at the European Atherosclerosis Society Congress and published in The New England Journal of Medicine.
In this interim analysis of 35 participants, a single dose of VERVE-102 led to dose-dependent reductions in circulating PCSK9 protein and corresponding drops in LDL-C across all dose levels tested. Mean reductions in PCSK9 ranged from 51% at the 0.3 mg/kg dose to 88% at the 1.0 mg/kg dose. LDL-C reductions 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), with effects sustained for up to 18 months after treatment.
Riyaz S. Patel, M.D., a cardiologist at Barts Health NHS Trust and professor of cardiology at University College London, said the early data provide encouraging evidence that in vivo base editing of PCSK9 could offer a one-time approach to substantial, durable LDL-C lowering. He noted that many patients with elevated LDL-C struggle to maintain control on current medicines and remain at high risk for cardiovascular events, while CAD continues to be one of the leading causes of death globally.
VERVE-102 was well tolerated at all tested doses, with no treatment-related serious adverse events and no dose-limiting toxicities reported. Adverse events related to VERVE-102 were limited to low-grade infusion reactions and fatigue. All participants received the full planned dose, and no one withdrew from the study.
Sekar Kathiresan, M.D., Lilly senior vice president and co-founder of Verve Therapeutics, said genetic studies two decades ago showed that people born with naturally inactivated PCSK9 have low LDL-C throughout life and are strongly protected from heart attacks, whereas today’s chronic therapies often fail to reproduce that lifelong lowering. He said the Heart-2 results provide early clinical evidence that a single dose of VERVE-102 may mimic the LDL-C–lowering effect of cardioprotective PCSK9 variants and could shift cardiovascular care from chronic management toward a one-time treatment.
The U.S. Food and Drug Administration has granted Fast Track designation to VERVE-102 for reducing LDL-C in people with hyperlipidemia and high lifetime cardiovascular risk. HeFH affects about 1 in 200 to 250 people and is marked by lifelong elevated LDL-C that leads to premature cardiovascular disease, including CAD. Worldwide, CAD remains a leading cause of death, affecting more than 300 million people. Lilly said it plans to start a Phase 2 clinical study of VERVE-102 by the end of this year.
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