VERVE-102 Lowers PCSK9, LDL-C in Interim Phase 1b Hypercholesterolemia Data

Eli Lilly reported interim phase 1b data for VERVE-102, an investigational in vivo base-editing therapy targeting PCSK9, with dose-dependent reductions in circulating PCSK9 and low-density lipoprotein cholesterol (LDL-C) after a single intravenous infusion.1

The results were announced on May 25, 2026, and presented as a late-breaking oral presentation at the European Atherosclerosis Society Congress (EASC). The US Food and Drug Administration (FDA) has also granted Fast Track designation for VERVE-102 for LDL-C reduction in participants with hyperlipidemia and high lifetime cardiovascular risk.1

“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,” Riyaz S. Patel, MD, a cardiologist at Barts Health NHS Trust and a professor of cardiology at University College London, said in a statement. “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.”1

Heart-2 Trial Results

Heart-2 is an ongoing, open-label, single-ascending-dose phase 1b study evaluating safety, tolerability, and pharmacodynamic effects of VERVE-102. Patients with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD) who require additional LDL-C lowering despite maximally tolerated oral lipid-lowering therapy are eligible for inclusion and are actively being enrolled.1

The interim analysis included 35 participants who received a single intravenous infusion across 6 dose cohorts: 0.3 mg/kg, 0.45 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 1.0 mg/kg. All participants received the full planned dose. Follow-up was at least 28 days for all participants, with a subset followed for up to 18 months; as of the data cutoff of February 27, 2026, median follow-up was approximately 9 months, and 15 participants had at least 1 year of follow-up.1

Across dose levels, mean PCSK9 reductions ranged from 51% at 0.3 mg/kg to 88% at 1.0 mg/kg. Mean LDL-C reductions were 9%, 44%, 45%, 33%, 51%, and 62% across the ascending dose cohorts, respectively. Lilly reported reductions in PCSK9 and LDL-C were sustained over available follow-up, including observations extending to 18 months in some participants.1

No treatment-related serious adverse events and no dose-limiting toxicities were recorded during the analysis. Adverse events attributed to VERVE-102 included low-grade infusion-related reactions and fatigue. No participants withdrew from the study.1

VERVE-102 Mechanism and PCSK9 Clinical Context

VERVE-102 is designed to durably inactivate the hepatic PCSK9 gene using an adenine base editor. The therapy consists of messenger RNA encoding the base editor and a guide RNA targeting PCSK9, encapsulated in a lipid nanoparticle and administered as a single intravenous infusion over approximately 4 hours. The delivery platform utilizes GalNAc-lipid nanoparticle technology intended to support hepatocyte uptake through the low-density lipoprotein receptor or asialoglycoprotein receptor.1

The rationale for targeting PCSK9 is grounded in human genetics and established pharmacologic experience with PCSK9 inhibition, although VERVE-102 differs from monoclonal antibodies and small interfering RNA approaches because it is intended to produce a durable genomic edit after 1 administration. Loss-of-function variants in PCSK9 have been associated with lower LDL-C exposure over the life course and lower risk of coronary heart disease.1

The Heart-2 population reflects patients with genetic or early-onset atherosclerotic risk. HeFH is characterized by lifelong LDL-C elevation and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The World Heart Federation estimates familial hypercholesterolemia affects approximately 1 in 200 to 250 people globally. A 2025 cross-sectional analysis also evaluated familial hypercholesterolemia prevalence and cardiovascular risk associations in an adult population.2,3

Next Steps for VERVE-102

The current findings remain early-phase: the study was not designed to evaluate cardiovascular outcomes, and the available data do not establish whether LDL-C reductions with VERVE-102 translate into fewer myocardial infarctions, revascularizations, strokes, or cardiovascular deaths. The durability analysis is also limited by variable follow-up, with all participants followed for at least 28 days, but only a subset followed for ≥12 months.1

According to the announcement, participants are expected to enroll in a long-term follow-up study for up to 15 years, an important element for an investigational gene-editing therapy because questions remain around long-term safety, durability, off-target effects, and clinical outcomes.1

The company said it plans to begin enrolling a phase 2 study of VERVE-102 by the end of 2026. Lilly also noted a separate phase 1b program, Pulse-1, which is ongoing for VERVE-201, an investigational ANGPTL3-targeting gene-editing medicine.1

“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,” Sekar Kathiresan, MD, senior vice president of Lilly and co-founder of Verve Therapeutics, said in a statement. “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.”1

Key Facts

• VERVE-102: PCSK9 base editor
• Phase 1b Heart-2
• HeFH or premature CAD
• LDL-C fell up to 62%
• No treatment-related serious AEs reported

References

1. Eli Lilly and Company. A single dose of Lilly's PCSK9 base editor, 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. Published May 25, 2026. https://investor.lilly.com/news-releases/news-release-details/single-dose-lillys-pcsk9-base-editor-verve-102-reduced-pcsk9-88

2. World Heart Federation. Familial Hypercholesterolemia. Accessed May 2026. https://world-heart-federation.org/what-we-do/cholesterol/familial-hypercholesterolemia/

3. Davletov K, et al. Prevalence of familial hypercholesterolemia and its association with cardiovascular risk in a cross-sectional adult population. J Clin Med. 2025;14(22):8213. doi:10.3390/jcm14228213